TY - JOUR AB - Despite lung cancer affecting all races and ethnicities, disparities are observed in incidence and mortality rates among different ethnic groups in the United States. Non-Hispanic African Americans had a high incidence rate of lung cancer at 55.8 per 100 000 people, as well as the highest death rate at 37.2 per 100 000 people from 2016 to 2020. While previous genome-wide association studies (GWAS) have identified over 45 susceptibility risk loci that influence lung cancer development, few GWAS have investigated the etiology of lung cancer in African Americans. To address this gap in knowledge, we conducted GWAS of lung cancer focused on studying African Americans, comprising 2267 lung cancer cases and 4264 controls. We identified three loci associated with lung cancer, one with lung adenocarcinoma, and four with lung squamous cell carcinoma in this population at the genomic-wide significance level. Among them, three novel loci were identified near VWF at 12p13.31 for overall lung cancer and GACAT3 at 2p24.3 and LMAN1L at 15q24.1 for lung squamous cell carcinoma. In addition, we confirmed previously reported risk loci with known or new lead variants near CHRNA5 at 15q25.1 and CYP2A6 at 19q13.2 associated with lung cancer and TRIP13 at 5p15.33 and ERC1 at 12p13.33 associated with lung squamous cell carcinoma. Further multi-step functional analyses shed light on biological mechanisms underlying these associations of lung cancer in this population. Our study highlights the importance of ancestry-specific studies for the potential alleviation of lung cancer burden in African Americans. AU - Byun, J.* AU - Han, Y.* AU - Choi, J.* AU - Sun, R.* AU - Shaw, V.R.* AU - Zhu, C.* AU - Xiao, X.* AU - Lusk, C.* AU - Badr, H.* AU - Lee, H.S.* AU - Jang, H.J.* AU - Li, Y.* AU - Lim, H.C.* AU - Long, E.* AU - Liu, Y.* AU - Kachuri, L.* AU - Walsh, K.M.* AU - Wiencke, J.K.* AU - Albanes, D.* AU - Lam, S.* AU - Tardón, A.* AU - Neuhouser, M.L.* AU - Barnett, M.J.* AU - Chen, C.* AU - Bojesen, S.E.* AU - Brenner, H.* AU - Landi, M.T.* AU - Johansson, M.* AU - Risch, A.* AU - Wichmann, H.-E. AU - Bickeböller, H.* AU - Christiani, D.C.* AU - Rennert, G.* AU - Arnold, S.* AU - Field, J.K.* AU - Shete, S.* AU - Le Marchand, L.* AU - Liu, G.* AU - Andrew, A.S.* AU - Zienolddiny, S.* AU - Grankvist, K.* AU - Caporaso, N.* AU - Taylor, F.* AU - Lazarus, P.* AU - Schabath, M.B.* AU - Aldrich, M.C.* AU - Patel, A.* AU - Lin, X.* AU - Zanetti, K.A.* AU - Harris, C.C.* AU - Chanock, S.* AU - Mckay, J.* AU - Schwartz, A.G.* AU - Hung, R.J.* AU - Amos, C.I.* C1 - 74360 C2 - 57348 CY - Great Clarendon St, Oxford Ox2 6dp, England SP - 1227-1237 TI - Genome-wide association study for lung cancer in 6531 African Americans reveals new susceptibility loci. JO - Hum. Mol. Genet. VL - 34 IS - 14 PB - Oxford Univ Press PY - 2025 SN - 0964-6906 ER - TY - JOUR AB - Type 2 diabetes (T2D) complications pose a significant global health challenge. Omics technologies have been employed to investigate these complications and identify the biological pathways involved. In this review, we focus on four major T2D complications: diabetic kidney disease, diabetic retinopathy, diabetic neuropathy, and cardiovascular complications. We discuss advancements in omics research, summarizing findings from genetic, epigenomic, transcriptomic, proteomic, and metabolomic studies across different ancestries and disease-relevant tissues. We stress the importance of integrating multi-omics techniques to elucidate the biological mechanisms underlying T2D complications and advocate for ancestrally diverse studies. Ultimately, these insights will improve risk prediction for T2D complications and inform translation strategies. AU - Singh, A. AU - Bocher, O. AU - Zeggini, E. C1 - 73030 C2 - 56900 CY - Great Clarendon St, Oxford Ox2 6dp, England SP - 469-480 TI - Insights into the molecular underpinning of type 2 diabetes complications. JO - Hum. Mol. Genet. VL - 34 IS - 6 PB - Oxford Univ Press PY - 2025 SN - 0964-6906 ER - TY - JOUR AB - Osteoarthritis is a prevalent, complex disease of the joints, and affects multiple intra-articular tissues. Here, we have examined genome-wide DNA methylation profiles of primary infrapatellar fat pad and matched blood samples from 70 osteoarthritis patients undergoing total knee replacement surgery. Comparing the DNA methylation profiles between these tissues reveal widespread epigenetic differences. We produce the first genome-wide methylation quantitative trait locus (mQTL) map of fat pad, and make the resource available to the wider community. Using two-sample Mendelian randomization and colocalization analyses, we resolve osteoarthritis GWAS signals and provide insights into the molecular mechanisms underpinning disease aetiopathology. Our findings provide the first view of the epigenetic landscape of infrapatellar fat pad primary tissue in osteoarthritis. AU - Kreitmaier, P. AU - Park, Y.-C. AU - Swift, D.* AU - Gilly, A. AU - Wilkinson, J.M.* AU - Zeggini, E. C1 - 68768 C2 - 54978 CY - Great Clarendon St, Oxford Ox2 6dp, England TI - Epigenomic profiling of the infrapatellar fat pad in osteoarthritis. JO - Hum. Mol. Genet. VL - 33 IS - 6 PB - Oxford Univ Press PY - 2023 SN - 0964-6906 ER - TY - JOUR AB - Inherited disorders of mitochondrial metabolism, including isolated methylmalonic aciduria, present unique challenges to energetic homeostasis by disrupting energy-producing pathways. To better understand global responses to energy shortage, we investigated a hemizygous mouse model of methylmalonyl-CoA mutase (Mmut)-type methylmalonic aciduria. We found Mmut mutant mice to have reduced appetite, energy expenditure and body mass compared with littermate controls, along with a relative reduction in lean mass but increase in fat mass. Brown adipose tissue showed a process of whitening, in line with lower body surface temperature and lesser ability to cope with cold challenge. Mutant mice had dysregulated plasma glucose, delayed glucose clearance and a lesser ability to regulate energy sources when switching from the fed to fasted state, while liver investigations indicated metabolite accumulation and altered expression of peroxisome proliferator-activated receptor and Fgf21-controlled pathways. Together, these shed light on the mechanisms and adaptations behind energy imbalance in methylmalonic aciduria and provide insight into metabolic responses to chronic energy shortage, which may have important implications for disease understanding and patient management. AU - Lucienne, M.* AU - Gerlini, R. AU - Rathkolb, B. AU - Calzada-Wack, J. AU - Forny, P.* AU - Wueest, S.* AU - Kaech, A.* AU - Traversi, F.* AU - Forny, M.* AU - Bürer, C.* AU - Aguilar-Pimentel, J.A. AU - Irmler, M. AU - Beckers, J. AU - Sauer, S.* AU - Kölker, S.* AU - Dewulf, J.P.* AU - Bommer, G.T.* AU - Hoces, D.* AU - Gailus-Durner, V. AU - Fuchs, H. AU - Rozman, J. AU - Froese, D.S.* AU - Baumgartner, M.R.* AU - Hrabě de Angelis, M. C1 - 68344 C2 - 54656 CY - Great Clarendon St, Oxford Ox2 6dp, England SP - 2717-2734 TI - Insights into energy balance dysregulation from a mouse model of methylmalonic aciduria. JO - Hum. Mol. Genet. VL - 32 IS - 17 PB - Oxford Univ Press PY - 2023 SN - 0964-6906 ER - TY - JOUR AB - Polygenic scores (PGS) can identify individuals at risk of adverse health events and guide genetics-based personalized medicine. However, it is not clear how well PGS translate between different populations, limiting their application to well-studied ethnicities. Proteins are intermediate traits linking genetic predisposition and environmental factors to disease, with numerous blood circulating protein levels representing functional readouts of disease-related processes. We hypothesized that studying the genetic architecture of a comprehensive set of blood-circulating proteins between a European and an Arab population could shed fresh light on the translatability of PGS to understudied populations. We therefore conducted a genome-wide association study with whole-genome sequencing data using 1301 proteins measured on the SOMAscan aptamer-based affinity proteomics platform in 2935 samples of Qatar Biobank and evaluated the replication of protein quantitative traits (pQTLs) from European studies in an Arab population. Then, we investigated the colocalization of shared pQTL signals between the two populations. Finally, we compared the performance of protein PGS derived from a Caucasian population in a European and an Arab cohort. We found that the majority of shared pQTL signals (81.8%) colocalized between both populations. About one-third of the genetic protein heritability was explained by protein PGS derived from a European cohort, with protein PGS performing ~ 20% better in Europeans when compared to Arabs. Our results are relevant for the translation of PGS to non-Caucasian populations, as well as for future efforts to extend genetic research to understudied populations. AU - Thareja, G.* AU - Belkadi, A.* AU - Arnold, M. AU - Albagha, O.M.E.* AU - Graumann, J.* AU - Schmidt, F.* AU - Grallert, H. AU - Peters, A. AU - Gieger, C. AU - Suhre, K.* C1 - 66379 C2 - 53160 SP - 907–916 TI - Differences and commonalities in the genetic architecture of protein quantitative trait loci in European and Arab populations. JO - Hum. Mol. Genet. VL - 32 IS - 6 PY - 2023 SN - 0964-6906 ER - TY - JOUR AB - INTRODUCTION: In the era of personalized medicine with more and more patient specific targeted therapies being used, we need reliable, dynamic, faster, and sensitive biomarkers both to track the causes of disease and to develop and evolve therapies during the course of treatment. Metabolomics recently has shown substantial evidence to support its emerging role in disease diagnosis and prognosis. Aside from biomarkers and development of therapies, it is also an important goal to understand the involvement of mitochondrial DNA mtDNA in metabolic regulation, aging, and disease development. Somatic mutations of the mitochondrial genome are also heavily implicated in age-related disease and aging. The general hypothesis is that an alteration in the concentration of metabolite profiles (possibly conveyed by lifestyle and environmental factors) influences the increase of mutation rate in the mtDNA, and thereby contributes to a range of pathophysiological alterations observed in complex diseases. METHODS: We performed an inverted mitochondrial genome wide association analysis between mitochondrial nucleotide variants (mtSNVs) and concentration of metabolites. We used 151 metabolites and the whole sequenced mitochondrial genome from 2718 individuals to identify genetic variants associated with metabolite profiles. Because of the high coverage, next generation sequencing-based analysis of the mitochondrial genome allows for an accurate detection of mitochondrial heteroplasmy and for identification of variants associated with the metabolome. RESULTS: The strongest association was found for mt715G > A located in the MT-12SrRNA with the metabolite ratio C2/C10:1 (p-value = 6.82*10-09, β = 0.909). The second most significant mtSNV was found for mt3714A > G located in the MT-ND1 with the metabolite ratio PC ae C42:5/PC ae C44:5 (p-value = 1.02*10-08, β = 3.631). A large number of significant metabolite ratios were observed involving PC aa C36:6 and the variant mt10689G > A, located in the MT-ND4L gene. CONCLUSION: These results show an important interconnection between mitochondria and metabolite concentrations. Considering that some of the significant metabolites found in this study have been previously related to complex diseases such as neurological disorders and metabolic conditions, these associations found here might play a crucial role for further investigations of such complex diseases. Understanding the mechanisms that control human health and disease, in particular the role of genetic predispositions and their interaction with environmental factors is a prerequisite for the development of safe and efficient therapies for complex disorders. AU - Aboulmaouahib, B.* AU - Kastenmüller, G. AU - Suhre, K.* AU - Zöllner, S.* AU - Weissensteiner, H.* AU - Prehn, C. AU - Adamski, J. AU - Gieger, C. AU - Wang-Sattler, R. AU - Lichtner, P. AU - Strauch, K. AU - Flaquer, A. C1 - 63429 C2 - 51531 SP - 3367-3376 TI - First mitochondrial genome wide association study with metabolomics. JO - Hum. Mol. Genet. VL - 31 IS - 19 PY - 2022 SN - 0964-6906 ER - TY - JOUR AB - Clonal hematopoiesis due to somatic mutations in hematopoietic stem/progenitor cells is an age-related phenomenon and commonly observed when sequencing blood DNA in elderly individuals. Several genes that are implicated in clonal hematopoiesis are also associated with Mendelian disorders when mutated in the germline, potentially leading to variant misinterpretation. We performed a literature search to identify genes associated with age-related clonal hematopoiesis followed by an OMIM query to identify the subset of genes in which germline variants are associated with Mendelian disorders. We retrospectively screened for diagnostic cases in which the presence of age-related clonal hematopoiesis confounded exome sequencing data interpretation. We found 58 genes in which somatic mutations are implicated in clonal hematopoiesis while germline variants in the same genes are associated with Mendelian (mostly neurodevelopmental) disorders. Using five selected cases of individuals with suspected monogenic disorders, we illustrate how clonal hematopoiesis in either variant databases or exome sequencing datasets poses a pitfall, potentially leading to variant misclassification and erroneous conclusions regarding gene-disease associations. AU - Brunet, T. AU - Berutti, R. AU - Dill, V.* AU - Hecker, J.S.* AU - Choukair, D.* AU - Andres, S.* AU - Deschauer, M.* AU - Diehl-Schmid, J.* AU - Krenn, M.* AU - Eckstein, G. AU - Graf, E.* AU - Gasser, T.* AU - Strom, T.M.* AU - Hoefele, J.* AU - Götze, K.S.* AU - Meitinger, T.* AU - Wagner, M. C1 - 64351 C2 - 52197 SP - 2386-2395 TI - Clonal hematopoiesis as a pitfall in germline variant interpretation in the context of Mendelian disorders. JO - Hum. Mol. Genet. VL - 31 IS - 14 PY - 2022 SN - 0964-6906 ER - TY - JOUR AB - Carotid intima media thickness (cIMT) is a biomarker of subclinical atherosclerosis and a predictor of future cardiovascular events. Identifying associations between gene expression levels and cIMT may provide insight to atherosclerosis etiology. Here, we use two approaches to identify associations between mRNA levels and cIMT: differential gene expression analysis in whole blood and S-PrediXcan. We used microarrays to measure genome-wide whole blood mRNA levels of 5647 European individuals from four studies. We examined the association of mRNA levels with cIMT adjusted for various potential confounders. Significant associations were tested for replication in three studies totaling 3943 participants. Next, we applied S-PrediXcan to summary statistics from a cIMT genome-wide association study of 71 128 individuals to estimate the association between genetically determined mRNA levels and cIMT and replicated these analyses using S-PrediXcan on an independent genome-wide association study on cIMT that included 22 179 individuals from the UK Biobank. mRNA levels of TNFAIP3, CEBPD, and METRNL were inversely associated with cIMT, but these associations were not significant in the replication analysis. S-PrediXcan identified associations between cIMT and genetically determined mRNA levels for 36 genes, of which six were significant in the replication analysis, including TLN2, which had not been previously reported for cIMT. There was weak correlation between our results using differential gene expression analysis and S-PrediXcan. Differential expression analysis and S-PrediXcan represent complementary approaches for the discovery of associations between phenotypes and gene expression. Using these approaches, we prioritize TNFAIP3, CEBPD, METRNL, and TLN2 as new candidate genes whose differential expression might modulate cIMT. AU - Castaneda, A.B.* AU - Petty, L.E.* AU - Scholz, M.* AU - Jansen, R.* AU - Weiss, S.* AU - Zhang, X.* AU - Schramm, K. AU - Beutner, F.* AU - Kirsten, H.* AU - Schminke, U.* AU - Hwang, S.J.* AU - Marzi, C. AU - Dhana, K.* AU - Seldenrijk, A.* AU - Krohn, K.* AU - Homuth, G.* AU - Wolf, P. AU - Peters, M.J.* AU - Dörr, M.* AU - Peters, A. AU - van Meurs, J.B.J.* AU - Uitterlinden, A.G.* AU - Kavousi, M.* AU - Levy, D.* AU - Herder, C.* AU - Grootheest, G.* AU - Waldenberger, M. AU - Meisinger, C. AU - Rathmann, W.* AU - Thiery, J.* AU - Polak, J.F.* AU - Koenig, W.* AU - Seissler, J.* AU - Bis, J.C.* AU - Franceshini, N.* AU - Giambartolomei, C.* AU - Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Subclinical Working Group* AU - Hofman, A.* AU - Franco, O.H.* AU - Penninx, B.W.J.H.* AU - Prokisch, H. AU - Völzke, H.* AU - Loeffler, M.* AU - O'Donnell, C.J.* AU - Below, J.E.* AU - Dehghan, A.* AU - de Vries, P.S.* C1 - 63644 C2 - 51718 SP - 1171-1182 TI - Associations of carotid intima media thickness with gene expression in whole blood and genetically predicted gene expression across 48 tissues. JO - Hum. Mol. Genet. VL - 31 IS - 7 PY - 2022 SN - 0964-6906 ER - TY - JOUR AB - Here we describe the results of a genome-wide study conducted in 11 939 COVID-19 positive cases with an extensive clinical information that were recruited from 34 hospitals across Spain (SCOURGE consortium). In sex-disaggregated genome-wide association studies for COVID-19 hospitalization, genome-wide significance (p < 5x10-8) was crossed for variants in 3p21.31 and 21q22.11 loci only among males (p = 1.3x10-22 and p = 8.1x10-12, respectively), and for variants in 9q21.32 near TLE1 only among females (p = 4.4x10-8). In a second phase, results were combined with an independent Spanish cohort (1598 COVID-19 cases and 1068 population controls), revealing in the overall analysis two novel risk loci in 9p13.3 and 19q13.12, with fine-mapping prioritized variants functionally associated with AQP3 (p = 2.7x10-8) and ARHGAP33 (p = 1.3x10-8), respectively. The meta-analysis of both phases with four European studies stratified by sex from the Host Genetics Initiative confirmed the association of the 3p21.31 and 21q22.11 loci predominantly in males and replicated a recently reported variant in 11p13 (ELF5, p = 4.1x10-8). Six of the COVID-19 HGI discovered loci were replicated and an HGI-based genetic risk score predicted the severity strata in SCOURGE. We also found more SNP-heritability and larger heritability differences by age (<60 or ≥ 60 years) among males than among females. Parallel genome-wide screening of inbreeding depression in SCOURGE also showed an effect of homozygosity in COVID-19 hospitalization and severity and this effect was stronger among older males. In summary, new candidate genes for COVID-19 severity and evidence supporting genetic disparities among sexes are provided. AU - Cruz, R.* AU - Almeida, S.D.* AU - Heredia, M.L.* AU - Quintela, I.* AU - Ceballos, F.C.* AU - Pita, G.* AU - Lorenzo-Salazar, J.M.* AU - González-Montelongo, R.* AU - Gago-Dominguez, M.* AU - Porras, M.S.* AU - Castaño, J.A.T.* AU - Nevado, J.* AU - Aguado, J.M.* AU - Aguilar, C.* AU - Aguilera-Albesa, S.* AU - Almadana, V.* AU - Almoguera, B.* AU - Alvarez, N.* AU - Andreu-Bernabeu,* AU - Arana-Arri, E.* AU - Arango, C.* AU - Arranz, M.J.* AU - Artiga, M.J.* AU - Baptista-Rosas, R.C.* AU - Barreda-Sánchez, M.* AU - Belhassen-Garcia, M.* AU - Bezerra, J.F.* AU - Bezerra, M.A.C.* AU - Boix-Palop, L.* AU - Brion, M.* AU - Brugada, R.* AU - Bustos, M.* AU - Calderón, E.J.* AU - Carbonell, C.* AU - Castelao, J.E.* AU - Conde-Vicente, R.* AU - Cordero-Lorenzana, M.L.* AU - Cortes-Sanchez, J.L.* AU - Corton, M.* AU - Darnaude, M.T.* AU - De Martino-Rodríguez, A.* AU - Campo-Pérez, V.* AU - Bustamante, A.D.* AU - Domínguez-Garrido, E.* AU - Luchessi, A.D.* AU - Eirós, R.* AU - Sanabria, G.M.E.* AU - Fariñas, M.C.* AU - Fernández-Robelo, U.* AU - Fernández-Rodríguez, A.* AU - Fernández-Villa, T.* AU - Gil-Fournier, B.* AU - Gómez-Arrue, J.* AU - Álvarez, B.G.* AU - Quirós, F.G.B.* AU - González-Peñas, J.* AU - Gutiérrez-Bautista, J.F.* AU - Herrero, M.J.* AU - Herrero-Gonzalez, A.* AU - Jimenez-Sousa, M.A.* AU - Lattig, M.C.* AU - Borja, A.L.* AU - Lopez-Rodriguez, R.* AU - Mancebo, E.* AU - Martín-López, C.* AU - Martín, V.* AU - Martinez-Nieto, O.* AU - Martinez-Lopez, I.* AU - Martinez-Resendez, M.F.* AU - Martinez-Perez,* AU - Mazzeu, J.A.* AU - Macías, E.M.* AU - Minguez, P.* AU - Cuerda, V.M.* AU - Silbiger, V.N.* AU - Oliveira, S.F.* AU - Ortega-Paino, E.* AU - Parellada, M.* AU - Paz-Artal, E.* AU - Santos, N.P.C.* AU - Pérez-Matute, P.* AU - Perez, P.* AU - Pérez-Tomás, M.E.* AU - Perucho, T.* AU - Pinsach-Abuin, M.L.* AU - Pompa-Mera, E.N.* AU - Porras-Hurtado, G.L.* AU - Pujol, A.* AU - León, S.R.* AU - Resino, S.* AU - Fernandes, M.R.* AU - Rodríguez-Ruiz, E.* AU - Rodriguez-Artalejo, F.* AU - Rodriguez-Garcia, J.A.* AU - Ruiz-Cabello, F.* AU - Ruiz-Hornillos, J.* AU - Ryan, P.* AU - Soria, J.M.* AU - Souto, J.C.* AU - Tamayo, E.* AU - Tamayo-Velasco, A.* AU - Taracido-Fernandez, J.C.* AU - Teper, A.* AU - Torres-Tobar, L.* AU - Urioste, M.* AU - Valencia-Ramos, J.* AU - Yáñez, Z.* AU - Zarate, R.* AU - Pigazzini, S.* AU - Degenhardt, F.* AU - Butler-Laporte, G.* AU - Maya-Miles, D.* AU - Bujanda, L.* AU - Bouysran, Y.* AU - Palom, A.* AU - Ellinghaus, D.* AU - Martínez-Bueno, M.* AU - Rolker, S.* AU - Amitrano, S.* AU - Roade, L.* AU - Fava, F.* AU - Spinner, C.D.* AU - Prati, D.* AU - Bernardo, D.* AU - Garcia, F.* AU - Darcis, G.* AU - Fernandez-Cadenas, I.* AU - Holter, J.C.* AU - Banales, J.M.* AU - Frithiof, R.* AU - Duga, S.* AU - Asselta, R.* AU - Pereira, A.C.* AU - Romero-Gómez, M.* AU - Nafría-Jiménez, B.* AU - Hov, J.R.* AU - Migeotte, I.* AU - Renieri, A.* AU - Planas, A.M.* AU - Ludwig, K.U.* AU - Buti, M.* AU - Rahmouni, S.* AU - Alarcón-Riquelme, M.E.* AU - Schulte, E.C. AU - Franke, A.* AU - Karlsen, T.H.* AU - Valenti, L.* AU - Zeberg, H.* AU - Richards, B.* AU - Ganna, A.* AU - Boada, M.* AU - Rojas, I.* AU - Ruiz, A.* AU - Sanchez, P.* AU - Real, L.M.* AU - Guillén-Navarro, E.* AU - Ayuso, C.* AU - González-Neira, A.* AU - Riancho, J.A.* AU - Rojas-Martinez, A.* AU - Carracedo, A.* AU - Lapunzina, P.* C1 - 65563 C2 - 52742 SP - 3789-3806 TI - Novel genes and sex differences in COVID-19 severity. JO - Hum. Mol. Genet. VL - 31 IS - 22 PY - 2022 SN - 0964-6906 ER - TY - JOUR AU - Degenhardt, F.* AU - Ellinghaus, D.* AU - Juzenas, S.* AU - Lerga-Jaso, J.* AU - Wendorff, M.* AU - Maya-Miles, D.* AU - Uellendahl-Werth, F.* AU - ElAbd, H.* AU - Rühlemann, M.C.* AU - Ozer, O.* AU - Lenning, O.B.* AU - Myhre, R.* AU - Vadla, M.S.* AU - Wacker, E.M.* AU - Wienbrandt, L.* AU - Ortiz, A.B.* AU - Salazar, A.* AU - Chercoles, A.G.* AU - Palom, A.* AU - Ruiz, A.* AU - Garcia-Fernandez, A.E.* AU - Blanco-Grau, A.* AU - Mantovani, A.* AU - Zanella, A.* AU - Holten, A.R.* AU - Mayer, A.* AU - Bandera, A.* AU - Cherubini, A.* AU - Protti, A.* AU - Aghemo, A.* AU - Gerussi, A.* AU - Braun, A.* AU - Nebel, A.* AU - Barreira, A.* AU - Lleõ, A.* AU - Teles, A.* AU - Kildal, A.B.* AU - Biondi, A.* AU - Caballero-Garralda, A.* AU - Ganna, A.* AU - Gori, A.* AU - Glück, A.* AU - Lind, A.* AU - Tanck, A.* AU - Hinney, A.* AU - Nolla, A.C.* AU - Fracanzani, A.L.* AU - Peschuck, A.* AU - Cavallero, A.* AU - Dyrhol-Riise, A.M.* AU - Ruello, A.* AU - Julià, A.* AU - Muscatello, A.* AU - Pesenti, A.* AU - Voza, A.* AU - Rando-Segura, A.* AU - Solier, A.* AU - Schmidt, A.* AU - Cortes, B.* AU - Mateos, B.* AU - Nafría-Jiménez, B.* AU - Schaefer, B.W.* AU - Jensen, B.* AU - Bellinghausen, C.* AU - Maj, C.* AU - Ferrando, C.* AU - Quereda, C.* AU - Skurk, C.* AU - Thibeault, C.* AU - Scollo, C.* AU - Herr, C.* AU - Spinner, C.D.* AU - Gassner, C.* AU - Lange, C.* AU - Hu, C.* AU - Paccapelo, C.* AU - Lehmann, C.* AU - Angelini, C.* AU - Cappadona, C.* AU - Azuure, C.* AU - COVICAT study group, Aachen Study (COVAS)* AU - Bianco, C.* AU - Cea, C.* AU - Sancho, C.* AU - Hoff, D.A.L.* AU - Galimberti, D.* AU - Prati, D.* AU - Haschka, D.* AU - Jimenez, D.L.R.M.* AU - Pestaña, D.* AU - Toapanta, D.* AU - Muñiz-Diaz, E.* AU - Azzolini, E.* AU - Sandoval, E.* AU - Binatti, E.* AU - Scarpini, E.* AU - Helbig, E.T.* AU - Casalone, E.* AU - Urrechaga, E.* AU - Paraboschi, E.M.* AU - Pontali, E.* AU - Reverter, E.* AU - Navas, E.* AU - Solligård, E.* AU - Contro, E.* AU - Arana-Arri, E.* AU - Aziz, F.* AU - Garcia, F.* AU - Sánchez, F.G.* AU - Ceriotti, F.* AU - Martinelli-Boneschi, F.* AU - Peyvandi, F.* AU - Kurth, F.* AU - Blasi, F.* AU - Malvestiti, F.* AU - Mesonero, F.* AU - Rodriguez-Frias, F.* AU - Hanses, F.* AU - Müller, F.* AU - Hemmrich-Stanisak, G.* AU - Bellani, G.* AU - Grasselli, G.* AU - Pezzoli, G.* AU - Costantino, G.* AU - Albano, G.* AU - Cardamone, G.* AU - Bellelli, G.* AU - Citerio, G.* AU - Foti, G.* AU - Lamorte, G.* AU - Matullo, G.* AU - Baselli, G.* AU - Kurihara, H.* AU - Neb, H.* AU - My, I.* AU - Kurth, I.* AU - Hernández, I.* AU - Pink, I.* AU - Rojas, I.* AU - Galván-Femenia, I.* AU - Holter, J.C.* AU - Afset, J.E.* AU - Heyckendorf, J.* AU - Kässens, J.* AU - Damås, J.K.* AU - Rybniker, J.* AU - Altmüller, J.* AU - Martin, J.* AU - Erdmann, J.* AU - Banales, J.M.* AU - Badia, J.R.* AU - Dopazo, J.* AU - Schneider, J.* AU - Bergan, J.* AU - Barretina, J.* AU - Walter, J.* AU - Quero, J.H.* AU - Goikoetxea, J.* AU - Guerrero, J.M.* AU - Fazaal, J.* AU - Kraft, J.* AU - Schröder, J.* AU - Risnes, K.* AU - Banasik, K.* AU - Müller, K.E.* AU - Gaede, K.I.* AU - Garcia-Etxebarria, K.* AU - Tonby, K.* AU - Heggelund, L.* AU - Izquierdo-Sanchez, L.* AU - Bettini, L.R.* AU - Sumoy, L.* AU - Sander, L.E.* AU - Lippert, L.J.* AU - Terranova, L.* AU - Nkambule, L.* AU - Knopp, L.* AU - Gustad, L.T.* AU - Garbarino, L.* AU - Santoro, L.* AU - Téllez, L.* AU - Roade, L.* AU - Ostadreza, M.* AU - Intxausti, M.* AU - Kogevinas, M.* AU - Riveiro-Barciela, M.* AU - Berger, M.M.* AU - Schaefer, M.* AU - Niemi, M.E.K.* AU - Gutiérrez-Stampa, M.A.* AU - Carrabba, M.* AU - Figuera Basso, M.E.* AU - Valsecchi, M.G.* AU - Hernandez-Tejero, M.* AU - Vehreschild, M.J.G.T.* AU - Manunta, M.* AU - Acosta-Herrera, M.* AU - D'Angiò, M.* AU - Baldini, M.* AU - Cazzaniga, M.* AU - Grimsrud, M.M.* AU - Cornberg, M.* AU - Nöthen, M.M.* AU - Marquié, M.* AU - Castoldi, M.* AU - Cordioli, M.* AU - Cecconi, M.* AU - D'Amato, M.* AU - Augustin, M.* AU - Tomasi, M.* AU - Boada, M.* AU - Dreher, M.R.* AU - Seilmaier, M.J.* AU - Joannidis, M.* AU - Wittig, M.* AU - Mazzocco, M.* AU - Ciccarelli, M.* AU - Rodríguez-Gandía, M.* AU - Bocciolone, M.* AU - Miozzo, M.* AU - Ayo, N.I.* AU - Blay, N.* AU - Chueca, N.* AU - Montano, N.* AU - Braun, N.* AU - Ludwig, N.* AU - Marx, N.* AU - Martínez, N.* AU - Cornely, O.A.* AU - Witzke, O.* AU - Palmieri, O.* AU - Faverio, P.* AU - Preatoni, P.* AU - Bonfanti, P.* AU - Omodei, P.* AU - Tentorio, P.* AU - Castro, P.* AU - Rodrigues, P.M.* AU - España, P.P.* AU - Hoffmann, P.* AU - Rosenstiel, P.* AU - Schommers, P.* AU - Suwalski, P.* AU - Pablo, R.* AU - Ferrer, R.* AU - Bals, R.* AU - Gualtierotti, R.* AU - Gallego-Durán, R.* AU - Nieto, R.* AU - Carpani, R.* AU - Badalamenti, S.* AU - Haider, S.* AU - Ciesek, S.* AU - May, S.* AU - Bombace, S.* AU - Marsal, S.* AU - Pigazzini, S.* AU - Klein, S.* AU - Pelusi, S.* AU - Wilfling, S.* AU - Bosari, S.* AU - Volland, S.* AU - Brunak, S.* AU - Schreiber, S.* AU - Heilmann-Heimbach, S.* AU - Aliberti, S.* AU - Ripke, S.* AU - Dudman, S.* AU - Wesse, T.* AU - Zheng, T.* AU - Bahmer, T.* AU - Eggermann, T.* AU - Illig, T.* AU - Brenner, T.* AU - Pumarola, T.* AU - Feldt, T.* AU - Folseraas, T.* AU - Cejudo, T.G.* AU - Landmesser, U.* AU - Protzer, U. AU - Hehr, U.* AU - Rimoldi, V.* AU - Monzani, V.* C1 - 65771 C2 - 52911 SP - 3945-3966 TI - Detailed stratified GWAS analysis for severe COVID-19 in four European populations. JO - Hum. Mol. Genet. VL - 31 IS - 23 PY - 2022 SN - 0964-6906 ER - TY - JOUR AB - BACKGROUND: The protein α-Klotho acts as transmembrane the co-receptor for fibroblast growth factor 23 (FGF-23) and is a key regulator of phosphate homeostasis. However, α-Klotho also exists in a circulating form, with pleiotropic, but incompletely understood functions and regulation. Therefore, we undertook a GWAS meta-analysis followed by Mendelian randomisation (MR) of circulating α-Klotho levels. METHODS: Plasma α-Klotho levels were measured by ELISA in the LURIC and ALSPAC (mothers) cohorts, followed by a GWAS meta-analysis in 4376 individuals across the two cohorts. RESULTS: Six signals at five loci were associated with circulating α-Klotho levels at genome-wide significance (p < 5 × 10-8), namely ABO, KL, FGFR1, and two post-translational modification genes, B4GALNT3 and CHST9. Together, these loci explained > 9% of the variation in circulating α-Klotho levels. MR analyses revealed no causal relationships between α-Klotho and renal function, FGF-23-dependent factors such as vitamin D and phosphate levels, or bone mineral density. The screening for genetic correlations with other phenotypes, followed by targeted MR suggested causal effects of liability of Crohn's disease risk [IVW beta = 0.059 (95% CI 0.026, 0.093)] and low-density lipoprotein cholesterol (LDL-C) levels [-0.198, (-0.332, -0.063)] on α-Klotho. CONCLUSIONS: Our GWAS findings suggest that two enzymes involved in post-translational modification, B4GALNT3 and CHST9, contribute to genetic influences on α-Klotho levels, presumably by affecting protein turnover and stability. Subsequent evidence from MR analyses on α-Klotho levels suggest regulation by mechanisms besides phosphate-homeostasis and raise the possibility of cross-talk with FGF19- and FGF21-dependent pathways, respectively. AU - Gergei, I.* AU - Zheng, J.* AU - Andlauer, T.F.M.* AU - Brandenburg, V.* AU - Mirza-Schreiber, N. AU - Müller-Myhsok, B.* AU - Krämer, B.K.* AU - Richard, D.* AU - Falk, L.* AU - Movérare-Skrtic, S.* AU - Ohlsson, C.* AU - Smith, G.D.* AU - März, W.* AU - Voelkl, J.* AU - Tobias, J.H.* C1 - 63034 C2 - 51222 CY - Great Clarendon St, Oxford Ox2 6dp, England SP - 792-802 TI - GWAS META-analysis followed by MENDELIAN randomisation revealed potential control mechanisms for circulating α-klotho levels. JO - Hum. Mol. Genet. VL - 31 IS - 5 PB - Oxford Univ Press PY - 2022 SN - 0964-6906 ER - TY - JOUR AB - Osteoarthritis is a prevalent joint disease and a major cause of disability worldwide with no curative therapy. Development of disease-modifying therapies requires a better understanding of the molecular mechanisms underpinning disease. A hallmark of osteoarthritis is cartilage degradation. To define molecular events characterising osteoarthritis at the whole transcriptome level, we performed deep RNA sequencing in paired samples of low- and high-osteoarthritis grade knee cartilage derived from 124 patients undergoing total joint replacement. We detected differential expression between low- and high-osteoarthritis grade articular cartilage for 365 genes and identified a 38-gene signature in osteoarthritis cartilage by replicating our findings in an independent dataset. We also found differential expression for 25 novel long non-coding RNA genes (lncRNAs) and identified potential lncRNA interactions with RNA-binding proteins in osteoarthritis. We assessed alterations in the relative usage of individual gene transcripts and identified differential transcript usage for 82 genes, including ABI3BP, coding for an extracellular matrix protein, AKT1S1, a negative regulator of the mTOR pathway, and TPRM4, coding for a transient receptor potential channel. We further assessed genome-wide differential splicing, for the first time in osteoarthritis, and detected differential splicing for 209 genes, which were enriched for extracellular matrix, proteoglycans and integrin surface interactions terms. In the largest study of its kind in osteoarthritis, we find that isoform and splicing changes, in addition to extensive differences in both coding and non-coding sequence expression, are associated with disease and demonstrate a novel layer of genomic complexity to osteoarthritis pathogenesis. AU - Katsoula, G. AU - Steinberg, J. AU - Tuerlings, M.* AU - de Almeida, R.C.* AU - Southam, L. AU - Swift, D.* AU - Meulenbelt, I.* AU - Wilkinson, J.M.* AU - Zeggini, E. C1 - 64263 C2 - 52165 CY - Great Clarendon St, Oxford Ox2 6dp, England SP - 2090-2105 TI - A molecular map of long non-coding RNA expression, isoform switching and alternative splicing in osteoarthritis. JO - Hum. Mol. Genet. VL - 31 IS - 12 PB - Oxford Univ Press PY - 2022 SN - 0964-6906 ER - TY - JOUR AB - To nominate novel disease genes for obesity and type 2 diabetes (T2D), we recently generated two mouse backcross populations of the T2D-susceptible New Zealand Obese (NZO/HI) mouse strain and two genetically different, lean and T2D-resistant strains, 129P2/OlaHsd and C3HeB/FeJ. Comparative linkage analysis of our two female backcross populations identified seven novel body fat-associated quantitative trait loci (QTL). Only the locus Nbw14 (NZO body weight on chromosome 14) showed linkage to obesity-related traits in both backcross populations, indicating that the causal gene variant is likely specific for the NZO strain as NZO allele carriers in both crosses displayed elevated body weight and fat mass. To identify candidate genes for Nbw14, we used a combined approach of gene expression and haplotype analysis to filter for NZO-specific gene variants in gonadal white adipose tissue (gWAT), defined as the main QTL-target tissue. Only two genes, Arl11 and Sgcg, fulfilled our candidate criteria. In addition, expression QTL analysis revealed cis-signals for both genes within the Nbw14 locus. Moreover, retroviral overexpression of Sgcg in 3 T3-L1 adipocytes resulted in increased insulin-stimulated glucose uptake. In humans, mRNA levels of SGCG correlated with BMI and body fat mass exclusively in diabetic subjects, suggesting that SGCG may present a novel marker for metabolically unhealthy obesity. In conclusion, our comparative-cross analysis could substantially improve the mapping resolution of the obesity locus Nbw14. Future studies will shine light on the mechanism by which Sgcg may protect from the development of obesity. AU - Kuhn, T.* AU - Kaiser, K.* AU - Lebek, S.* AU - Altenhofen, D.* AU - Knebel, B.* AU - Herwig, R.* AU - Rasche, A.* AU - Pelligra, A.* AU - Görigk, S.* AU - Khuong, J.M.* AU - Vogel, H.* AU - Schürmann, A.* AU - Blüher, M. AU - Chadt, A.* AU - Al-Hasani, H.* C1 - 65658 C2 - 52855 SP - 4019-4033 TI - Comparative genomic analyses of multiple backcross mouse populations suggest SGCG as a novel potential obesity-modifier gene. JO - Hum. Mol. Genet. VL - 31 IS - 23 PY - 2022 SN - 0964-6906 ER - TY - JOUR AB - Gestational diabetes mellitus (GDM) is associated with increased risk of pregnancy complications and adverse perinatal outcomes. GDM often reoccurs and is associated with increased risk of subsequent diagnosis of type 2 diabetes (T2D). To improve our understanding of the aetiological factors and molecular processes driving the occurrence of GDM, including the extent to which these overlap with T2D pathophysiology, the GENetics of Diabetes In Pregnancy (GenDIP) Consortium assembled genome-wide association studies (GWAS) of diverse ancestry in a total of 5485 women with GDM and 347 856 without GDM. Through multi-ancestry meta-analysis, we identified five loci with genome-wide significant association (p < 5x10-8) with GDM, mapping to/near MTNR1B (p = 4.3x10-54), TCF7L2 (p = 4.0x10-16), CDKAL1 (p = 1.6 × 10-14), CDKN2A-CDKN2B (p = 4.1x10-9) and HKDC1 (p = 2.9x10-8). Multiple lines of evidence pointed to the shared pathophysiology of GDM and T2D: (i) four of the five GDM loci (not HKDC1) have been previously reported at genome-wide significance for T2D; (ii) significant enrichment for associations with GDM at previously reported T2D loci; (iii) strong genetic correlation between GDM and T2D; and (iv) enrichment of GDM associations mapping to genomic annotations in diabetes-relevant tissues and transcription factor binding sites. Mendelian randomisation analyses demonstrated significant causal association (5% false discovery rate) of higher body mass index on increased GDM risk. Our results provide support for the hypothesis that GDM and T2D are part of the same underlying pathology but that, as exemplified by the HKDC1 locus, there are genetic determinants of GDM that are specific to glucose regulation in pregnancy. AU - Pervjakova, N.* AU - Moen, G.H.* AU - Borges, M.C.* AU - Ferreira, T.* AU - Cook, J.P.* AU - Allard, C.* AU - Beaumont, R.N.* AU - Canouil, M.* AU - Hatem, G.* AU - Heiskala, A.* AU - Joensuu, A.* AU - Karhunen, V.* AU - Kwak, S.H.* AU - Lin, F.T.J.* AU - Liu, J.* AU - Rifas-Shiman, S.L.* AU - Tam, C.H.* AU - Tam, W.H.* AU - Thorleifsson, G.* AU - Andrew, T.* AU - Auvinen, J.* AU - Bhowmik, B.* AU - Bonnefond, A.* AU - Delahaye, F.* AU - Demirkan, A.* AU - Froguel, P.* AU - Haller-Kikkatalo, K.* AU - Hardardottir, H.* AU - Hummel, S. AU - Hussain, A.* AU - Kajantie, E.* AU - Keikkala, E.* AU - Khamis, A.* AU - Lahti, J.* AU - Lekva, T.* AU - Mustaniemi, S.* AU - Sommer, C.* AU - Tagoma, A.* AU - Tzala, E.* AU - Uibo, R.* AU - Vääräsmäki, M.* AU - Villa, P.M.* AU - Birkeland, K.I.* AU - Bouchard, L.* AU - Duijn, C.M.* AU - Finer, S.* AU - Groop, L.* AU - Hämäläinen, E.* AU - Hayes, G.M.* AU - Hitman, G.A.* AU - Jang, H.C.* AU - Järvelin, M.R.* AU - Jenum, A.K.* AU - Laivuori, H.* AU - Ma, R.C.* AU - Melander, O.* AU - Oken, E.* AU - Park, K.S.* AU - Perron, P.* AU - Prasad, R.B.* AU - Qvigstad, E.* AU - Sebert, S.* AU - Stefansson, K.* AU - Steinthorsdottir, V.* AU - Tuomi, T.* AU - Hivert, M.F.* AU - Franks, P.W.* AU - McCarthy, M.I.* AU - Lindgren, C.M.* AU - Freathy, R.M.* AU - Lawlor, D.A.* AU - Morris, A.P.* AU - Mägi, R.* C1 - 64539 C2 - 52259 SP - 3377–3391 TI - Multi-ancestry genome-wide association study of gestational diabetes mellitus highlights genetic links with type 2 diabetes. JO - Hum. Mol. Genet. VL - 31 IS - 19 PY - 2022 SN - 0964-6906 ER - TY - JOUR AB - Cardiometabolic diseases, such as type 2 diabetes and cardiovascular disease, have a high public health burden. Understanding the genetically-determined regulation of proteins that are dysregulated in disease can help to dissect the complex biology underpinning them. Here, we perform a protein quantitative trait locus (pQTL) analysis of 255 serum proteins relevant to cardiometabolic processes in 2893 individuals. Meta-analysing whole-genome sequencing (WGS) data from two Greek cohorts, MANOLIS (n = 1356; 22.5x WGS) and Pomak (n = 1537; 18.4x WGS), we detect 302 independently-associated pQTL variants for 171 proteins, including 12 rare variants (minor allele frequency [MAF] < 1%). We additionally find 15 pQTL variants that are rare in non-Finnish European populations, but have drifted up in frequency in the discovery cohorts here. We identify proteins causally associated with cardiometabolic traits, including MEP1B for high-density lipoprotein levels; and describe a knock-out Mep1b mouse model. Our findings furnish insights into the genetic architecture of the serum proteome, identify new protein-disease relationships, and demonstrate the importance of isolated populations in pQTL analysis. AU - Png, G. AU - Gerlini, R. AU - Hatzikotoulas, K. AU - Barysenska, A. AU - Rayner, N.W. AU - Klarić, L.* AU - Rathkolb, B. AU - Aguilar-Pimentel, J.A. AU - Rozman, J. AU - Fuchs, H. AU - Gailus-Durner, V. AU - Tsafantakis, E.* AU - Karaleftheri, M.* AU - Dedoussis, G.* AU - Pietrzik, C.U.* AU - Wilson, J.F.* AU - Hrabě de Angelis, M. AU - Becker-Pauly, C.* AU - Gilly, A. AU - Zeggini, E. C1 - 66664 C2 - 53067 CY - Great Clarendon St, Oxford Ox2 6dp, England SP - 1266-1275 TI - Identifying causal serum protein-cardiometabolic trait relationships using whole genome sequencing. JO - Hum. Mol. Genet. VL - 32 IS - 8 PB - Oxford Univ Press PY - 2022 SN - 0964-6906 ER - TY - JOUR AB - Progressive dilation of the infrarenal aortic diameter is a consequence of the ageing process and is considered the main determinant of Abdominal Aortic Aneurysm (AAA). We aimed to investigate the genetic and clinical determinants of abdominal aortic diameter (AAD). We conducted a meta-analysis of genome-wide association studies in ten cohorts (n = 13 542) imputed to the 1000 Genome Project reference panel including 12 815 subjects in the discovery phase and 727 subjects (PBIO) as replication. Maximum anterior-posterior diameter of the infrarenal aorta was used as AAD. We also included exome array data (n = 14 480) from seven epidemiologic studies. Single-variant and gene-based associations were done using SeqMeta package. A Mendelian randomization analysis was applied to investigate the causal effect of a number of clinical risk factors on AAD. In GWAS on AAD, rs74448815 in the intronic region of LDLRAD4 reached genome-wide significance (beta = -0.02, SE = 0.004, p-value = 2.10 × 10-8). The association replicated in the PBIO1 cohort (p-value = 8.19 × 10-4). In exome-array single-variant analysis (p-value threshold = 9 × 10-7), the lowest p-value was found for rs239259 located in SLC22A20 (beta = 0.007, p-value =1.2 × 10-5). In the gene-based analysis (p-value threshold = 1.85 × 10-6), PCSK5 showed an association with AAD (p-value = 8.03 × 10-7). Furthermore, in Mendelian randomization analyses, we found evidence for genetic association of pulse pressure (beta = -0.003, p-value = 0.02), triglycerides (beta = -0.16, p-value = 0.008) and height (beta = 0.03, p-value<0.0001), known risk factors for AAA, consistent with a causal association with AAD. Our findings point to new biology as well as highlighting gene regions in mechanisms that have previously been implicated in the genetics of other vascular diseases. AU - Portilla-Fernandez, E.* AU - Klarin, D.* AU - Hwang, S.J.* AU - Biggs, M.L.* AU - Bis, J.C.* AU - Weiss, S.* AU - Rospleszcz, S. AU - Natarajan, P.* AU - Hoffmann, U.* AU - Rogers, I.S.* AU - Truong, Q.A.* AU - Völker, U.* AU - Dörr, M.* AU - Bülow, R.* AU - Criqui, M.H.* AU - Allison, M.* AU - Ganesh, S.K.* AU - Yao, J.* AU - Waldenberger, M. AU - Bamberg, F.* AU - Rice, K.M.* AU - Essers, J.* AU - Kapteijn, D.M.C.* AU - van der Laan, S.W.* AU - de Knegt, R.J.* AU - Ghanbari, M.* AU - Felix, J.F.* AU - Ikram, M.A.* AU - Kavousi, M.* AU - Uitterlinden, A.G.* AU - Roks, A.J.M.* AU - Danser, A.H.J.* AU - Tsao, P.S.* AU - Damrauer, S.M.* AU - Guo, X.* AU - Rotter, J.I.* AU - Psaty, B.M.* AU - Kathiresan, S.* AU - Völzke, H.* AU - Peters, A. AU - Johnson, C.* AU - Strauch, K. AU - Meitinger, T. AU - O'Donnell, C.J.* AU - Dehghan, A.* C1 - 64527 C2 - 52253 SP - 3566-3579 TI - Genetic and clinical determinants of abdominal aortic diameter: Genome-wide association studies, exome array data and Mendelian randomization study. JO - Hum. Mol. Genet. VL - 31 IS - 20 PY - 2022 SN - 0964-6906 ER - TY - JOUR AB - BACKGROUND: TASP1 encodes an endopeptidase activating histone methyltransferases of the KMT2 family. Homozygous loss-of-function variants in TASP1 have recently been associated with Suleiman-El-Hattab syndrome. We report six individuals with Suleiman-El-Hattab syndrome and provide functional characterization of this novel histone modification disorder in a multi-omics approach. Methods Chromosomal microarray/exome sequencing in all individuals. Western blotting from fibroblasts in two individuals. RNA sequencing and proteomics from fibroblasts in one individual. Methylome analysis from blood in two individuals. Knock-out of tasp1 orthologue in zebrafish and phenotyping. RESULTS: All individuals had biallelic TASP1 loss-of-function variants and a phenotype including developmental delay, multiple congenital anomalies (including cardiovascular and posterior fossa malformations), a distinct facial appearance, and happy demeanor. Western blot revealed absence of TASP1. RNA sequencing/proteomics showed HOX gene downregulation (HOXA4, HOXA7, HOXA1, HOXB2) and dysregulation of transcription factor TFIIA. A distinct methylation profile intermediate between control and Kabuki syndrome (KMT2D) profiles could be produced. Zebrafish tasp1 knock-out revealed smaller head size and abnormal cranial cartilage formation in tasp1 crispants. CONCLUSION: This work further delineates Suleiman-El-Hattab syndrome, a recognizable neurodevelopmental syndrome. Possible downstream mechanisms of TASP1 deficiency include perturbed HOX gene expression and dysregulated TFIIA complex. Methylation pattern suggests that Suleiman-El-Hattab syndrome can be categorized into the group of histone modification disorders including Wiedemann-Steiner and Kabuki syndrome. AU - Riedhammer, K.M.* AU - Burgemeister, A.L.* AU - Cantagrel, V.* AU - Amiel, J.* AU - Siquier, K.* AU - Boddaert, N.* AU - Hertecant, J.* AU - Kannouche, P.L.* AU - Pouvelle, C.* AU - Htun, S.* AU - Slavotinek, A.M.* AU - Beetz, C.* AU - Diego-Alvarez, D.* AU - Kampe, K.* AU - Fleischer, N.* AU - Awamleh, Z.* AU - Weksberg, R.* AU - Kopajtich, R. AU - Meitinger, T.* AU - Suleiman, J.* AU - El-Hattab, A.W.* C1 - 65022 C2 - 52619 SP - 3083-3094 TI - Suleiman-El-Hattab syndrome: A histone modification disorder caused by TASP1 deficiency. JO - Hum. Mol. Genet. VL - 31 IS - 18 PY - 2022 SN - 0964-6906 ER - TY - JOUR AB - Interleukin-6 (IL-6) is a multifunctional cytokine with both pro- and anti-inflammatory properties with a heritability estimate of up to 61%. The circulating levels of IL-6 in blood have been associated with an increased risk of complex disease pathogenesis. We conducted a two-staged, discovery, and replication meta genome-wide association study (GWAS) of circulating serum IL-6 levels comprising up to 67 428 (ndiscovery = 52 654 and nreplication = 14 774) individuals of European ancestry. The inverse variance fixed-effects based discovery meta-analysis, followed by replication led to the identification of two independent loci, IL1F10/IL1RN rs6734238 on Chromosome (Chr) 2q14, (pcombined = 1.8 × 10-11), HLA-DRB1/DRB5 rs660895 on Chr6p21 (pcombined = 1.5 × 10-10) in the combined meta-analyses of all samples. We also replicated the IL6R rs4537545 locus on Chr1q21 (pcombined = 1.2 × 10-122). Our study identifies novel loci for circulating IL-6 levels uncovering new immunological and inflammatory pathways that may influence IL-6 pathobiology. AU - Ahluwalia, T.S.* AU - Prins, B.P.* AU - Abdollahi, M.* AU - Armstrong, N.J.* AU - Aslibekyan, S.* AU - Bain, L.* AU - Jefferis, B.* AU - Baumert, J.J. AU - Beekman, M.* AU - Ben-Shlomo, Y.* AU - Bis, J.C.* AU - Mitchell, B.D.* AU - de Geus, E.* AU - Delgado, G.E.* AU - Marek, D.* AU - Eriksson, J.* AU - Kajantie, E.* AU - Kanoni, S.* AU - Kemp, J.P.* AU - Lu, C.* AU - Marioni, R.E.* AU - McLachlan, S.* AU - Milaneschi, Y.* AU - Nolte, I.M.* AU - Petrelis, A.M.* AU - Porcu, E.* AU - Sabater-Lleal, M.* AU - Naderi, E.* AU - Seppälä, I.* AU - Shah, T.* AU - Singhal, G.* AU - Standl, M. AU - Teumer, A.* AU - Thalamuthu, A.* AU - Thiering, E. AU - Trompet, S.* AU - Ballantyne, C.M.* AU - Benjamin, E.J.* AU - Casas, J.P.* AU - Toben, C.* AU - Dedoussis, G.* AU - Deelen, J.* AU - Durda, P.* AU - Engmann, J.* AU - Feitosa, M.F.* AU - Grallert, H. AU - Hammarstedt, A.* AU - Harris, S.E.* AU - Homuth, G.* AU - Hottenga, J.J.* AU - Jalkanen, S.* AU - Jamshidi, Y.* AU - Jawahar, M.C.* AU - Jess, T.* AU - Kivimaki, M.* AU - Kleber, M.E.* AU - Lahti, J.* AU - Liu, Y.* AU - Marques-Vidal, P.* AU - Mellström, D.* AU - Mooijaart, S.P.* AU - Müller-Nurasyid, M. AU - Penninx, B.* AU - Revez, J.A.* AU - Rossing, P.* AU - Räikkönen, K.* AU - Sattar, N.* AU - Scharnagl, H.* AU - Sennblad, B.* AU - Silveira, A.* AU - Pourcain, B.S.* AU - Timpson, N.J.* AU - Trollor, J.* AU - van Dongen, J.* AU - van Heemst, D.* AU - Visvikis-Siest, S.* AU - Vollenweider, P.* AU - Völker, U.* AU - Waldenberger, M. AU - Willemsen, G.* AU - Zabaneh, D.* AU - Morris, R.W.* AU - Arnett, D.K.* AU - Baune, B.T.* AU - Boomsma, D.I.* AU - Chang, Y.C.* AU - Deary, I.J.* AU - Deloukas, P.* AU - Eriksson, J.G.* AU - Evans, D.M* AU - Ferreira, M.A.* AU - Gaunt, T.* AU - Gudnason, V.* AU - Hamsten, A.* AU - Heinrich, J. AU - Hingorani, A.* AU - Humphries, S.E.* AU - Jukema, J.W.* AU - Koeing, W.* AU - Kumari, M.* AU - Kutalik, Z.* AU - Lawlor, D.A.* AU - Lehtimäki, T.* AU - März, W.* AU - Mather, K.* AU - Naitza, S.* AU - Nauck, M.* AU - Ohlsson, C.* AU - Price, J.F.* AU - Raitakari, O.* AU - Rice, K.* AU - Sachdev, P.S.* AU - Slagboom, E.* AU - Sørensen, T.I.A.* AU - Spector, T.* AU - Stacey, D.* AU - Stathopoulou, M.G.* AU - Tanaka, T.* AU - Wannamethee, S.G.* AU - Whincup, P.* AU - Rotter, J.I.* AU - Dehghan, A.* AU - Boerwinkle, E.* AU - Psaty, B.M.* AU - Snieder, H.* AU - Alizadeh, B.Z.* C1 - 61192 C2 - 50094 CY - Great Clarendon St, Oxford Ox2 6dp, England SP - 393-409 TI - Genome-wide association study of circulating interleukin 6 levels identifies novel loci. JO - Hum. Mol. Genet. VL - 30 IS - 5 PB - Oxford Univ Press PY - 2021 SN - 0964-6906 ER - TY - JOUR AB - A highly evolutionarily conserved MEIS1 intronic region is strongly associated with restless legs syndrome (RLS) and insomnia. To understand its regulatory function, we dissected the region by analyzing chromatin accessibility, enhancer-promoter contacts, DNA methylation, and eQTLs in different human neural cell types and tissues. We observed specific activity with respect to cell type and developmental maturation, indicating a prominent role for distinct highly conserved intronic elements in forebrain inhibitory neuron differentiation. Two elements were hypomethylated in neural cells with higher MEIS1 expression, suggesting a role of enhancer demethylation in gene regulation. MEIS1 eQTLs showed a striking modular chromosomal distribution, with forebrain eQTLs clustering in intron 8/9. CRISPR interference targeting of individual elements in this region attenuated MEIS1 expression, revealing a complex regulatory interplay of distinct elements. In summary, we found that MEIS1 regulation is organized in a modular pattern. Disease-associated intronic regulatory elements control MEIS1 expression with cell type and maturation stage specificity, particularly in the inhibitory neuron lineage. The precise spatiotemporal activity of these elements likely contributes to the pathogenesis of insomnia and RLS. AU - Lam, D.D. AU - Nikolic, A.A. AU - Zhao, C. AU - Mirza-Schreiber, N. AU - Krezel, W.* AU - Oexle, K. AU - Winkelmann, J. C1 - 63785 C2 - 51695 SP - 1733-1746 TI - Intronic elements associated with insomnia and restless legs syndrome exhibit cell type-specific epigenetic features contributing to MEIS1 regulation. JO - Hum. Mol. Genet. VL - 31 IS - 11 PY - 2021 SN - 0964-6906 ER - TY - JOUR AB - BACKGROUND: Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a key player in lipid metabolism, as it degrades LDL receptors from hepatic cell membranes. So far, only variants of the PCSK9 gene locus were found to be associated with PCSK9 levels. Here we aimed to identify novel genetic loci that regulate PCSK9 levels and how they relate to other lipid traits. Additionally, we investigated to what extend the causal effect of PCSK9 on coronary artery disease (CAD) is mediated by LDL-C. METHODS & RESULTS: We performed a genome-wide association study meta-analysis of PCSK9 levels in up to 12,721 samples of European ancestry. The estimated heritability was 10.3%, which increased to 12.6% using only samples from patients without statin treatment. We successfully replicated the known PCSK9 hit consisting of three independent signals. Interestingly, in a study of 300 African Americans, we confirmed the locus with a different PCSK9 variant. Beyond PCSK9, our meta-analysis detected three novel loci with genome-wide significance. Co-localization analysis with cis-eQTLs and lipid traits revealed biologically plausible candidate genes at two of them: APOB and TM6SF2. In a bivariate Mendelian Randomization analysis, we detected a strong effect of PCSK9 on LDL-C, but not vice versa. LDL-C mediated 63% of the total causal effect of PCSK9 on CAD. CONCLUSION: Our study identified novel genetic loci with plausible candidate genes affecting PCSK9 levels. Ethnic heterogeneity was observed at the PCSK9 locus itself. While the causal effect of PCSK9 on CAD is mainly mediated by LDL-C, an independent direct effect also occurs. AU - Pott, J.* AU - Gadin, J.* AU - Theusch, E.* AU - Kleber, M.E.* AU - Delgado, G.E.* AU - Kirsten, H.* AU - Hauck, S.M. AU - Burkhardt, R.* AU - Scharnagl, H.* AU - Krauss, R.M.* AU - Loeffler, M.* AU - März, W.* AU - Thiery, J.* AU - Silveira, A.* AU - Vant Hooft, F.M.* AU - Scholz, M.* C1 - 63190 C2 - 51377 SP - 999-1011 TI - Meta-GWAS of PCSK9 levels detects two novel loci at APOB and TM6SF2. JO - Hum. Mol. Genet. VL - 31 IS - 6 PY - 2021 SN - 0964-6906 ER - TY - JOUR AB - With progress in genome-wide association studies (GWAS) of depression, from identifying zero hits in ~ 16 000 individuals in 2013 to 223 hits in more than a million individuals in 2020, understanding the genetic architecture of this debilitating condition no longer appears to be an impossible task. The pressing question now is whether recently discovered variants describe the etiology of a single disease entity. There are a myriad of ways to measure and operationalize depression severity, and major depressive disorder (MDD) as defined in the DSM-5 can manifest in more than ten thousand ways based on symptom profiles alone. Variations in developmental timing, comorbidity, and environmental contexts across individuals and samples further add to the heterogeneity. With big data increasingly enabling genomic discovery in psychiatry, it is more timely than ever to explicitly disentangle genetic contributions to what is likely 'depressions' rather than depression. Here, we introduce three sources of heterogeneity: operationalization, manifestation, and etiology. We review recent efforts to identify depression subtypes using clinical and data-driven approaches, examine differences in genetic architecture of depression across contexts, and argue that heterogeneity in operationalizations of depression is likely a considerable source of inconsistency. Finally, we offer recommendations and considerations for the field going forward. AU - Cai, N. AU - Choi, K.W.* AU - Fried, E.I.* C1 - 59535 C2 - 48897 CY - Great Clarendon St, Oxford Ox2 6dp, England SP - R10-R18 TI - Reviewing the genetics of heterogeneity in depression: Operationalizations, manifestations, and etiologies. JO - Hum. Mol. Genet. VL - 29 IS - R1 PB - Oxford Univ Press PY - 2020 SN - 0964-6906 ER - TY - JOUR AB - Saliva, as a biofluid, is inexpensive and non-invasive to obtain, and provides a vital tool to investigate oral health and its interaction with systemic health conditions. There is growing interest in salivary biomarkers for systemic diseases, notably cardiovascular disease. Whereas hundreds of genetic loci have been shown to be involved in the regulation of blood metabolites, leading to significant insights into the pathogenesis of complex human diseases, little is known about the impact of host genetics on salivary metabolites. Here we report the first genome-wide association study exploring 476 salivary metabolites in 1419 subjects from the Twins UK cohort (discovery phase), followed by replication in the Study of Health in Pomerania (SHIP-2) cohort. A total of 14 distinct locus-metabolite associations were identified in the discovery phase, most of which were replicated in SHIP-2. While only a limited number of the loci that are known to regulate blood metabolites were also associated with salivary metabolites in our study, we identified several novel saliva-specific locus-metabolite associations, including associations for the AGMAT (with the metabolites 4-guanidinobutanoate and beta-guanidinopropanoate), ATP13A5 (with the metabolite creatinine) and DPYS (with the metabolites 3-ureidopropionate and 3-ureidoisobutyrate) loci. Our study suggests that there may be regulatory pathways of particular relevance to the salivary metabolome. In addition, some of our findings may have clinical significance, such as the utility of the pyrimidine (uracil) degradation metabolites in predicting 5-fluorouracil toxicity and the role of the agmatine pathway metabolites as biomarkers of oral health. AU - Nag, A.* AU - Kurushima, Y.* AU - Bowyer, R.C.E.* AU - Wells, P.M.* AU - Weiss, S.* AU - Pietzner, M.* AU - Kocher, T.* AU - Raffler, J. AU - Völker, U.* AU - Mangino, M.* AU - Spector, T.D.* AU - Milburn, M.V.* AU - Kastenmüller, G. AU - Mohney, R.P.* AU - Suhre, K.* AU - Menni, C.* AU - Steves, C.J.* C1 - 58802 C2 - 48347 CY - Great Clarendon St, Oxford Ox2 6dp, England SP - 864-875 TI - Genome-wide scan identifies novel genetic loci regulating salivary metabolite levels. JO - Hum. Mol. Genet. VL - 29 IS - 5 PB - Oxford Univ Press PY - 2020 SN - 0964-6906 ER - TY - JOUR AB - Although hundreds of genome-wide association studies-implicated loci have been reported for adult obesity-related traits, less is known about the genetics specific for early-onset obesity and with only a few studies conducted in non-European populations to date. Searching for additional genetic variants associated with childhood obesity, we performed a trans-ancestral meta-analysis of 30 studies consisting of up to 13005 cases (>= 95th percentile of body mass index (BMI) achieved 2-18 years old) and 15599 controls (consistently <50th percentile of BMI) of European, African, North/South American and East Asian ancestry. Suggestive loci were taken forward for replication in a sample of 1888 cases and 4689 controls from seven cohorts of European and North/South American ancestry. In addition to observing 18 previously implicated BMI or obesity loci, for both early and late onset, we uncovered one completely novel locus in this trans-ancestral analysis (nearest gene, METTL15). The variant was nominally associated with only the European subgroup analysis but had a consistent direction of effect in other ethnicities. We then utilized trans-ancestral Bayesian analysis to narrow down the location of the probable causal variant at each genome-wide significant signal. Of all the fine-mapped loci, we were able to narrow down the causative variant at four known loci to fewer than 10 single nucleotide polymorphisms (SNPs) (FAIM2, GNPDA2, MC4R and SEC16B loci). In conclusion, an ethnically diverse setting has enabled us to both identify an additional pediatric obesity locus and further fine-map existing loci. AU - Bradfield, J.P.* AU - Vogelezang, S.* AU - Felix, J.F.* AU - Chesi, A.* AU - Helgeland, Ø.* AU - Horikoshi, M.* AU - Karhunen, V.* AU - Lowry, E.* AU - Cousminer, D.L.* AU - Ahluwalia, T.S.* AU - Thiering, E. AU - Boh, E.T.* AU - Zafarmand, M.H.* AU - Wang, C.A.* AU - Joro, R.* AU - Chen, Z.* AU - Gauderman, W.J.* AU - Pitkänen, N.* AU - Parra, E.J.* AU - Fernández-Rhodes, L.* AU - Alyass, A.* AU - Monnereau, C.* AU - Curtin, J.A.* AU - Have, C.T.* AU - McCormack, S.E.* AU - Hollensted, M.* AU - Frithioff-Bøjsøe, C.* AU - Valladares-Salgado, A.* AU - Peralta-Romero, J.* AU - Standl, M. AU - Leinonen, J.T.* AU - Holm, J.C.* AU - Peters, T.* AU - Vioque, J.* AU - Vrijheid, M.* AU - Simpson, A.* AU - Custovic, A.* AU - Vaudel, M.* AU - Canouil, M.* AU - Lindi, V.* AU - Atalay, M.* AU - Kähönen, M.* AU - Raitakari, O.T.* AU - van Schaik, B.D.C.* AU - Berkowitz, R.I.* AU - Cole, S.A.* AU - Voruganti, V.S.* AU - Wang, Y.* AU - Highland, H.M.* AU - Comuzzie, A.G.* AU - Butte, N.F.* AU - Justice, A.E.* AU - Gahagan, S.* AU - Blanco, E.* AU - Lehtimäki, T.* AU - Lakka, T.A.* AU - Hebebrand, J.* AU - Bonnefond, A.* AU - Grarup, N.* AU - Froguel, P.* AU - Lyytikäinen, L.P.* AU - Cruz, M.* AU - Kobes, S.* AU - Hanson, R.L.* AU - Zemel, B.S.* AU - Hinney, A.* AU - Teo, K.K.* AU - Meyre, D.* AU - North, K.E.* AU - Gilliland, F.D.* AU - Bisgaard, H.* AU - Bustamante, M.* AU - Bonnelykke, K.* AU - Pennell, C.E.* AU - Rivadeneira, F.* AU - Uitterlinden, A.G.* AU - Baier, L.J.* AU - Vrijkotte, T.G.M.* AU - Heinrich, J. AU - Sørensen, T.I.A.* AU - Saw, S.M.* AU - Pedersen, O.* AU - Hansen, T.* AU - Eriksson, J.* AU - Widén, E.* AU - McCarthy, M.I.* AU - Njølstad, P.R.* AU - Power, C.* AU - Hyppönen, E.* AU - Sebert, S.* AU - Brown, C.D.* AU - Timpson, N.J.* AU - Johansson, S.* AU - Hakonarson, H.* AU - Jaddoe, V.W.V.* C1 - 56859 C2 - 47341 CY - Great Clarendon St, Oxford Ox2 6dp, England SP - 3327-3338 TI - A trans-ancestral meta-analysis of genome-wide association studies reveals loci associated with childhood obesity. JO - Hum. Mol. Genet. VL - 28 IS - 19 PB - Oxford Univ Press PY - 2019 SN - 0964-6906 ER - TY - JOUR AB - The effect of mitochondrial DNA (mtDNA) variation on peripheral blood transcriptomics in health and disease is not fully known. Sex-specific mitochondrially controlled gene expression patterns have been shown in Drosophila melanogaster but in humans, evidence is lacking. Functional variation in mtDNA may also have a role in the development of type 2 diabetes and its precursor state, i. e. prediabetes. We examined the associations between mitochondrial single-nucleotide polymorphisms (mtSNPs) and peripheral blood transcriptomics with a focus on sex-and prediabetes-specific effects. The genome-wide blood cell expression data of 19 637 probes, 199 deep-sequenced mtSNPs and nine haplogroups of 955 individuals from a population-based Young Finns Study cohort were used. Significant associations were identified with linear regression and analysis of covariance. The effects of sex and prediabetes on the associations between gene expression and mtSNPs were studied using random-effect meta-analysis. Our analysis identified 53 significant expression probe-mtSNP associations after Bonferroni correction, involving 7 genes and 31 mtSNPs. Eight probe-mtSNP signals remained independent after conditional analysis. In addition, five genes showed differential expression between haplogroups. The meta-analysis did not show any significant differences in linear model effect sizes between males and females but identified the association between the OASL gene and mtSNP C16294T to show prediabetes-specific effects. This study pinpoints new independent mtSNPs associated with peripheral blood transcriptomics and replicates six previously reported associations, providing further evidence of the mitochondrial genetic control of blood cell gene expression. In addition, we present evidence that prediabetes might lead to perturbations in mitochondrial control. AU - Laaksonen, J.* AU - Seppälä, I.* AU - Raitoharju, E.* AU - Mononen, N.* AU - Lyytikäinen, L.P.* AU - Waldenberger, M. AU - Illig, T.* AU - Lepistö, M.* AU - Almusa, H.* AU - Ellonen, P.* AU - Hutri-Kähönen, N.* AU - Juonala, M.* AU - Kähönen, M.* AU - Raitakari, O.* AU - Salonen, J.T.* AU - Lehtimäki, T.* C1 - 55937 C2 - 46674 CY - Great Clarendon St, Oxford Ox2 6dp, England SP - 1381-1391 TI - Discovery of mitochondrial DNA variants associated with genome-wide blood cell gene expression: A population-based mtDNA sequencing study. JO - Hum. Mol. Genet. VL - 28 IS - 8 PB - Oxford Univ Press PY - 2019 SN - 0964-6906 ER - TY - JOUR AB - Glycosylation is a common post-translational modification of proteins. Glycosylation is associated with a number of human diseases. Defining genetic factors altering glycosylation may provide a basis for novel approaches to diagnostic and pharmaceutical applications. Here we report a genome-wide association study of the human blood plasma N-glycome composition in up to 3811 people measured by Ultra Performance Liquid Chromatography (UPLC) technology. Starting with the 36 original traits measured by UPLC, we computed an additional 77 derived traits leading to a total of 113 glycan traits. We studied associations between these traits and genetic polymorphisms located on human autosomes. We discovered and replicated 12 loci. This allowed us to demonstrate an overlap in genetic control between total plasma protein and IgG glycosylation. The majority of revealed loci contained genes that encode enzymes directly involved in glycosylation (FUT3/FUT6, FUT8, B3GAT1, ST6GAL1, B4GALT1, ST3GAL4, MGAT3 and MGAT5) and a known regulator of plasma protein fucosylation (HNF1A). However, we also found loci that could possibly reflect other more complex aspects of glycosylation process. Functional genomic annotation suggested the role of several genes including DERL3, CHCHD10, TMEM121, IGH and IKZF1. The hypotheses we generated may serve as a starting point for further functional studies in this research area. AU - Sharapov, S.Z.* AU - Tsepilov, Y.A.* AU - Klaric, L.* AU - Mangino, M.* AU - Thareja, G.* AU - Shadrina, A.S.* AU - Simurina, M.* AU - Dagostino, C.* AU - Dmitrieva, J.* AU - Vilaj, M.* AU - Vučković, F.* AU - Pavić, T.* AU - Stambuk, J.* AU - Trbojević-Akmačić, I.* AU - Krištić, J.* AU - Simunovic, J.* AU - Momcilovic, A.* AU - Campbell, H.* AU - Doherty, M.* AU - Dunlop, M.G.* AU - Farrington, S.M.* AU - Pučić-Baković, M.* AU - Gieger, C. AU - Allegri, M.* AU - Louis, E.* AU - Georges, M.* AU - Suhre, K.* AU - Spector, T.* AU - Williams, F.M.K.* AU - Lauc, G.* AU - Aulchenko, Y.S.* C1 - 56209 C2 - 46903 CY - Great Clarendon St, Oxford Ox2 6dp, England SP - 2062-2077 TI - Defining the genetic control of human blood plasma N-glycome using genome-wide association study. JO - Hum. Mol. Genet. VL - 28 IS - 12 PB - Oxford Univ Press PY - 2019 SN - 0964-6906 ER - TY - JOUR AB - Elevated blood pressure (BP), a leading cause of global morbidity and mortality, is influenced by both genetic and lifestyle factors. Cigarette smoking is one such lifestyle factor. Across five ancestries, we performed a genome-wide gene-smoking interaction study of mean arterial pressure (MAP) and pulse pressure (PP) in 129 913 individuals in stage 1 and follow-up analysis in 480 178 additional individuals in stage 2. We report here 136 loci significantly associated with MAP and/or PP. Of these, 61 were previously published through main-effect analysis of BP traits, 37 were recently reported by us for systolic BP and/or diastolic BP through gene-smoking interaction analysis and 38 were newly identified (P < 5 x 10(-8), false discovery rate < 0.05). We also identified nine new signals near known loci. Of the 136 loci, 8 showed significant interaction with smoking status. They include CSMD1 previously reported for insulin resistance and BP in the spontaneously hypertensive rats. Many of the 38 new loci show biologic plausibility for a role in BP regulation. SLC26A7 encodes a chloride/bicarbonate exchanger expressed in the renal outer medullary collecting duct. AVPR1A is widely expressed, including in vascular smooth muscle cells, kidney, myocardium and brain. FHAD1 is a long non-coding RNA overexpressed in heart failure. TMEM51 was associated with contractile function in cardiomyocytes. CASP9 plays a central role in cardiomyocyte apoptosis. Identified only in African ancestry were 30 novel loci. Our findings highlight the value of multi-ancestry investigations, particularly in studies of interaction with lifestyle factors, where genomic and lifestyle differences may contribute to novel findings. AU - Sung, Y.J.* AU - de Las Fuentes, L.* AU - Winkler, T.W.* AU - Chasman, D.I.* AU - Bentley, A.R.* AU - Kraja, A.T.* AU - Ntalla, I.* AU - Warren, H.R.* AU - Guo, X.* AU - Schwander, K.* AU - Manning, A.K.* AU - Brown, M.R.* AU - Aschard, H.* AU - Feitosa, M.F.* AU - Franceschini, N.* AU - Lu, Y.* AU - Cheng, C.Y.* AU - Sim, X.* AU - Vojinovic, D.* AU - Marten, J.* AU - Musani, S.K.* AU - Kilpeläinen, T.O.* AU - Richard, M.A.* AU - Aslibekyan, S.* AU - Bartz, T.M.* AU - Dorajoo, R.* AU - Li, C.* AU - Liu, Y.* AU - Rankinen, T.* AU - Smith, A.V.* AU - Tajuddin, S.M.* AU - Tayo, B.O.* AU - Zhao, W.* AU - Zhou, Y.* AU - Matoba, N.* AU - Sofer, T.* AU - Alver, M.* AU - Amini, M.* AU - Boissel, M.* AU - Chai, J.F.* AU - Chen, X.* AU - Divers, J.* AU - Gandin, I.* AU - Gao, C.* AU - Giulianini, F.* AU - Goel, A.* AU - Harris, S.E.* AU - Hartwig, F.P.* AU - He, M.* AU - Horimoto, A.R.V.R.* AU - Hsu, F.C.* AU - Jackson, A.U.* AU - Kammerer, C.M.* AU - Kasturiratne, A.* AU - Komulainen, P. AU - Kühnel, B. AU - Leander, K.* AU - Lee, W.J.* AU - Lin, K.H.* AU - Luan, J.* AU - Lyytikäinen, L.P.* AU - McKenzie, C.A.* AU - Nelson, C.P.* AU - Noordam, R.* AU - Scott, R.A.* AU - Sheu, W.H.H.* AU - Stancáková, A.* AU - Takeuchi, F.* AU - van der Most, P.J.* AU - Varga, T.V.* AU - Waken, R.J.* AU - Wang, H.* AU - Wang, Y.* AU - Ware, E.B.* AU - Weiss, S.* AU - Wen, W.* AU - Yanek, L.R.* AU - Zhang, W.* AU - Zhao, J.H.* AU - Afaq, S.* AU - Alfred, T.* AU - Amin, N.* AU - Arking, D.E.* AU - Aung, T.* AU - Barr, R.G.* AU - Bielak, L.F.* AU - Boerwinkle, E.* AU - Bottinger, E.P.* AU - Braund, P.S.* AU - Brody, J.A.* AU - Broeckel, U.* AU - Cade, B.* AU - Campbell, A.* AU - Canouil, M.* AU - Chakravarti, A.* AU - Cocca, M.* AU - Collins, F.S.* AU - Connell, J.M.* AU - de Mutsert, R.* AU - de Silva, H.J.* AU - Dörr, M.* AU - Duan, Q.* AU - Eaton, C.B.* AU - Ehret, G.* AU - Evangelou, E.* AU - Faul, J.D.* AU - Forouhi, N.G.* AU - Franco, O.H.* AU - Friedlander, Y.* AU - Gao, H.* AU - Gigante, B.* AU - Gu, C.C.* AU - Gupta, P.* AU - Hagenaars, S.P.* AU - Harris, T.B.* AU - He, J.* AU - Heikkinen, S.* AU - Heng, C.K.* AU - Hofman, A.* AU - Howard, B.V.* AU - Hunt, S.C.* AU - Irvin, M.R.* AU - Jia, Y.* AU - Katsuya, T.* AU - Kaufman, J.* AU - Kerrison, N.D.* AU - Khor, C.C.* AU - Koh, W.P.* AU - Koistinen, H.A.* AU - Kooperberg, C.B.* AU - Krieger, J.E.* AU - Kubo, M.* AU - Kutalik, Z.* AU - Kuusisto, J.* AU - Lakka, T.A.* AU - Langefeld, C.D.* AU - Langenberg, C.* AU - Launer, L.J.* AU - Lee, J.H.* AU - Lehne, B.* AU - Levy, D.* AU - Lewis, C.E.* AU - Li, Y.* AU - Lim, S.H.* AU - Liu, C.T.* AU - Liu, J.* AU - Loh, M.* AU - Lohman, K.K.* AU - Louie, T.* AU - Mägi, R.* AU - Matsuda, K.* AU - Meitinger, T. AU - Metspalu, A.* AU - Milani, L.* AU - Momozawa, Y.* AU - Mosley, T.H.* AU - Nalls, M.A.* AU - Nasri, U.* AU - O'Connell, J.R.* AU - Ogunniyi, A.* AU - Palmas, W.R.* AU - Palmer, N.D.* AU - Pankow, J.S.* AU - Pedersen, N.L.* AU - Peters, A. AU - Peyser, P.A.* AU - Polasek, O.* AU - Porteous, D.* AU - Raitakari, O.T.* AU - Renström, F.* AU - Rice, T.K.* AU - Ridker, P.M.* AU - Robino, A.* AU - Robinson, J.G.* AU - Rose, L.M.* AU - Rudan, I.* AU - Sabanayagam, C.* AU - Salako, B.L.* AU - Sandow, K.* AU - Schmidt, C.O.* AU - Schreiner, P.J.* AU - Scott, W.R.* AU - Sever, P.* AU - Sims, M.* AU - Sitlani, C.M.* AU - Smith, B.H.* AU - Smith, J.A.* AU - Snieder, H.* AU - Starr, J.M.* AU - Strauch, K. AU - Tang, H.* AU - Taylor, K.D.* AU - Teo, Y.Y.* AU - Tham, Y.C.* AU - Uitterlinden, A.G.* AU - Waldenberger, M. AU - Wang, L.* AU - Wang, Y.X.* AU - Wei, W.B.* AU - Wilson, G.* AU - Wojczynski, M.K.* AU - Xiang, Y.B.* AU - Yao, J.* AU - Yuan, J.M.* AU - Zonderman, A.B.* AU - Becker, D.M.* AU - Boehnke, M.* AU - Bowden, D.W.* AU - Chambers, J.C.* AU - Chen, Y.I.* AU - Weir, D.R.* AU - de Faire, U.* AU - Deary, I.J.* AU - Esko, T.* AU - Farrall, M.* AU - Forrester, T.* AU - Freedman, B.I.* AU - Froguel, P.* AU - Gasparini, P.* AU - Gieger, C. AU - Horta, B.L.* AU - Hung, Y.J.* AU - Jonas, J.B.* AU - Kato, N.* AU - Kooner, J.S.* AU - Laakso, M.* AU - Lehtimäki, T.* AU - Liang, K.W.* AU - Magnusson, P.K.E.* AU - Oldehinkel, A.J.* AU - Pereira, A.C.* AU - Perls, T.* AU - Rauramaa, R.* AU - Redline, S.* AU - Rettig, R.* AU - Samani, N.J.* AU - Scott, J.* AU - Shu, X.O.* AU - van der Harst, P.* AU - Wagenknecht, L.E.* AU - Wareham, N.J.* AU - Watkins, H.* AU - Wickremasinghe, A.R.* AU - Wu, T.* AU - Kamatani, Y.* AU - Laurie, C.C.* AU - Bouchard, C.* AU - Cooper, R.S.* AU - Evans, M.K.* AU - Gudnason, V.* AU - Hixson, J.* AU - Kardia, S.L.R.* AU - Kritchevsky, S.B.* AU - Psaty, B.M.* AU - van Dam, R.M.* AU - Arnett, D.K.* AU - Mook-Kanamori, D.O.* AU - Fornage, M.* AU - Fox, E.R.* AU - Hayward, C.* AU - van Duijn, C.M.* AU - Tai, E.S.* AU - Wong, T.Y.* AU - Loos, R.J.F.* AU - Reiner, A.P.* AU - Rotimi, C.N.* AU - Bierut, L.J.* AU - Zhu, X.* AU - Cupples, L.A.* AU - Province, M.A.* AU - Rotter, J.I.* AU - Franks, P.W.* AU - Rice, K.* AU - Elliott, P.* AU - Caulfield, M.J.* AU - Gauderman, W.J.* AU - Munroe, P.B.* AU - Rao, D.C.* AU - Morrison, A.C.* C1 - 56162 C2 - 46858 CY - Great Clarendon St, Oxford Ox2 6dp, England SP - 2615-2633 TI - A multi-ancestry genome-wide study incorporating gene-smoking interactions identifies multiple new loci for pulse pressure and mean arterial pressure. JO - Hum. Mol. Genet. VL - 28 IS - 15 PB - Oxford Univ Press PY - 2019 SN - 0964-6906 ER - TY - JOUR AB - Mutations in the mitochondrially located protein CHCHD10 cause motoneuron disease by an unknown mechanism. In this study, we investigate the mutations p. R15L and p. G66V in comparison to wild-type CHCHD10 and the non-pathogenic variant p. P34S in vitro, in patient cells as well as in the vertebrate in vivo model zebrafish. We demonstrate a reduction of CHCHD10 protein levels in p. R15L and p. G66V mutant patient cells to approximately 50%. Quantitative real-time PCR revealed that expression of CHCHD10 p. R15L, but not of CHCHD10 p. G66V, is already abrogated at the mRNA level. Altered secondary structure and rapid protein degradation are observed with regard to the CHCHD10 p. G66V mutant. In contrast, no significant differences in expression, degradation rate or secondary structure of non-pathogenic CHCHD10 p. P34S are detected when compared with wild-type protein. Knockdown of CHCHD10 expression in zebrafish to about 50% causes motoneuron pathology, abnormal myofibrillar structure and motility deficits in vivo. Thus, our data show that the CHCHD10 mutations p. R15L and p. G66V cause motoneuron disease primarily based on haploinsufficiency of CHCHD10. AU - Brockmann, S.J.* AU - Freischmidt, A.* AU - Oeckl, P.* AU - Müller, K.* AU - Ponna, S.K.* AU - Helferich, A.M.* AU - Paone, C.* AU - Reinders, J.* AU - Kojer, K.* AU - Orth, M.* AU - Jokela, M.* AU - Auranen, M.* AU - Udd, B.* AU - Hermann, A.* AU - Danzer, K.M.* AU - Lichtner, P. AU - Walther, P.* AU - Ludolph, A.C.* AU - Andersen, P.M.* AU - Otto, M.* AU - Kursula, P.* AU - Just, S.* AU - Weishaupt, J.H.* C1 - 52699 C2 - 44115 SP - 706-715 TI - CHCHD10 mutations p. R15L and p. G66V cause motoneuron disease by haploinsufficiency. JO - Hum. Mol. Genet. VL - 27 IS - 4 PY - 2018 SN - 0964-6906 ER - TY - JOUR AB - Prior studies suggest dental caries traits in children and adolescents are partially heritable, but there has been no large-scale consortium genome-wide association study (GWAS) to date. We therefore performed GWAS for caries in participants aged 2.5-18.0 years from nine contributing centres. Phenotype definitions were created for the presence or absence of treated or untreated caries, stratified by primary and permanent dentition. All studies tested for association between caries and genotype dosage and the results were combined using fixed-effects meta-analysis. Analysis included up to 19 003 individuals (7530 affected) for primary teeth and 13 353 individuals (5875 affected) for permanent teeth. Evidence for association with caries status was observed at rs1594318-C for primary teeth [intronic within ALLC, odds ratio (OR) 0.85, effect allele frequency (EAF) 0.60, P 4.13e-8] and rs7738851-A (intronic within NEDD9, OR 1.28, EAF 0.85, P 1.63e-8) for permanent teeth. Consortiumwide estimated heritability of caries was low [h2 of 1% (95% CI: 0%: 7%) and 6% (95% CI 0%: 13%) for primary and permanent dentitions, respectively] compared with corresponding within-study estimates [h2 of 28% (95% CI: 9%: 48%) and 17% (95% CI: 2%: 31%)] or previously published estimates. This study was designed to identify common genetic variants with modest effects which are consistent across different populations. We found few single variants associated with caries status under these assumptions. Phenotypic heterogeneity between cohorts and limited statistical power will have contributed; these findings could also reflect complexity not captured by our study design, such as genetic effects which are conditional on environmental exposure. AU - Haworth, S.* AU - Shungin, D.* AU - van der Tas, J.T.* AU - Vucic, S.* AU - Medina-Gomez, C.* AU - Yakimov, V.* AU - Feenstra, B.* AU - Shaffer, J.R.* AU - Lee, M.K.* AU - Standl, M. AU - Thiering, E. AU - Wang, C.* AU - Bønnelykke, K.* AU - Waage, J.* AU - Eyrich Jessen, L.* AU - Nørrisgaard, P.E.* AU - Joro, R.* AU - Seppälä, I.* AU - Raitakari, O.* AU - Dudding, T.* AU - Grgic, O.* AU - Ongkosuwito, E.* AU - Vierola, A.* AU - Eloranta, A.M.* AU - West, N.X.* AU - Thomas, S.J.* AU - McNeil, D.W.* AU - Levy, S.M.* AU - Slayton, R.* AU - Nohr, E.A.* AU - Lehtimäki, T.* AU - Lakka, T.* AU - Bisgaard, H.* AU - Pennell, C.E.* AU - Kühnisch, J.* AU - Marazita, M.L.* AU - Melbye, M.* AU - Geller, F.* AU - Rivadeneira, F.* AU - Wolvius, E.B.* AU - Franks, P.W.* AU - Johansson, I.* AU - Timpson, N.J.* C1 - 53691 C2 - 44952 CY - Great Clarendon St, Oxford Ox2 6dp, England SP - 3113-3127 TI - Consortium-based genome-wide meta-analysis for childhood dental caries traits. JO - Hum. Mol. Genet. VL - 27 IS - 17 PB - Oxford Univ Press PY - 2018 SN - 0964-6906 ER - TY - JOUR AB - © The Author(s) 2017. Published by Oxford University Press. All rights reserved. Progranulin is a secreted protein with important functions in processes including immune and inflammatory response, metabolism and embryonic development. The present study aimed at identification of genetic factors determining progranulin concentrations. We conducted a genome-wide association meta-analysis for serum progranulin in three independent cohorts from Europe: Sorbs (N=848) and KORA (N=1628) from Germany and PPP-Botnia (N=335) from Finland (total N=2811). Single nucleotide polymorphisms (SNPs) associated with progranulin levels were replicated in two additional German cohorts: LIFE-Heart Study (Leipzig; N=967) and Metabolic Syndrome Berlin Potsdam (Berlin cohort; N=833). We measured mRNA expression of genes in peripheral blood mononuclear cells (PBMC) by micro-arrays and performed mRNA expression quantitative trait and expression-progranulin association studies to functionally substantiate identified loci. Finally, we conducted siRNA silencing experiments in vitro to validate potential candidate genes within the associated loci. Heritability of circulating progranulin levels was estimated at 31.8% and 26.1% in the Sorbs and LIFE-Heart cohort, respectively. SNPs at three loci reached study-wide significance (rs660240 in CELSR 2-PSRC1-MYBPHL-SORT1, rs4747197 in CDH23- PSAP and rs5848 in GRN) explaining 19.4%/15.0% of the variance and 61%/57% of total heritability in the Sorbs/LIFE-Heart Study. The strongest evidence for association was at rs660240 (P=5.75x10 -50 ), which was also associated with mRNA expression of PSRC1 in PBMC (P=1.51x10 -21 ). Psrc1 knockdown in murine preadipocytes led to a consecutive 30% reduction in progranulin secretion. In conclusion, the present meta-GWAS combined with mRNA expression identified three loci associated with progranulin and supports the role of PSRC1 in the regulation of progranulin secretion. AU - Tönjes, A.* AU - Scholz, M.* AU - Krüger, J.* AU - Krause, K.* AU - Schleinitz, D.* AU - Kirsten, H.* AU - Gebhardt, C.* AU - Marzi, C. AU - Grallert, H. AU - Ladenvall, C.* AU - Heyne, H.* AU - Laurila, E.* AU - Kriebel, J. AU - Meisinger, C. AU - Rathmann, W.* AU - Gieger, C. AU - Groop, L.* AU - Prokopenko, I.* AU - Isomaa, B.* AU - Beutner, F.* AU - Kratzsch, J.* AU - Fischer-Rosinsky, A.* AU - Pfeiffer, A.* AU - Krohn, K.* AU - Spranger, J.* AU - Thiery, J.* AU - Blüher, M.* AU - Stumvoll, M.* AU - Kovacs, P.* C1 - 52913 C2 - 44122 CY - Oxford SP - 546-558 TI - Genome-wide meta-analysis identifies novel determinants of circulating serum progranulin. JO - Hum. Mol. Genet. VL - 27 IS - 3 PB - Oxford Univ Press PY - 2018 SN - 0964-6906 ER - TY - JOUR AB - © The Author(s) 2018. To explore the genetic determinants of obesity and Type 2 diabetes (T2D), the German Center for Diabetes Research (DZD) conducted crossbreedings of the obese and diabetes-prone New Zealand Obese mouse strain with four different lean strains (B6, DBA, C3H, 129P2) that vary in their susceptibility to develop T2D. Genome-wide linkage analyses localized more than 290 quantitative trait loci (QTL) for obesity, 190 QTL for diabetes-related traits and 100 QTL for plasma metabolites in the outcross populations. A computational framework was developed that allowed to refine critical regions and to nominate a small number of candidate genes by integrating reciprocal haplotype mapping and transcriptome data. The efficiency of the complex procedure was demonstrated for one obesity QTL. The genomic interval of 35 Mb with 502 annotated candidate genes was narrowed down to six candidates. Accordingly, congenic mice retained the obesity phenotype owing to an interval that contains three of the six candidate genes. Among these the phospholipase PLA2G4A exhibited an elevated expression in adipose tissue of obese human subjects and is therefore a critical regulator of the obesity locus. Together, our broad and complex approach demonstrates that combined- and comparative-cross analysis exhibits improved mapping resolution and represents a valid tool for the identification of disease genes. AU - Vogel, H.* AU - Kamitz, A.* AU - Hallahan, N.* AU - Lebek, S.* AU - Schallschmidt, T.* AU - Jonas, W.* AU - Jaehnert, M.* AU - Gottmann, P.* AU - Zellner, L.* AU - Kanzleiter, T.* AU - Damen, M.* AU - Altenhofen, D.* AU - Burkhardt, R.* AU - Renner, S.* AU - Dahlhoff, M.* AU - Wolf, E.* AU - Müller, T.D. AU - Blueher, M.* AU - Joost, H.G.* AU - Chadt, A.* AU - Al-Hasani, H.* AU - Schuermann, A.* C1 - 54413 C2 - 45528 CY - Great Clarendon St, Oxford Ox2 6dp, England SP - 3099-3112 TI - A collective diabetes cross in combination with a computational framework to dissect the genetics of human obesity and Type 2 diabetes. JO - Hum. Mol. Genet. VL - 27 IS - 17 PB - Oxford Univ Press PY - 2018 SN - 0964-6906 ER - TY - JOUR AB - Epigenetic regulation of cellular function provides a mechanism for rapid organismal adaptation to changes in health, lifestyle and environment. Associations of cytosine-guanine di-nucleotide (CpG) methylation with clinical endpoints that overlap with metabolic phenotypes suggest a regulatory role for these CpG sites in the body's response to disease or environmental stress. We previously identified 20 CpG sites in an epigenome-wide association study (EWAS) with metabolomics that were also associated in recent EWASs with diabetes-, obesity-, and smoking-related endpoints. To elucidate the molecular pathways that connect these potentially regulatory CpG sites to the associated disease or lifestyle factors, we conducted a multi-omics association study including 2474 mass-spectrometry-based metabolites in plasma, urine and saliva, 225 NMR-based lipid and metabolite measures in blood, 1124 blood-circulating proteins using aptamer technology, 113 plasma protein N-glycans and 60 IgG-glyans, using 359 samples from the multi-ethnic Qatar Metabolomics Study on Diabetes (QMDiab). We report 138 multi-omics associations at these CpG sites, including diabetes biomarkers at the diabetes-associated TXNIP locus, and smoking-specific metabolites and proteins at multiple smoking-associated loci, including AHRR. Mendelian randomization suggests a causal effect of metabolite levels on methylation of obesity-associated CpG sites, i.e. of glycerophospholipid PC(O-36: 5), glycine and a very low-density lipoprotein (VLDL-A) on the methylation of the obesity-associated CpG loci DHCR24, MYO5C and CPT1A, respectively. Taken together, our study suggests that multi-omics-associated CpG methylation can provide functional read-outs for the underlying regulatory response mechanisms to disease or environmental insults. AU - Zaghlool, S.B.* AU - Mook-Kanamori, D.O.* AU - Kader, S.* AU - Stephan, N.* AU - Halama, A.* AU - Engelke, R.* AU - Sarwath, H.* AU - Al-Dous, E.K.* AU - Mohamoud, Y.A.* AU - Römisch-Margl, W. AU - Adamski, J. AU - Kastenmüller, G. AU - Friedrich, N.* AU - Visconti, A.* AU - Tsai, P.C.* AU - Spector, T.* AU - Bell, J.* AU - Falchi, M.* AU - Wahl, A. AU - Waldenberger, M. AU - Peters, A. AU - Gieger, C. AU - Pezer, M.* AU - Lauc, G.* AU - Graumann, J.* AU - Malek, J.A.* AU - Suhre, K.* C1 - 52721 C2 - 44352 CY - Oxford SP - 1106-1121 TI - Deep molecular phenotypes link complex disorders and physiological insult to CpG methylation. JO - Hum. Mol. Genet. VL - 27 IS - 6 PB - Oxford Univ Press PY - 2018 SN - 0964-6906 ER - TY - JOUR AB - De novo mutations in ATAD3A (ATPase family AAA-domain containing protein 3A) were recently found to cause a neurological syndrome with developmental delay, hypotonia, spasticity, optic atrophy, axonal neuropathy, and hypertrophic cardiomyopathy. Using whole-exome sequencing, we identified a dominantly inherited heterozygous variant c.1064G>A (p. G355D) in ATAD3A in a mother presenting with hereditary spastic paraplegia (HSP) and axonal neuropathy and her son with dyskinetic cerebral palsy, both with disease onset in childhood. HSP is a clinically and genetically heterogeneous disorder of the upper motor neurons. Symptoms beginning in early childhood may resemble spastic cerebral palsy. The function of ATAD3A, a mitochondrial inner membrane AAA ATPase, is yet undefined. AAA ATPases form hexameric rings, which are catalytically dependent on the co-operation of the subunits. The dominant-negative patient mutation affects the Walker A motif, which is responsible for ATP binding in the AAA module of ATAD3A, and we show that the recombinant mutant ATAD3A protein has a markedly reduced ATPase activity. We further show that overexpression of the mutant ATAD3A fragments the mitochondrial network and induces lysosome mass. Similarly, we observed altered dynamics of the mitochondrial network and increased lysosomes in patient fibroblasts and neurons derived through differentiation of patient-specific induced pluripotent stem cells. These alterations were verified in patient fibroblasts to associate with upregulated basal autophagy through mTOR inactivation, resembling starvation. Mutations in ATAD3A can thus be dominantly inherited and underlie variable neurological phenotypes, including HSP, with intrafamiliar variability. This finding extends the group of mitochondrial inner membrane AAA proteins associated with spasticity. AU - Cooper, H.M.* AU - Yang, Y.* AU - Ylikallio, E.* AU - Khairullin, R.* AU - Woldegebriel, R.* AU - Lin, K.L.* AU - Euro, L.* AU - Palin, E.* AU - Wolf, A. AU - Trokovic, R.* AU - Isohanni, P.* AU - Kaakkola, S.* AU - Auranen, M.* AU - Lönnqvist, T.* AU - Wanrooij, S.* AU - Tyynismaa, H.* C1 - 51171 C2 - 42735 CY - Oxford SP - 1432-1443 TI - ATPase-deficient mitochondrial inner membrane protein ATAD3a disturbs mitochondrial dynamics in dominant hereditary spastic paraplegia. JO - Hum. Mol. Genet. VL - 26 IS - 8 PB - Oxford Univ Press PY - 2017 SN - 0964-6906 ER - TY - JOUR AB - Psoriasis is a common inflammatory skin disorder for which multiple genetic susceptibility loci have been identified, but few resolved to specific functional variants. In this study we sought to identify common and rare psoriasis-associated gene-centric variation. Using exome arrays we genotyped four independent cohorts, totalling 11,861 psoriasis cases and 28,610 controls, aggregating the dataset through statistical meta-analysis. Single variant analysis detected a previously unreported risk locus at TNFSF15 (rs6478108; p = 1.50 × 10-8, OR = 1.10), and association of common protein-altering variants at 11 loci previously implicated in psoriasis susceptibility. We validate previous reports of protective low-frequency protein-altering variants within IFIH1 (encoding an innate antiviral receptor) and TYK2 (encoding a Janus kinase), in each case establishing a further series of protective rare variants (minor allele frequency < 0.01) via gene-wide aggregation testing (IFIH1: pburden = 2.53 × 10-7, OR = 0.707; TYK2: pburden = 6.17 × 10-4, OR = 0.744). Both genes play significant roles in type I interferon (IFN) production and signalling. Several of the protective rare and low-frequency variants in IFIH1 and TYK2 disrupt conserved protein domains, highlighting potential mechanisms through which their effect may be exerted. AU - Dand, N.* AU - Mucha, S.* AU - Tsoi, L.C.* AU - Mahil, S.K.* AU - Stuart, P.E.* AU - Arnold, A.* AU - Baurecht, H.* AU - Burden, A.D.* AU - Duffin, K.C.* AU - Chandran, V.* AU - Curtis, C.J.* AU - Das, S.* AU - Ellinghaus, D.* AU - Ellinghaus, E.* AU - Enerbäck, C.* AU - Esko, T.* AU - Gladman, D.D.* AU - Griffiths, C.E.M.* AU - Gudjonsson, J.E.* AU - Hoffman, P.* AU - Homuth, G.* AU - Hüffmeier, U.* AU - Krueger, G.G.* AU - Laudes, M.* AU - Lee, S.H.* AU - Lieb, W.* AU - Lim, H.W.* AU - Löhr, S.* AU - Mrowietz, U.* AU - Müller-Nurasyid, M. AU - Nöthen, M.* AU - Peters, A. AU - Rahman, P.* AU - Reis, A.* AU - Reynolds, N.J.* AU - Rodriguez, E.* AU - Schmidt, C.O.* AU - Spain, S.L.* AU - Strauch, K. AU - Tejasvi, T.* AU - Voorhees, J.J.* AU - Warren, R.B.* AU - Weichenthal, M.* AU - Weidinger, S.* AU - Zawistowski, M.* AU - Nair, R.P.* AU - Capon, F.* AU - Smith, C.H.* AU - Trembath, R.C.* AU - Abecasis, G.R.* AU - Elder, J.T.* AU - Franke, A.* AU - Simpson, M.A.* AU - Barker, J.N.* C1 - 52030 C2 - 43671 CY - Oxford SP - 4301-4313 TI - Exome-wide association study reveals novel psoriasis susceptibility locus at TNFSF15 and rare protective alleles in genes contributing to type I IFN signalling. JO - Hum. Mol. Genet. VL - 26 IS - 21 PB - Oxford Univ Press PY - 2017 SN - 0964-6906 ER - TY - JOUR AB - Resting heart rate is a heritable trait, and an increase in heart rate is associated with increased mortality risk. Genome-wide association study analyses have found loci associated with resting heart rate, at the time of our study these loci explained 0.9% of the variation. This study aims to discover new genetic loci associated with heart rate from Exome Chip meta-analyses. Heart rate was measured from either elecrtrocardiograms or pulse recordings. We meta-analysed heart rate association results from 104 452 European-ancestry individuals from 30 cohorts, genotyped using the Exome Chip. Twenty-four variants were selected for follow-up in an independent dataset (UK Biobank, N = 134 251). Conditional and gene-based testing was undertaken, and variants were investigated with bioinformatics methods. We discovered five novel heart rate loci, and one new independent low-frequency non-synonymous variant in an established heart rate locus (KIAA1755). Lead variants in four of the novel loci are non-synonymous variants in the genes C10orf71, DALDR3, TESK2 and SEC31B. The variant at SEC31B is significantly associated with SEC31B expression in heart and tibial nerve tissue. Further candidate genes were detected from long-range regulatory chromatin interactions in heart tissue (SCD, SLF2 and MAPK8). We observed significant enrichment in DNase I hypersensitive sites in fetal heart and lung. Moreover, enrichment was seen for the first time in human neuronal progenitor cells (derived from embryonic stem cells) and fetal muscle samples by including our novel variants. Our findings advance the knowledge of the genetic architecture of heart rate, and indicate new candidate genes for follow-up functional studies. AU - van den Berg, M.* AU - Warren, H.R.* AU - Cabrera, C.P.* AU - Verweij, N.* AU - Mifsud, B.* AU - Haessler, J.* AU - Bihlmeyer, N.A.* AU - Fu, Y.* AU - Weiss, S.* AU - Lin, H.J.* AU - Grarup, N.* AU - Li-Gao, R.* AU - Pistis, G.* AU - Shah, N.* AU - Brody, J.A.* AU - Müller-Nurasyid, M. AU - Lin, H.* AU - Mei, H.* AU - Smith, A.V.* AU - Lyytikäinen, L.-P.* AU - Hall, L.M.* AU - van Setten, J.* AU - Trompet, S.* AU - Prins, B.P.* AU - Isaacs, A.* AU - Radmanesh, F.* AU - Marten, J.* AU - Entwistle, A.* AU - Kors, J.A.* AU - Silva, C.T.* AU - Alonso, A.* AU - Bis, J.C.* AU - de Boer, R.A.* AU - de Haan, H.G.* AU - de Mutsert, R.* AU - Dedoussis, G.* AU - Dominiczak, A.F.* AU - Doney, A.S.F.* AU - Ellinor, P.T.* AU - Eppinga, R.N.* AU - Felix, S.B.* AU - Guo, X.* AU - Hagemeijer, Y.* AU - Hansen, T.* AU - Harris, T.B.* AU - Heckbert, S.R.* AU - Huang, P.L.* AU - Hwang, S.H.* AU - Kähönen, M.* AU - Kanters, J.K.* AU - Kolcic, I.* AU - Launer, L.J.* AU - Li, M.* AU - Yao, J.* AU - Linneberg, A.* AU - Liu, S.* AU - Macfarlane, P.W.* AU - Mangino, M.* AU - Morris, A.D.* AU - Mulas, A.* AU - Murray, A.D.* AU - Nelson, C.P.* AU - Orrù, M.* AU - Padmanabhan, S.* AU - Peters, A. AU - Porteous, D.J.* AU - Poulter, N.* AU - Psaty, B.M.* AU - Qi, L.* AU - Raitakari, O.T.* AU - Rivadeneira, F.* AU - Roselli, C.* AU - Rudan, I.* AU - Sattar, N.* AU - Sever, P.* AU - Sinner, M.F.* AU - Soliman, E.Z.* AU - Spector, T.D.* AU - Stanton, A.V.* AU - Stirrups, K.E.* AU - Taylor, K.D.* AU - Tobin, M.D.* AU - Uitterlinden, A.* AU - Vaartjes, I.* AU - Hoes, A.W. AU - van der Meer, P.* AU - Voelker, U.* AU - Waldenberger, M. AU - Xie, Z.* AU - Zoledziewska, M.* AU - Tinker, A.* AU - Polasek, O.* AU - Rosand, J.* AU - Jamshidi, Y.* AU - van Duijn, C.M.* AU - Zeggini, E.* AU - Jukema, J.W.* AU - Asselbergs, F.W.* AU - Samani, N.J.* AU - Lehtimäki, T.* AU - Gudnason, V.* AU - Wilson, J.B.* AU - Lubitz, S.A.* AU - Kaeaeb, S.* AU - Sotoodehnia, N.* AU - Caulfield, M.J.* AU - Palmer, C.N.A.* AU - Sanna, S.* AU - Mook-Kanamori, D.O.* AU - Deloukas, P.* AU - Pedersen, O.* AU - Rotter, J.I.* AU - Doerr, M.* AU - O'Donnell, C.J.* AU - Hayward, C.* AU - Arking, D.E.* AU - Kooperberg, C.* AU - van der Harst, P.* AU - Eijgelsheim, M.* AU - Stricker, B.H.* AU - Munroe, P.B.* C1 - 51372 C2 - 43004 CY - Oxford SP - 2346-2363 TI - Discovery of novel heart rate-associated loci using the Exome Chip. JO - Hum. Mol. Genet. VL - 26 IS - 12 PB - Oxford Univ Press PY - 2017 SN - 0964-6906 ER - TY - JOUR AB - More than a million childhood diarrhoeal episodes occur worldwide each year, and in developed countries a considerable part of them are caused by viral infections. In this study we aimed to search for genetic variants associated with diarrhoeal disease in young children by meta-analyzing genome-wide association studies, and to elucidate plausible biological mechanisms.The study was conducted in the context of the Early Genetics and Lifecourse Epidemiology (EAGLE) consortium. Data about diarrhoeal disease in two time windows (around one year of age and around two years of age) was obtained via parental questionnaires, doctor interviews or medical records. Standard quality control and statistical tests were applied to the 1000 Genomes imputed genotypic data.The meta-analysis (N=5,758) followed by replication (N=3,784) identified a genome-wide significant association between rs8111874 and diarrhoea at age one year. Conditional analysis suggested that the causal variant could be rs601338 (W154X) in the FUT2 gene. Children with the A allele, which results in a truncated FUT2 protein, had lower risk of diarrhoea. FUT2 participates in the production of histo-blood group antigens and has previously been implicated in the susceptibility to infections, including Rotavirus and Norovirus Gene-set enrichment analysis suggested pathways related to the histo-blood group antigen production, and the regulation of ion transport and blood pressure. Among others, the gastrointestinal tract, the immune and neuro-secretory systems were detected as relevant organs.In summary, this genome-wide association meta-analysis suggests the implication of the FUT2 gene in diarrhoeal disease in young children from the general population. AU - Bustamante, M.* AU - Standl, M. AU - Bassat, Q.* AU - Vilor-Tejedor, N.* AU - Medina-Gomez, C.* AU - Bonilla, C.* AU - Ahluwalia, T.S.* AU - Bacelis, J.* AU - Bradfield, J.P.* AU - Tiesler, C.M. AU - Rivadeneira, F.* AU - Ring, S.* AU - Vissing, N.H.* AU - Fink, N.R.* AU - Jugessur, A.* AU - Mentch, F.D.* AU - Ballester, F.* AU - Kriebel, J. AU - Kiefte-de Jong, J.C.* AU - Wolsk, H.M.* AU - Llop, S.* AU - Thiering, E. AU - Beth, S.A.* AU - Timpson, N.J.* AU - Andersen, J.* AU - Schulz, H. AU - Jaddoe, V.W.* AU - Evans, D.M* AU - Waage, J.* AU - Hakonarson, H.* AU - Grant, S.F.* AU - Jacobsson, B.* AU - Bønnelykke, K.* AU - Bisgaard, H.* AU - Smith, G.D.* AU - Moll, H.A.* AU - Heinrich, J. AU - Estivill, X.* AU - Sunyer, J.* C1 - 49327 C2 - 41760 CY - Oxford SP - 4127-4142 TI - A genome-wide association meta-analysis of diarrhoeal disease in young children identifies FUT2 locus and provides plausible biological pathways. JO - Hum. Mol. Genet. VL - 25 IS - 18 PB - Oxford Univ Press PY - 2016 SN - 0964-6906 ER - TY - JOUR AB - Caffeine is the most widely consumed psychoactive substance in the world and presents with wide interindividual variation in metabolism. This variation may modify potential adverse or beneficial effects of caffeine on health. We conducted a genome-wide association study (GWAS) of plasma caffeine, paraxanthine, theophylline, theobromine and paraxanthine/caffeine ratio among up to 9,876 individuals of European ancestry from six population-based studies. A single SNP at 6p23 (near CD83) and several SNPs at 7p21 (near AHR), 15q24 (near CYP1A2) and 19q13.2 (near CYP2A6) met GW-significance (P<5×10(-8)) and were associated with one or more metabolites. Variants at 7p21 and 15q24 associated with higher plasma caffeine and lower plasma paraxanthine/caffeine (slow caffeine metabolism) were previously associated with lower coffee and caffeine consumption behavior in GWAS. Variants at 19q13.2 associated with higher plasma paraxanthine/caffeine (slow paraxanthine metabolism) were also associated with lower coffee consumption in the UK Biobank (n=94,343, P<1.0 × (10-6)). Variants at 2p24 (in GCKR), 4q22 (in ABCG2) and 7q11.23 (near POR) that were previously associated with coffee consumption in GWAS were nominally associated with plasma caffeine or its metabolites. Taken together, we have identified genetic factors contributing to variation in caffeine metabolism and confirm an important modulating role of systemic caffeine levels in dietary caffeine consumption behavior. Moreover, candidate genes identified encode proteins with important clinical functions that extend beyond caffeine metabolism. AU - Cornelis, M.C.* AU - Kacprowski, T.* AU - Menni, C.* AU - Gustafsson, S.* AU - Pivin, E.* AU - Adamski, J. AU - Artati, A. AU - Eap, C.B.* AU - Ehret, G.* AU - Friedrich, N.* AU - Ganna, A.* AU - Guessous, I.* AU - Homuth, G.* AU - Lind, L.* AU - Magnusson, P.K.* AU - Mangino, M.* AU - Pedersen, N.L.* AU - Pietzner, M.* AU - Suhre, K. AU - Völzke, H.* AU - Bochud, M.* AU - Spector, T.D.* AU - Grabe, H.J.* AU - Ingelsson, E.* C1 - 49680 C2 - 40790 CY - Oxford SP - 5472-5482 TI - Genome-wide association study of caffeine metabolites provides new insights to caffeine metabolism and dietary caffeine-consumption behavior. JO - Hum. Mol. Genet. VL - 25 IS - 24 PB - Oxford Univ Press PY - 2016 SN - 0964-6906 ER - TY - JOUR AB - Genome-wide association studies have previously identified 23 genetic loci associated with circulating fibrinogen concentration. These studies used HapMap imputation and did not examine the X chromosome. 1000 Genomes imputation provides better coverage of uncommon variants, and includes indels. We conducted a genome-wide association analysis of 34 studies imputed to the 1000 Genomes Project reference panel and including ∼120,000 participants of European ancestry (95,806 participants with data on the X chromosome). Approximately 10.7 million SNPs and 1.2 million indels were examined. We identified 41 genome-wide significant fibrinogen loci of which 18 were newly identified. There were no genome-wide significant signals on the X chromosome. The lead variants of 5 significant loci were indels. We further identified 6 additional independent signals, including 3 rare variants, at two previously characterized loci: FGB and IRF1. Together the 41 loci explain 3% of the variance in plasma fibrinogen concentration. AU - de Vries, P.S.* AU - Chasman, D.I.* AU - Sabater-Lleal, M.* AU - Chen, M.H.* AU - Huffman, J.E.* AU - Steri, M.* AU - Tang, W.* AU - Teumer, A.* AU - Marioni, R.E.* AU - Grossmann, V.* AU - Hottenga, J.J.* AU - Trompet, S.* AU - Müller-Nurasyid, M. AU - Zhao, J.H.* AU - Brody, J.A.* AU - Kleber, M.E.* AU - Guo, X.* AU - Wang, J.J.* AU - Auer, P.L.* AU - Attia, J.R.* AU - Yanek, L.R.* AU - Ahluwalia, T.S.* AU - Lahti, J.* AU - Venturini, C.* AU - Tanaka, T.* AU - Bielak, L.F.* AU - Joshi, P.K.* AU - Rocanin-Arjo, A.* AU - Kolcic, I.* AU - Navarro, P.* AU - Rose, L.M.* AU - Oldmeadow, C.* AU - Riess, H. AU - Mazur, J.* AU - Basu, S.* AU - Goel, A.* AU - Yang, Q.* AU - Ghanbari, M.* AU - Willemsen, G.* AU - Rumley, A.* AU - Fiorillo, E.* AU - de Craen, A.J.* AU - Grotevendt, A.* AU - Scott, R.A.* AU - Taylor, K.D.* AU - Delgado, G.E.* AU - Yao, J.* AU - Kifley, A.* AU - Kooperberg, C.* AU - Qayyum, R.* AU - Lopez, L.M.* AU - Berentzen, T.L.* AU - Räikkönen, K.* AU - Mangino, M.* AU - Bandinelli, S.* AU - Peyser, P.A.* AU - Wild, S.* AU - Tregouet, D.A.* AU - Wright, A.F.* AU - Marten, J.* AU - Zemunik, T.* AU - Morrison, A.C.* AU - Sennblad, B.* AU - Tofler, G.* AU - de Maat, M.P.M.* AU - de Geus, E.J.* AU - Lowe, G.D.* AU - Zoledziewska, M.* AU - Sattar, N.* AU - Binder, H.* AU - Völker, U.* AU - Waldenberger, M. AU - Khaw, K.T.* AU - McKnight, B.* AU - Huang, J.* AU - Jenny, N.S.* AU - Holliday, E.G.* AU - Qi, L.* AU - McEvoy, M.G.* AU - Becker, D.M.* AU - Starr, J.M.* AU - Sarin, A.P.* AU - Hysi, P.G.* AU - Hernandez, D.G.* AU - Jhun, M.A.* AU - Campbell, H.* AU - Hamsten, A.* AU - Rivadeneira, F.* AU - McArdle, W.L.* AU - Slagboom, P.E.* AU - Zeller, T.* AU - Koenig, W.* AU - Psaty, B.M.* AU - Haritunians, T.* AU - Liu, J.* AU - Palotie, A.* AU - Uitterlinden, A.G.* AU - Stott, D.J.* AU - Hofman, A.* AU - Franco, O.H.* AU - Polasek, O.* AU - Rudan, I.* AU - Morange, P.E.* AU - Wilson, J.F.* AU - Kardia, S.L.* AU - Ferrucci, L.* AU - Spector, T.D.* AU - Eriksson, J.G.* AU - Hansen, T.* AU - Deary, I.J.* AU - Becker, L.C.* AU - Scott, R.J.* AU - Mitchell, P.* AU - Marz, W.* AU - Wareham, N.J.* AU - Peters, A. AU - Greinacher, A.* AU - Wild, P.S.* AU - Jukema, J.W.* AU - Boomsma, D.I.* AU - Hayward, C.* AU - Cucca, F.* AU - Tracy, R.* AU - Watkins, H.* AU - Reiner, A.P.* AU - Folsom, A.R.* AU - Ridker, P.M.* AU - O'Donnell, C.J.* AU - Smith, N.L.* AU - Strachan, D.P.* AU - Dehghan, A.* C1 - 47297 C2 - 40590 CY - Oxford SP - 358-370 TI - A meta-analysis of 120,246 individuals identifies 18 new loci for fibrinogen concentration. JO - Hum. Mol. Genet. VL - 25 IS - 2 PB - Oxford Univ Press PY - 2016 SN - 0964-6906 ER - TY - JOUR AB - A large number of genetic loci are associated with adult body mass index. However, the genetics of childhood body mass index are largely unknown. We performed a meta-analysis of genome-wide association studies of childhood body mass index, using sex- and age-adjusted standard deviation scores. We included 35,668 children from 20 studies in the discovery phase and 11,873 children from 13 studies in the replication phase. In total, 15 loci reached genome-wide-significance (P-value<5 x 10(-8)) in the joint discovery and replication analysis, of which 12 are previously identified loci in or close to ADCY3, GNPDA2, TMEM18, SEC16B, FAIM2, FTO, TFAP2B, TNNI3K, MC4R, GPR61, LMX1B and OLFM4 associated with adult body mass index or childhood obesity. We identified three novel loci: rs13253111 near ELP3, rs8092503 near RAB27B, and rs13387838 near ADAM23. Per additional risk allele, body mass index increased 0.04 Standard Deviation Score (SDS) (Standard Error (SE) 0.007), 0.05 SDS (SE 0.008) and 0.14 SDS (SE 0.025), for rs13253111, rs8092503, and rs13387838, respectively. A genetic risk score combining all 15 SNPs showed that each additional average risk allele was associated with a 0.073 SDS (SE 0.011, P-value=3.12 x 10(-10)) increase in childhood body mass index in a population of 1,955 children. This risk score explained 2% of the variance in childhood body mass index. This study highlights the shared genetic background between childhood and adult body mass index and adds three novel loci. These loci likely represent age-related differences in strength of the associations with body mass index. AU - Felix, J.F.* AU - Bradfield, J.P.* AU - Monnereau, C.* AU - van der Valk, R.J.* AU - Stergiakouli, E.* AU - Chesi, A.* AU - Gaillard, R.* AU - Feenstra, B.* AU - Thiering, E. AU - Kreiner-Møller, E.* AU - Mahajan, A.* AU - Pitkänen, N.* AU - Joro, R.* AU - Cavadino, A.* AU - Huikari, V.* AU - Franks, S.* AU - Groen-Blokhuis, M.M.* AU - Cousminer, D.L.* AU - Marsh, J.A.* AU - Lehtimäki, T.* AU - Curtin, J.A.* AU - Vioque, J.* AU - Ahluwalia, T.S.* AU - Myhre, R.* AU - Price, T.S.* AU - Vilor-Tejedor, N.* AU - Yengo, L.* AU - Grarup, N.* AU - Ntalla, I.* AU - Ang, W.* AU - Atalay, M.* AU - Bisgaard, H.* AU - Blakemore, A.I.* AU - Bonnefond, A.* AU - Carstensen, L.* AU - Eriksson, J.* AU - Flexeder, C. AU - Franke, L.* AU - Geller, F.* AU - Geserick, M.* AU - Hartikainen, A.L.* AU - Haworth, C.M.* AU - Hirschhorn, J.N.* AU - Hofman, A.* AU - Holm, J.C.* AU - Horikoshi, M.* AU - Hottenga, J.J.* AU - Huang, J.* AU - Kadarmideen, H.N.* AU - Kähönen, M.* AU - Kiess, W.* AU - Lakka, H.M.* AU - Lakka, T.A.* AU - Lewin, A.M.* AU - Liang, L.* AU - Lyytikäinen, L.-P.* AU - Ma, B.* AU - Magnus, P.* AU - McCormack, S.E.* AU - McMahon, G.* AU - Mentch, F.D.* AU - Middeldorp, C.M.* AU - Murray, C.S.* AU - Pahkala, K.* AU - Pers, T.H.* AU - Pfäffle, R.* AU - Postma, D.S.* AU - Power, C.* AU - Simpson, A.* AU - Sengpiel, V.* AU - Tiesler, C.M. AU - Torrent, M.* AU - Uitterlinden, A.G.* AU - van Meurs, J.B.* AU - Vinding, R.* AU - Waage, J.* AU - Wardle, J.* AU - Zeggini, E.* AU - Zemel, B.S.* AU - Dedoussis, G.V.* AU - Pedersen, O.* AU - Froguel, P.* AU - Sunyer, J.* AU - Plomin, R.* AU - Jacobsson, B.* AU - Hansen, T.* AU - Gonzalez, J.R.* AU - Custovic, A.* AU - Raitakari, O.T.* AU - Pennell, C.E.* AU - Widen, E.* AU - Boomsma, D.I.* AU - Koppelman, G.H.* AU - Sebert, S.* AU - Jarvelin, M.R.* AU - Hyppönen, E.* AU - McCarthy, M.I.* AU - Lindi, V.* AU - Harri, N.* AU - Körner, A.* AU - Bønnelykke, K.* AU - Heinrich, J. AU - Melbye, M.* AU - Rivadeneira, F.* AU - Hakonarson, H.* AU - Ring, S.M.* AU - Smith, G.D.* AU - Sørensen, T.I.* AU - Timpson, N.J.* AU - Grant, S.F.A.* AU - Jaddoe, V.W.* C1 - 47422 C2 - 40576 CY - Oxford SP - 389-403 TI - Genome-wide association analysis identifies three new susceptibility loci for childhood body mass index. JO - Hum. Mol. Genet. VL - 25 IS - 2 PB - Oxford Univ Press PY - 2016 SN - 0964-6906 ER - TY - JOUR AB - Cigarette smoking is a leading modifiable cause of death worldwide. We hypothesized that cigarette smoking induces extensive transcriptomic changes that lead to target-organ damage and smoking-related diseases. We performed a meta-analysis of transcriptome-wide gene expression using whole blood-derived RNA from 10,233 participants of European ancestry in six cohorts (including 1421 current and 3955 former smokers) to identify associations between smoking and altered gene expression levels. At a false discovery rate (FDR) <0.1, we identified 1270 differentially expressed genes in current vs. never smokers, and 39 genes in former vs. never smokers. Expression levels of 12 genes remained elevated up to 30 years after smoking cessation, suggesting that molecular consequence of smoking may persist for decades. Gene ontology analysis revealed enrichment of smoking-related genes for activation of platelets and lymphocytes, immune response, and apoptosis. Many of the top smoking-related differentially expressed genes, including LRRN3 and GPR15, have DNA methylation loci in promoter regions that were recently reported to be hypomethylated among smokers. By linking differential gene expression with smoking-related disease phenotypes, we demonstrated that stroke and pulmonary function show enrichment for smoking-related gene expression signatures. Mediation analysis revealed expression of several genes (e.g. ALAS2) to be putative mediators of the associations between smoking and inflammatory biomarkers (IL6 and C-reactive protein levels). Our transcriptomic study provides potential insights into the effects of cigarette smoking on gene expression in whole blood and their relations to smoking-related diseases. The results of such analyses may highlight attractive targets for treating or preventing smoking-related health effects. AU - Huan, T.* AU - Joehanes, R.* AU - Schurmann, C.* AU - Schramm, K. AU - Pilling, L.C.* AU - Peters, M.J.* AU - Mägi, R.* AU - DeMeo, D.* AU - O'Connor, G.T.* AU - Ferrucci, L.* AU - Teumer, A.* AU - Homuth, G.* AU - Biffar, R.* AU - Völker, U.* AU - Herder, C.* AU - Waldenberger, M. AU - Peters, A. AU - Zeilinger, S. AU - Metspalu, A.* AU - Hofman, A.* AU - Uitterlinden, A.G.* AU - Hernandez, D.G.* AU - Singleton, A.B.* AU - Bandinelli, S.* AU - Munson, P.J.* AU - Lin, H.* AU - Benjamin, E.J.* AU - Esko, T.* AU - Grabe, H.J.* AU - Prokisch, H. AU - van Meurs, J.B.* AU - Melzer, D.* AU - Levy, D.* C1 - 49349 C2 - 41765 CY - Oxford SP - 4611-4623 TI - A whole-blood transcriptome meta-analysis identifies gene expression signatures of cigarette smoking. JO - Hum. Mol. Genet. VL - 25 IS - 21 PB - Oxford Univ Press PY - 2016 SN - 0964-6906 ER - TY - JOUR AB - It has been hypothesised that low frequency (1-5% MAF) and rare (<1% MAF) variants with large effect sizes may contribute to the missing heritability in complex traits. Here we report an association analysis of lipid traits (total cholesterol, LDL-cholesterol, HDL-cholesterol triglycerides) in up to 27,312 individuals with a comprehensive set of low frequency coding variants (ExomeChip), combined with conditional analysis in the known lipid loci. No new locus reached genome-wide significance. However, we found a new lead variant in 26 known lipid association regions of which 16 were >1000 fold more significant than the previous sentinel variant and not in close LD (6 had MAF < 5%). Furthermore, conditional analysis revealed multiple independent signals (ranging from 1-5) in a third of the 98 lipid loci tested, including rare variants. Addition of our novel associations resulted in between 1.5-2.5 fold increase in the proportion of heritability explained for the different lipid traits. Our findings suggest that rare coding variants contribute to the genetic architecture of lipid traits. AU - Kanoni, S.* AU - Masca, N.G.D.* AU - Stirrups, K.E.* AU - Varga, T.V.* AU - Warren, H.R.* AU - Scott, R.A.* AU - Southam, L.* AU - Zhang, W.* AU - Yaghootkar, H.* AU - Müller-Nurasyid, M. AU - Couto Alves, A.* AU - Strawbridge, R.J.* AU - Lataniotis, L.* AU - Hashim, N.A.* AU - Besse, C.* AU - Boland, A.* AU - Braund, P.S.* AU - Connell, J.M.* AU - Dominiczak, A.* AU - Farmaki, A.-E.* AU - Franks, S.* AU - Grallert, H. AU - Jansson, J.H.* AU - Karaleftheri, M.* AU - Keinanen-Kiukaanniemi, S.* AU - Matchan, A.* AU - Pasko, D.* AU - Peters, A. AU - Poulter, N.* AU - Rayner, N.W.* AU - Renström, F.* AU - Rolandsson, O.* AU - Sabater-Lleal, M.* AU - Sennblad, B.* AU - Sever, P.* AU - Shields, D.* AU - Silveira, A.* AU - Stanton, A.V.* AU - Strauch, K. AU - Tomaszewski, M.* AU - Tsafantakis, E.* AU - Waldenberger, M. AU - Blakemore, A.I.* AU - Dedoussis, G.* AU - Escher, S.A.* AU - Kooner, J.S.* AU - McCarthy, M.I.* AU - Palmer, C.N.* AU - Hamsten, A.* AU - Caulfield, M.J.* AU - Frayling, T.M.* AU - Tobin, M.D.* AU - Jarvelin, M.R.* AU - Zeggini, E.* AU - Gieger, C. AU - Chambers, J.C.* AU - Wareham, N.J.* AU - Munroe, P.B.* AU - Franks, P.W.* AU - Samani, N.J.* AU - Deloukas, P.* C1 - 49185 C2 - 41704 CY - Oxford SP - 4094-4106 TI - Analysis with the exome array identifies multiple new independent variants in lipid loci. JO - Hum. Mol. Genet. VL - 25 IS - 18 PB - Oxford Univ Press PY - 2016 SN - 0964-6906 ER - TY - JOUR AB - Age-related maculopathy susceptibility 2 (ARMS2) is a small (11 kDa), primate-specific protein found in the extracellular matrix of the choroid layer in the eye. Variants in the corresponding genetic locus are highly associated with age-related macular degeneration (AMD), a leading cause of blindness in the elderly. So far, the physiological function of ARMS2 has remained enigmatic. It has been demonstrated that ARMS2 is a genuine secreted protein devoid of an N-terminal leader sequence, yet the mechanism how it exits the cells and enters the choroidal matrix is not understood.Here we show that ARMS2 efficiently recruits lectin chaperones from the cytosol and colocalizes with calnexin-positive and PDI-negative vesicle-like structures. Site-directed mutagenesis revealed critical elements for this interaction. Mutant forms proving unable to interact with the calnexin/calreticulin system failed secretion. On the other hand, blocking the ER to Golgi transport with BFA had no effect on ARMS2 secretion.As we found ARMS2 colocalizing with GRASP65, a marker for unconventional protein secretion, autophagic factors are likely to be key in its export. Interleukin-1ß (IL-1ß) is the most established example of secretory autophagy. Co-expression experiments, however, suggest that the transport of ARMS2 is different from that of IL-1ß. In conclusion, in this work we show that ARMS2 is externalized via an unconventional pathway bypassing Golgi. Its intracellular separation from the classical secretion pathway suggests that the maturation of the protein requires a specific biochemical niche and/or may be needed to impede the premature formation of unwanted protein-protein interactions. AU - Kortvely, E.* AU - Hauck, S.M. AU - Behler, J. AU - Ho, N.* AU - Ueffing, M.* C1 - 48777 C2 - 41320 CY - Oxford SP - 3143-3151 TI - The unconventional secretion of ARMS2. JO - Hum. Mol. Genet. VL - 25 IS - 15 PB - Oxford Univ Press PY - 2016 SN - 0964-6906 ER - TY - JOUR AB - Apolipoprotein A-IV (apoA-IV) is a major component of HDL and chylomicron particles and is involved in reverse cholesterol transport. It is an early marker of impaired renal function. We aimed to identify genetic loci associated with apoA-IV concentrations and to investigate relationships with known susceptibility loci for kidney function and lipids. A genome-wide association meta-analysis on apoA-IV concentrations was conducted in five population-based cohorts (n=13,813) followed by two additional replication studies (n=2,267) including approximately 10 M SNPs. Three independent SNPs from two genomic regions were significantly associated with apoA-IV concentrations: rs1729407 near APOA4 (p=6.77x10(-44)), rs5104 in APOA4 (p=1.79x10(-24)) and rs4241819 in KLKB1 (p=5.6x10(-14)). Additionally, a look-up of the replicated SNPs in downloadable GWAS meta-analysis results was performed on kidney function (defined by eGFR), HDL-cholesterol and triglycerides. From these three SNPs mentioned above, only rs1729407 showed an association with HDL-cholesterol (p=7.1x10(-07)). Moreover, weighted SNP-scores were built involving known susceptibility loci for the aforementioned traits (53, 70 and 38 SNPs, respectively) and were associated with apoA-IV concentrations. This analysis revealed a significant and inverse association for kidney function with apoA-IV concentrations (p=5.5x10(-05)). Furthermore, an increase of triglyceride-increasing alleles was found to decrease apoA-IV concentrations (p=0.0078). In summary, we identified two independent SNPs located in or next the APOA4 gene and one SNP in KLKB1 The association of KLKB1 with apoA-IV suggests an involvement of apoA-IV in renal metabolism and/or an interaction within HDL particles. Analyses of SNP-scores indicate potential causal effects of kidney function and by lesser extent triglycerides on apoA-IV concentrations. AU - Lamina, C.* AU - Friedel, S.* AU - Coassin, S.* AU - Rueedi, R.* AU - Yousri, N.A.* AU - Seppälä, I.* AU - Gieger, C. AU - Schönherr, S.* AU - Forer, L.* AU - Erhart, G.* AU - Kollerits, B.* AU - Marques-Vidal, P.* AU - Ried, J.S. AU - Waeber, G.* AU - Bergmann, S.* AU - Dähnhardt, D.* AU - Stöckl, A.* AU - Kiechl, S.* AU - Raitakari, O.T.* AU - Kähönen, M.* AU - Willeit, J.* AU - Kedenko, L.* AU - Paulweber, B.* AU - Peters, A. AU - Meitinger, T. AU - Strauch, K. AU - Lehtimäki, T.* AU - Hunt, S.C.* AU - Vollenweider, P.* AU - Kronenberg, F.* C1 - 49085 C2 - 41647 CY - Oxford SP - 3635-3646 TI - A genome-wide association meta-analysis on apolipoprotein A-IV concentrations. JO - Hum. Mol. Genet. VL - 25 IS - 16 PB - Oxford Univ Press PY - 2016 SN - 0964-6906 ER - TY - JOUR AB - Although the role of complete gene inactivation by two loss-of-function mutations inherited in trans is well-established in recessive Mendelian diseases, we have not yet explored how such gene knockouts (KOs) could influence complex human phenotypes. Here, we developed a statistical framework to test the association between gene KOs and quantitative human traits. Our method is flexible, publicly available, and compatible with common genotype format files (e.g. PLINK and vcf). We characterized gene KOs in 4,498 participants from the NHLBI Exome Sequence Project (ESP) sequenced at high coverage (>100X), 1,976 French Canadians from the Montreal Heart Institute Biobank sequenced at low coverage (5.7X), and >100,000 participants from the GIANT Consortium genotyped on an exome array. We tested associations between gene KOs and three anthropometric traits: body mass index (BMI), height and BMI-adjusted waist-to-hip ratio (WHR). Despite our large sample size and multiple datasets available, we could not detect robust associations between specific gene KOs and quantitative anthropometric traits. Our results highlight several limitations and challenges for future gene KO studies in humans, in particular when there is no prior knowledge on the phenotypes that might be affected by the tested gene KOs. They also suggest that gene KOs identified with current DNA sequencing methodologies probably do not strongly influence normal variation in BMI, height, and WHR in the general human population. AU - Lessard, S.* AU - Manning, A.K.* AU - Low-Kam, C.* AU - Auer, P.L.* AU - Giri, A.K.* AU - Graff, M.* AU - Schurmann, C.* AU - Yaghootkar, H.* AU - Luan, J.* AU - Esko, T.* AU - Karaderi, T.* AU - NHLBI Grand Opportunity Exome Sequencing Project (*) AU - GoT2D Consortium (Gieger, C. AU - Grallert, H. AU - Hrabě de Angelis, M. AU - Huth, C. AU - Meisinger, C. AU - Meitinger, T. AU - Müller-Nurasyid, M. AU - Peters, A. AU - Rathmann, W. AU - Ried, J.S. AU - Strauch, K. AU - Strom, T.M.) AU - T2D-GENES Consortium (*) AU - Bottinger, E.P.* AU - Lu, Y.* AU - Carlson, C.S.* AU - Caulfield, M.* AU - Dubé, M.-P.* AU - Jackson, R.D.* AU - Kooperberg, C.* AU - McKnight, B.* AU - Mongrain, I.* AU - Peters, U.* AU - Reiner, A.P.* AU - Rhainds, D.* AU - Sotoodehnia, N.* AU - Hirschhorn, J.N.* AU - Scott, R.* AU - Munroe, P.B.* AU - Frayling, T.M.* AU - Loos, R.J.* AU - North, K.E.* AU - Edwards, T.L.* AU - Tardif, J.-C.* AU - Lindgren, C.M.* AU - Lettre, G.* AU - GIANT Consortium (Albrecht, E. AU - Heid, I.M. AU - Illig, T. AU - Klopp, N. AU - Lichtner, P. AU - Waldenberger, M. AU - Wichmann, H.-E.) C1 - 48004 C2 - 39836 CY - Oxford SP - 2082-2092 TI - Testing the role of predicted gene knockouts in human anthropometric trait variation. JO - Hum. Mol. Genet. VL - 25 IS - 10 PB - Oxford Univ Press PY - 2016 SN - 0964-6906 ER - TY - JOUR AB - Oligogenic inheritance implies a role for several genetic factors in disease etiology. We studied oligogenic inheritance in Parkinson's (PD) by assessing the potential burden of additional rare variants in established Mendelian genes and/or GBA, in individuals with and without a primary pathogenic genetic cause in two large independent cohorts totaling 7,900 PD cases and 6,166 controls. An excess (≥30%) of cases with a recognised primary genetic cause had ≥1 additional rare variants in Mendelian PD genes, as compared with no known mutation PD cases (17%) and unaffected controls (16%), supporting our hypothesis. Carriers of additional Mendelian gene variants have younger ages at onset (AAO). The effect of additional Mendelian variants in LRRK2 G2019S mutation carriers, of which ATP13A2 variation is particularly common, may account for some of the variation in penetrance. About 10% of No Known Mutation-PD cases harbour a rare GBA variant compared to known pathogenic mutation PD cases (8%) and controls (5%), with carriers having earlier AAOs. Together, the data suggest that the oligogenic inheritance of rare Mendelian variants may be important in patient with a primary pathogenic cause, whereas GBA increases risk across all forms of PD. This study highlights the potential genetic complexity of Mendelian PD. The identification of potential modifying variants provides new insights into disease mechanisms by potentially separating relevant from benign variants and by the interaction between genes in specific pathways. In the future this may be relevant to genetic testing and counselling of patients with PD and their families. AU - Lubbe, S.J.* AU - Escott-Price, V.* AU - Gibbs, J.R.* AU - Nalls, M.A.* AU - Bras, J.* AU - Price, T.R.* AU - Nicolas, A.* AU - Jansen, I.E.* AU - Mok, K.Y.* AU - Pittman, A.M.* AU - Tomkins, J.E.* AU - Lewis, P.A.* AU - Noyce, A.J.* AU - Lesage, S.* AU - Sharma, M.* AU - Schiff, E.R.* AU - Levine, A.P.* AU - Brice, A.* AU - Gasser, T.* AU - Hardy, J.* AU - Heutink, P.* AU - Wood, N.W.* AU - Singleton, A.B.* AU - Williams, N.M.* AU - Morris, H.R.* AU - International Parkinson's Disease Genomics Consortium (IPDGC) (Illig, T. AU - Lichtner, P.) C1 - 52951 C2 - 44256 SP - 5483-5489 TI - Additional rare variant analysis in Parkinson's disease cases with and without known pathogenic mutations: Evidence for oligogenic inheritance. JO - Hum. Mol. Genet. VL - 25 IS - 24 PY - 2016 SN - 0964-6906 ER - TY - JOUR AB - DNA methylation based biomarkers of aging are highly correlated with actual age. Departures of methylation-estimated age from actual age can be used to define epigenetic measures of child development or age acceleration in adults. Very little is known about genetic or environmental determinants of these epigenetic measures of aging. We obtained DNA methylation profiles using Infinium HumanMethylation450 BeadChips across five time points in 1018 mother-child pairs from the Avon Longitudinal Study of Parents and Children. Using the Horvath age estimation method, we calculated epigenetic age for these samples. Age acceleration (AA) was defined as the residuals from regressing epigenetic age on actual age. AA was tested for associations with cross-sectional clinical variables in children. We identified associations between AA and sex, birth weight, birth by caesarean section and several maternal characteristics in pregnancy, namely smoking, weight, BMI, selenium and cholesterol level. Offspring of non-drinkers had higher AA on average but this difference appeared to resolve during childhood. The associations between sex, birth weight and AA found in ARIES were replicated in an independent cohort (GOYA). In children, epigenetic AA measures are associated with several clinically relevant variables, and early life exposures appear to be associated with changes in AA during adolescence. Further research into epigenetic aging, including the use of causal inference methods, is required to better our understanding of aging. AU - Simpkin, A.J.* AU - Hemani, G.* AU - Suderman, M.J.* AU - Gaunt, T.R.* AU - Lyttleton, O.* AU - McArdle, W.L.* AU - Ring, S.M.* AU - Sharp, G.C.* AU - Tilling, K.* AU - Horvath, S.* AU - Kunze, S. AU - Peters, A. AU - Waldenberger, M. AU - Ward-Caviness, C.K. AU - Nohr, E.A.* AU - Sørensen, T.I.* AU - Relton, C.L.* AU - Smith, G.D.* C1 - 47222 C2 - 39182 CY - Oxford SP - 191-201 TI - Prenatal and early life influences on epigenetic age in children: A study of mother-offspring pairs from two cohort studies. JO - Hum. Mol. Genet. VL - 25 IS - 1 PB - Oxford Univ Press PY - 2016 SN - 0964-6906 ER - TY - JOUR AB - Cone photoreceptor cell death as it occurs in certain hereditary retinal diseases is devastating, with the affected patients suffering from a loss of accurate and color vision. Regrettably, these hereditary cone diseases are still untreatable to date. Thus, the identification of substances able to block or restrain cone cell death is of primary importance. We studied the neuroprotective effects of a histone deacetylase inhibitor, Trichostatin A (TSA), in a mouse model of inherited, primary cone degeneration (cpfl1). We show that HDAC inhibition protects cpfl1 cones in vitro, in retinal explant cultures. More importantly, in vivo, a single intravitreal TSA injection significantly increased cone survival for up to 16 days post-injection. In addition, the abnormal, incomplete cone migration pattern in the cpfl1 retina was significantly improved by HDAC inhibition. These findings suggest a crucial role for HDAC activity in primary cone degeneration and highlight a new avenue for future therapy developments for cone dystrophies and retinal diseases associated with impaired cone migration. AU - Trifunovic, D.* AU - Arango-González, B.* AU - Comitato, A.* AU - Barth, M.* AU - del Amo, E.M.* AU - Kulkarni, M.* AU - Sahaboglu, A.* AU - Hauck, S.M. AU - Urtti, A.* AU - Arsenijevic, Y.* AU - Ueffing, M.* AU - Marigo, V.* AU - Paquet-Durand, F.* C1 - 49280 C2 - 41728 CY - Oxford SP - 4462-4472 TI - HDAC inhibition in the cpfl1 mouse protects degenerating cone photoreceptors in vivo. JO - Hum. Mol. Genet. VL - 25 IS - 20 PB - Oxford Univ Press PY - 2016 SN - 0964-6906 ER - TY - JOUR AB - Inactivating mutations of the TSC1/TSC2 complex (TSC1/2) cause tuberous sclerosis (TSC), a hereditary syndrome with neurological symptoms and benign hamartoma tumors in the brain. Since TSC effectors are largely unknown in the human brain, TSC patient cortical tubers were used to uncover hyperphosphorylation unique to TSC primary astrocytes, the cell type affected in the brain. We found abnormal hyperphosphorylation of catenin delta-1 S268, which was reversible by mTOR-specific inhibitors. In contrast, in three metastatic astrocytoma cell lines, S268 was under phosphorylated, suggesting S268 phosphorylation controls metastasis. TSC astrocytes appeared epithelial (i.e., tightly adherent, less motile, and epithelial (E)-cadherin positive), whereas wild-type astrocytes were mesenchymal (i.e., E-cadherin negative and highly motile). Despite their epithelial phenotype, TSC astrocytes outgrew contact inhibition, and monolayers sporadically generated tuberous foci, a phenotype blocked by the mTOR inhibitor, Torin1. Also, mTOR-regulated phosphokinase C epsilon (PKCe) activity induced phosphorylation of catenin delta-1 S268, which in turn mediated cell-cell adhesion in astrocytes. The mTOR-dependent, epithelial phenotype of TSC astrocytes suggests TSC1/2 and mTOR tune the phosphorylation level of catenin delta-1 by controlling PKCe activity, thereby regulating the mesenchymal-epithelial-transition (MET). Thus, some forms of TSC could be treated with PKCe inhibitors, while metastasis of astrocytomas might be blocked by PKCe stimulators. AU - Yang, J.* AU - Bassuk, A.G.* AU - Merl-Pham, J. AU - Hsu, C.W.* AU - Colgan, D.F.* AU - Li, X.* AU - Au, K.S.* AU - Zhang, L.* AU - Smemo, S.* AU - Justus, S.* AU - Nagahama, Y.* AU - Grossbach, A.J.* AU - Howard, M.A.* AU - Kawasaki, H.* AU - Feldstein, N.A.* AU - Dobyns, W.B.* AU - Northrup, H.* AU - Hauck, S.M. AU - Ueffing, M.* AU - Mahajan, V.B.* AU - Tsang, S.H.* C1 - 49266 C2 - 41716 CY - Oxford SP - 4201-4210 TI - Catenin delta-1 (CTNND1) phosphorylation controls the mesenchymal to epithelial transition in astrocytic tumors. JO - Hum. Mol. Genet. VL - 25 IS - 19 PB - Oxford Univ Press PY - 2016 SN - 0964-6906 ER - TY - JOUR AB - Somatic copy number alterations (SCNAs) play an important role in carcinogenesis. However, the impact of genomic architecture on the global patterns of SCNAs in cancer genomes remains elusive. In this work we conducted multiple linear regression (MLR) analyses of the pooled SCNA data from The Cancer Genome Atlas Pan-Cancer project. We performed MLR analyses for 11 individual cancer types and three different kinds of SCNAs - amplifications and deletions, telomere-bound and interstitial SCNAs, and local SCNAs. Our MLR model explains more than 30% of the pooled SCNA breakpoint variation, with the explanatory power ranging from 13% to 32% for different cancer types and SCNA types. In addition to confirming previously identified features (e.g., Long interspersed element-1 (L1) and SINEs) we also identified several novel informative features, including distance to telomere, distance to centromere, and low complexity repeats. The results of the MLR analyses were additionally confirmed on an independent SCNA data set obtained from the COSMIC database. Using a rare event logistic regression model and an extremely randomized tree classifier we revealed that genomic features are informative for defining common SCNA breakpoint hotspots. Our findings shed light on the molecular mechanisms of SCNA generation in cancer. AU - Zhang, Y.* AU - Xu, H.* AU - Frishman, D. C1 - 47649 C2 - 40678 CY - Oxford SP - 1019-1030 TI - Genomic determinants of somatic copy number alterations across human cancers. JO - Hum. Mol. Genet. VL - 25 IS - 5 PB - Oxford Univ Press PY - 2016 SN - 0964-6906 ER - TY - JOUR AB - Colobomatous macrophthalmia with microcornea syndrome (MACOM, OMIM 602499) is an autosomal dominantly inherited malformation of the eye which is characterized by microcornea with increased axial length, coloboma of the iris and of the optic disc, and severe myopia. We performed whole-exome sequencing (WES) in two affected individuals from the 2p23-p16-linked MACOM family, which includes 13 affected individuals in three generations. Since no shared novel variation was found on the linked haplotype, we performed CNV analysis by comparing the coverage of all exons in the WES data sets of the two patients with the coverage of 26 control exomes. We identified a heterozygous deletion predicted to span 22 kb including exons 14 to 17 of CRIM1 (cysteine rich transmembrane BMP regulator 1). qPCR analysis confirmed the deletion, which was present in 11 affected individuals. Split-read analysis of WES data followed by breakpoint-PCR and Sanger sequencing determined both breakpoints flanked by a 4-bp microhomology (CTTG). In the mouse, Crim1 is a growth-factor-binding protein with pleiotropic roles in the development of multiple organs, including the eye. To investigate the role of Crim1 during eye development in mice, we crossed a Crim1(flox) mouse line with the Ap2α-cre mouse line, which expresses Cre in the head surface ectoderm. Strikingly, we observed alterations of eye development in homozygous mice leading to severe anatomical and morphological changes overlapping with the anomalies observed in MACOM patients. Taken together, these findings identify CRIM1 as the causative gene for MACOM syndrome and emphasize the importance of CRIM1 in eye development. AU - Beleggia, F.* AU - Li, Y.* AU - Fan, J.* AU - Elcioğlu, N.H.* AU - Toker, E.* AU - Wieland, T. AU - Maumenee, I.H.* AU - Akarsu, N.A.* AU - Meitinger, T. AU - Strom, T.M. AU - Lang, R.* AU - Wollnik, B.* C1 - 43059 C2 - 35990 CY - Oxford SP - 2267-2273 TI - CRIM1 haploinsufficiency causes defects in eye development in human and mouse. JO - Hum. Mol. Genet. VL - 24 IS - 8 PB - Oxford Univ Press PY - 2015 SN - 0964-6906 ER - TY - JOUR AB - Chronic respiratory disorders are important contributors to the global burden of disease. Genome-wide association studies (GWASs) of lung function measures have identified several trait-associated loci, but explain only a modest portion of the phenotypic variability. We postulated that integrating pathway-based methods with GWASs of pulmonary function and airflow obstruction would identify a broader repertoire of genes and processes influencing these traits. We performed two independent GWASs of lung function and applied gene set enrichment analysis to one of the studies and validated the results using the second GWAS. We identified 131 significantly enriched gene sets associated with lung function and clustered them into larger biological modules involved in diverse processes including development, immunity, cell signaling, proliferation and arachidonic acid. We found that enrichment of gene sets was not driven by GWAS-significant variants or loci, but instead by those with less stringent association P-values. Next, we applied pathway enrichment analysis to a meta-analyzed GWAS of airflow obstruction. We identified several biologic modules that functionally overlapped with those associated with pulmonary function. However, differences were also noted, including enrichment of extracellular matrix (ECM) processes specifically in the airflow obstruction study. Network analysis of the ECM module implicated a candidate gene, matrix metalloproteinase 10 (MMP10), as a putative disease target. We used a knockout mouse model to functionally validate MMP10's role in influencing lung's susceptibility to cigarette smoke-induced emphysema. By integrating pathway analysis with population-based genomics, we unraveled biologic processes underlying pulmonary function traits and identified a candidate gene for obstructive lung disease. AU - Gharib, S.A.* AU - Loth, D.W.* AU - Soler Artigas, M.* AU - Birkland, T.P.* AU - Wilk, J.B.* AU - Wain, L.V.* AU - Brody, J.A.* AU - Obeidat, M.* AU - Hancock, D.B.* AU - Tang, W.* AU - Rawal, R. AU - Boezen, H.M.* AU - Imboden, M.* AU - Huffman, J.E.* AU - Lahousse, L.* AU - Alves, A.C.* AU - Manichaikul, A.* AU - Hui, J.* AU - Morrison, A.C.* AU - Ramasamy, A.* AU - Smith, A.V.* AU - Gudnason, V.* AU - Surakka, I.* AU - Vitart, V.* AU - Evans, D.M* AU - Strachan, D.P.* AU - Deary, I.J.* AU - Hofman, A.* AU - Gläser, S.* AU - Wilson, J.F.* AU - North, K.E.* AU - Zhao, J.H.* AU - Heckbert, S.R.* AU - Jarvis, D.L.* AU - Probst-Hensch, N.* AU - Schulz, H. AU - Barr, R.G.* AU - Jarvelin, M.R.* AU - O'Connor, G.T.* AU - Kähönen, M.* AU - Cassano, P.A.* AU - Hysi, P.G.* AU - Dupuis, J.* AU - Hayward, C.* AU - Psaty, B.M.* AU - Hall, I.P.* AU - Parks, W.C.* AU - Tobin, M.D.* AU - London, S.J.* AU - CHARGE Consortium (Gieger, C. AU - Illig, T. AU - Meisinger, C. AU - Prokisch, H. AU - Wichmann, H.-E.) AU - SpiroMeta Consortium (*) C1 - 46947 C2 - 39077 SP - 6836-6848 TI - Integrative pathway genomics of lung function and airflow obstruction. JO - Hum. Mol. Genet. VL - 24 IS - 23 PY - 2015 SN - 0964-6906 ER - TY - JOUR AB - Genome-wide association studies with metabolomics (mGWAS) identify genetically influenced metabotypes (GIMs), their ensemble defining the heritable part of every human's metabolic individuality. Knowledge of genetic variation in metabolism has many applications of biomedical and pharmaceutical interest, including the functional understanding of genetic associations with clinical endpoints, design of strategies to correct dysregulations in metabolic disorders, and the identification of genetic effect modifiers of metabolic disease biomarkers. Furthermore, it has been shown that GIMs provide testable hypotheses for functional genomics and metabolomics and for the identification of novel gene functions and metabolite identities. mGWAS with growing sample sizes and increasingly complex metabolic trait panels are being conducted, allowing for more comprehensive and systems based downstream analyses. The generated large data sets of genetic associations can now be mined by the biomedical research community and provide valuable resources for hypothesis driven studies. In this review, we provide a brief summary of the key aspects of mGWAS, followed by an update of recently published mGWAS. We then discuss new approaches of integrating and exploring mGWAS results and finish by presenting selected applications of GIMs in recent studies. AU - Kastenmüller, G. AU - Raffler, J. AU - Gieger, C. AU - Suhre, K. C1 - 46301 C2 - 37491 SP - R93-R101 TI - Genetics of human metabolism: An update. JO - Hum. Mol. Genet. VL - 24 IS - R1 PY - 2015 SN - 0964-6906 ER - TY - JOUR AB - Despite the many advances in our understanding of the genetic basis of Mendelian forms of Parkinson's disease (PD), a large number of early-onset cases still remain to be explained. Many of these cases, present with a form of disease that is identical to that underlined by genetic causes, but do not have mutations in any of the currently known disease-causing genes. Here, we hypothesized that de novo mutations may account for a proportion of these early-onset, sporadic cases. We performed exome sequencing in full parent-child trios where the proband presents with typical PD to unequivocally identify de novo mutations. This approach allows us to test all genes in the genome in an unbiased manner. We have identified and confirmed 20 coding de novo mutations in 21 trios. We have used publicly available population genetic data to compare variant frequencies and our independent in-house dataset of exome sequencing in PD (with over 1200 cases) to identify additional variants in the same genes. Of the genes identified to carry de novo mutations, PTEN, VAPB and ASNA1 are supported by various sources of data to be involved in PD. We show that these genes are reported to be within a protein-protein interaction network with PD genes and that they contain additional rare, case-specific, mutations in our independent cohort of PD cases. Our results support the involvement of these three genes in PD and suggest that testing for de novo mutations in sporadic disease may aid in the identification of novel disease-causing genes. AU - Kun-Rodrigues, C.* AU - Ganos, C.* AU - Guerreiro, R.* AU - Schneider, S.A.* AU - Schulte, C.* AU - Lesage, S.* AU - Darwent, L.* AU - Holmans, P.* AU - Singleton, A.* AU - International Parkinson's Disease Genomics Consortium (IPDGC) (Illig, T. AU - Lichtner, P.) AU - Bhatia, K.* AU - Bras, J.* C1 - 46933 C2 - 39065 SP - 6711-6720 TI - A systematic screening to identify de novo mutations causing sporadic early-onset Parkinson's disease. JO - Hum. Mol. Genet. VL - 24 IS - 23 PY - 2015 SN - 0964-6906 ER - TY - JOUR AB - Mitochondrial dysfunction is a well-established cause of sensorineural deafness, but the pathophysiological events are poorly understood. Non-syndromic deafness and predisposition to aminoglycoside-induced deafness can be caused by specific mutations in the 12S rRNA gene of mtDNA and are thus maternally inherited traits. The pathophysiology induced by mtDNA mutations has traditionally been attributed to deficient oxidative phosphorylation, which causes energy crisis with functional impairment of multiple cellular processes. In contrast, it was recently reported that signaling induced by 'hypermethylation' of two conserved adenosines of 12S rRNA in the mitoribosome is of key pathophysiological importance in sensorineural deafness. In support for this concept, it was reported that overexpression of the essential mitochondrial methyltransferase TFB1M in the mouse was sufficient to induce mitoribosomal hypermethylation and deafness. At variance with this model, we show here that 12S rRNA is near fully methylated in vivo in the mouse and thus cannot be further methylated to any significant extent. Furthermore, bacterial artificial chromosome transgenic mice overexpressing TFB1M have no increase of 12S rRNA methylation levels and hear normally. We thus conclude that therapies directed against mitoribosomal methylation are unlikely to be beneficial to patients with sensorineural hearing loss or other types of mitochondrial disease. AU - Lee, S.* AU - Rose, S.* AU - Metodiev, M.D.* AU - Becker, L. AU - Vernaleken, A. AU - Klopstock, T.* AU - Gailus-Durner, V. AU - Fuchs, H. AU - Hrabě de Angelis, M. AU - Douthwaite, S.* AU - Larsson, N.-G.* C1 - 47093 C2 - 39170 SP - 7286-7294 TI - Overexpression of the mitochondrial methyltransferase TFB1M in the mouse does not impact mitoribosomal methylation status of hearing. JO - Hum. Mol. Genet. VL - 24 IS - 25 PY - 2015 SN - 0964-6906 ER - TY - JOUR AB - Polymorphisms rs6232 and rs6234/rs6235 in PCSK1 have been associated with extreme obesity [e.g. body mass index (BMI) ≥ 40 kg/m(2)], but their contribution to common obesity (BMI ≥ 30 kg/m(2)) and BMI variation in a multi-ethnic context is unclear. To fill this gap, we collected phenotypic and genetic data in up to 331 175 individuals from diverse ethnic groups. This process involved a systematic review of the literature in PubMed, Web of Science, Embase and the NIH GWAS catalog complemented by data extraction from pre-existing GWAS or custom-arrays in consortia and single studies. We employed recently developed global meta-analytic random-effects methods to calculate summary odds ratios (OR) and 95% confidence intervals (CIs) or beta estimates and standard errors (SE) for the obesity status and BMI analyses, respectively. Significant associations were found with binary obesity status for rs6232 (OR = 1.15, 95% CI 1.06-1.24, P = 6.08 × 10(-6)) and rs6234/rs6235 (OR = 1.07, 95% CI 1.04-1.10, P = 3.00 × 10(-7)). Similarly, significant associations were found with continuous BMI for rs6232 (β = 0.03, 95% CI 0.00-0.07; P = 0.047) and rs6234/rs6235 (β = 0.02, 95% CI 0.00-0.03; P = 5.57 × 10(-4)). Ethnicity, age and study ascertainment significantly modulated the association of PCSK1 polymorphisms with obesity. In summary, we demonstrate evidence that common gene variation in PCSK1 contributes to BMI variation and susceptibility to common obesity in the largest known meta-analysis published to date in genetic epidemiology. AU - Nead, K.T.* AU - Li, A.* AU - Wehner, M.R.* AU - Neupane, B.* AU - Gustafsson, S.* AU - Butterworth, A.S.* AU - Engert, J.C.* AU - Davis, A.D.* AU - Hegele, R.A.* AU - Miller, R.* AU - den Hoed, M.* AU - Khaw, K.T.* AU - Kilpeläinen, T.O.* AU - Wareham, N.J.* AU - Edwards, T.L.* AU - Hallmans, G.* AU - Varga, T.V.* AU - Kardia, S.L.* AU - Smith, J.A.* AU - Zhao, W.* AU - Faul, J.D.* AU - Weir, D.R.* AU - Mi, J.* AU - Xi, B.* AU - Quinteros, S.C.* AU - Cooper, C.* AU - Sayer, A.A.* AU - Jameson, K.* AU - Grøntved, A.* AU - Fornage, M.* AU - Sidney, S.* AU - Hanis, C.L.* AU - Highland, H.M.* AU - Häring, H.-U. AU - Heni, M.* AU - Lasky-Su, J.* AU - Weiss, S.T.* AU - Gerhard, G.S.* AU - Still, C.* AU - Melka, M.M.* AU - Pausova, Z.* AU - Paus, T.* AU - Grant, S.F.A.* AU - Hakonarson, H.* AU - Price, R.A.* AU - Wang, K.* AU - Scherag, A.* AU - Hebebrand, J.* AU - Hinney, A.* AU - BIoBank Japan (Meyre, D.*) AU - GIANT Consortium (Albrecht, E. AU - Gieger, C. AU - Grallert, H. AU - Heid, I.M. AU - Illig, T. AU - Müller-Nurasyid, M. AU - Peters, A. AU - Thorand, B. AU - Wichmann, H.-E.) AU - Franks, P.W.* AU - Frayling, T.M.* AU - McCarthy, M.I.* AU - Hirschhorn, J.N.* AU - Loos, R.J.* AU - Ingelsson, E.* AU - Gerstein, H.C.* AU - Yusuf, S.* AU - Beyene, J.* AU - Anand, S.S.* C1 - 44384 C2 - 36816 CY - Oxford SP - 3582-3594 TI - Contribution of common non-synonymous variants in PCSK1 to body mass index variation and risk of obesity: A systematic review and meta-analysis with evidence from up to 331 175 individuals. JO - Hum. Mol. Genet. VL - 24 IS - 12 PB - Oxford Univ Press PY - 2015 SN - 0964-6906 ER - TY - JOUR AB - Results from genome-wide association studies (GWAS) have indicated that strong single-gene effects are the exception, not the rule, for most diseases. We assessed the joint effects of germline genetic variations through a pathway-based approach that considers the tissue-specific contexts of GWAS findings. From GWAS meta-analyses of lung cancer (12 160 cases/16 838 controls), breast cancer (15 748 cases/18 084 controls) and prostate cancer (14 160 cases/12 724 controls) in individuals of European ancestry, we determined the tissue-specific interaction networks of proteins expressed from genes that are likely to be affected by disease-associated variants. Reactome pathways exhibiting enrichment of proteins from each network were compared across the cancers. Our results show that pathways associated with all three cancers tend to be broad cellular processes required for growth and survival. Significant examples include the nerve growth factor (P = 7.86 × 10(-33)), epidermal growth factor (P = 1.18 × 10(-31)) and fibroblast growth factor (P = 2.47 × 10(-31)) signaling pathways. However, within these shared pathways, the genes that influence risk largely differ by cancer. Pathways found to be unique for a single cancer focus on more specific cellular functions, such as interleukin signaling in lung cancer (P = 1.69 × 10(-15)), apoptosis initiation by Bad in breast cancer (P = 3.14 × 10(-9)) and cellular responses to hypoxia in prostate cancer (P = 2.14 × 10(-9)). We present the largest comparative cross-cancer pathway analysis of GWAS to date. Our approach can also be applied to the study of inherited mechanisms underlying risk across multiple diseases in general. AU - Qian, D.C.* AU - Byun, J.* AU - Han, Y.* AU - Greene, C.S.* AU - Field, J.K.* AU - Hung, R.J.* AU - Brhane, Y.* AU - McLaughlin, J.R.* AU - Fehringer, G.* AU - Landi, M.T.* AU - Rosenberger, A.* AU - Bickeböller, H.* AU - Malhotra, J.* AU - Risch, A.* AU - Heinrich, J. AU - Hunter, D.J.* AU - Henderson, B.E.* AU - Haiman, C.A.* AU - Schumacher, F.R.* AU - Eeles, R.A.* AU - Easton, D.F.* AU - Seminara, D.* AU - Amos, C.I.* C1 - 47442 C2 - 39330 SP - 7406-7420 TI - Identification of shared and unique susceptibility pathways among cancers of the lung, breast, and prostate from genome-wide association studies and tissue-specific protein interactions. JO - Hum. Mol. Genet. VL - 24 IS - 25 PY - 2015 SN - 0964-6906 ER - TY - JOUR AB - Endometriosis is a chronic inflammatory condition in women that results in pelvic pain and subfertility, and has been associated with decreased body mass index (BMI). Genetic variants contributing to the heritable component have started to emerge from genome-wide association studies (GWAS), although the majority remain unknown. Unexpectedly, we observed an intergenic locus on 7p15.2 that was genome-wide significantly associated with both endometriosis and fat distribution (waist-to-hip ratio adjusted for BMI; WHRadjBMI) in an independent meta-GWAS of European ancestry individuals. This led us to investigate the potential overlap in genetic variants underlying the aetiology of endometriosis, WHRadjBMI and BMI using GWAS data. Our analyses demonstrated significant enrichment of common variants between fat distribution and endometriosis (P = 3.7 × 10(-3)), which was stronger when we restricted the investigation to more severe (Stage B) cases (P = 4.5 × 10(-4)). However, no genetic enrichment was observed between endometriosis and BMI (P = 0.79). In addition to 7p15.2, we identify four more variants with statistically significant evidence of involvement in both endometriosis and WHRadjBMI (in/near KIFAP3, CAB39L, WNT4, GRB14); two of these, KIFAP3 and CAB39L, are novel associations for both traits. KIFAP3, WNT4 and 7p15.2 are associated with the WNT signalling pathway; formal pathway analysis confirmed a statistically significant (P = 6.41 × 10(-4)) overrepresentation of shared associations in developmental processes/WNT signalling between the two traits. Our results demonstrate an example of potential biological pleiotropy that was hitherto unknown, and represent an opportunity for functional follow-up of loci and further cross-phenotype comparisons to assess how fat distribution and endometriosis pathogenesis research fields can inform each other. AU - Rahmioglu, N.* AU - MacGregor, S.* AU - Drong, A.W.* AU - Hedman, A.K.* AU - Harris, H.R.* AU - Randall, J.C.* AU - Prokopenko, I.* AU - International Endogene Consortium (IEC) (Zondervan, K.T.*) AU - GIANT Consortium (Albrecht, E. AU - Gieger, C. AU - Grallert, H. AU - Heid, I.M. AU - Illig, T. AU - Müller-Nurasyid, M. AU - Peters, A. AU - Thorand, B. AU - Wichmann, H.-E.) AU - Nyholt, D.R.* AU - Morris, A.P.* AU - Montgomery, G.W.* AU - Missmer, S.A.* AU - Lindgren, C.M.* C1 - 43808 C2 - 36534 CY - Oxford SP - 1185-1199 TI - Genome-wide enrichment analysis between endometriosis and obesity-related traits reveals novel susceptibility loci. JO - Hum. Mol. Genet. VL - 24 IS - 4 PB - Oxford Univ Press PY - 2015 SN - 0964-6906 ER - TY - JOUR AB - Acyl-CoA dehydrogenase 9 (ACAD9) is an assembly factor for mitochondrial respiratory chain Complex I (CI), and ACAD9 mutations are recognized as a frequent cause of CI deficiency. ACAD9 also retains enzyme ACAD activity for long-chain fatty acids in vitro but the biological relevance of this function remains controversial partly because of the tissue-specificity of ACAD9 expression: high in liver and neurons and minimal in skin fibroblasts. In this study, we hypothesized that this enzymatic ACAD activity is required for full fatty acid oxidation capacity in cells expressing high levels of ACAD9, and that loss of this function is important in determining phenotype in ACAD9 deficient patients. First, we confirmed that HEK293 cells express ACAD9 abundantly. Then, we showed that ACAD9 knockout in HEK293 cells affected long-chain fatty acid oxidation along with Cl, both of which were rescued by wild-type ACAD9. Further, we evaluated whether the loss of ACAD9 enzymatic fatty acid oxidation affects clinical severity in patients with ACAD9 mutations. The effects on ACAD activity of 16 ACAD9 mutations identified in 24 patients were evaluated using a prokaryotic expression system. We showed that there was a significant inverse correlation between residual enzyme ACAD activity and phenotypic severity of ACAD9 deficient patients. These results provide evidence that in cells where it is strongly expressed, ACAD9 plays a physiological role in fatty acid oxidation which contributes to the severity of the phenotype in ACAD9 deficient patients. Accordingly, treatment of ACAD9 patients should aim at counteracting both CI and fatty acid oxidation dysfunctions. AU - Schiff, M.* AU - Haberberger, B. AU - Xia, C.P.* AU - Mohsen, A.W.* AU - Goetzman, E.S.* AU - Wang, Y.* AU - Uppala, R.* AU - Zhang, Y.* AU - Karunanidhi, A.* AU - Prabhu, D.* AU - Alharbi, H.* AU - Prochownik, E.V.* AU - Haack, T.B. AU - Häberle, J.* AU - Munnich, A.* AU - Rotig, A.* AU - Taylor, R.W.* AU - Nicholls, R.D.* AU - Kim, J.J.* AU - Prokisch, H. AU - Vockley, J.* C1 - 43518 C2 - 36653 CY - Oxford SP - 3238-3247 TI - Complex I assembly function and fatty acid oxidation enzyme activity of ACAD9 both contribute to disease severity in ACAD9 deficiency. JO - Hum. Mol. Genet. VL - 24 IS - 11 PB - Oxford Univ Press PY - 2015 SN - 0964-6906 ER - TY - JOUR AB - DNA methylation may contribute to the etiology of complex genetic disorders through its impact on genome integrity and gene expression; it is modulated by DNA-sequence variants, named methylation quantitative-trait loci (meQTLs). Most meQTLs influence methylation of a few CpG dinucleotides within short genomic regions (<3kb). Here we identified a layered genetic control of DNA methylation at numerous CpGs across a long 300-kb genomic region. This control involved a single long-range meQTL and multiple local meQTLs. The long-range meQTL explained up to 75% of variance in methylation of CpGs located over extended areas of the 300-kb region. The meQTL was identified in four samples (p=2.8x10(-17), p=3.1x10(-31), 4.0x10(-71), 5.2x10(-199)), comprising a total of 2,796 individuals. The long-range meQTL was strongly associated not only with DNA methylation but also with mRNA expression of several genes within the 300-kb region (p=7.1x10(-18)-1.0x10(-123)). The associations of the meQTL with gene expression became attenuated when adjusted for DNA methylation (causal inference test: p=2.4×10(-13)-7.1×10(-20)), indicating coordinated regulation of DNA methylation and gene expression. Further, the long-range meQTL was found to be in linkage disequilibrium with the most replicated locus of multiple sclerosis, a disease affecting primarily the brain white matter. In middle-aged adults free of the disease, we observed that the risk allele was associated with subtle structural properties of the brain white matter found in multiple sclerosis (p=0.02). In summary, we identified a long-range meQTL that controls methylation and expression of several genes and may be involved in increasing brain vulnerability to multiple sclerosis. AU - Shin, J.T.* AU - Bourdon, C.* AU - Bernard, M.* AU - Wilson, M.* AU - Reischl, E. AU - Waldenberger, M. AU - Ruggeri, B.* AU - Schumann, G.* AU - Desrivières, S.* AU - Leemans, A.* AU - Abrahamowicz, M.* AU - Leonard, G.T.* AU - Richer, L.* AU - Bouchard, L.* AU - Gaudet, D.* AU - Paus, T.* AU - Pausova, Z.* C1 - 46442 C2 - 37536 SP - 5733-5745 TI - Layered genetic control of DNA methylation and gene expression: A locus of multiple sclerosis in healthy individuals. JO - Hum. Mol. Genet. VL - 24 IS - 20 PY - 2015 SN - 0964-6906 ER - TY - JOUR AB - Mitochondrial diseases often exhibit tissue-specific pathologies, but this phenomenon is poorly understood. Here we present regulation of mitochondrial translation by the Mitochondrial Translation Optimization Factor 1, MTO1, as a novel player in this scenario. We demonstrate that MTO1 mediates tRNA modification and controls mitochondrial translation rate in a highly tissue specific manner associated with tissue-specific OXPHOS defects. Activation of mitochondrial proteases, aberrant translation products, as well as defects in OXPHOS complex assembly observed in MTO1 KO mice further imply that MTO1 impacts translation fidelity. In our mouse model, MTO1-related OXPHOS deficiency can be bypassed by feeding a ketogenic diet. This therapeutic intervention is independent of the MTO1-mediated tRNA modification and involves balancing of mitochondrial and cellular secondary stress responses. Our results thereby establish mammalian MTO1 as a novel factor in the tissue-specific regulation of OXPHOS and fine-tuning of mitochondrial translation accuracy. AU - Tischner, C.* AU - Hofer, A.* AU - Wulff, V.* AU - Stepek, J.* AU - Dumitru, I.* AU - Becker, L. AU - Haack, T.B. AU - Kremer, L.S. AU - Datta, A.N.* AU - Sperl, W.* AU - Floß, T. AU - Wurst, W. AU - Chrzanowska-Lightowlers, Z.M.* AU - Hrabě de Angelis, M. AU - Klopstock, T. AU - Prokisch, H. AU - Wenz, T.* C1 - 43023 C2 - 35928 CY - Oxford SP - 2247-2266 TI - MTO1 mediates tissue-specificity of OXPHOS defects via tRNA modification and translation optimization, which can be bypassed by dietary intervention. JO - Hum. Mol. Genet. VL - 24 IS - 8 PB - Oxford Univ Press PY - 2015 SN - 0964-6906 ER - TY - JOUR AB - Common genetic variants have been identified for adult height, but not much is known about the genetics of skeletal growth in early life. To identify common genetic variants that influence fetal skeletal growth, we meta-analyzed 22 genome-wide association studies (Stage 1; N=28,459). We identified 7 independent top SNPs (P<1x10(-6)) for birth length, of which 3 were novel and 4 were in or near loci known to be associated with adult height (LCORL, PTCH1, GPR126 and HMGA2). The 3 novel SNPs were followed-up in 9 replication studies (Stage 2; N=11,995), with rs905938 in DC-STAMP domain containing 2 (DCST2) genome-wide significantly associated with birth length in a joint analysis (Stages 1+2; ß=0.046, S.E.=0.008, P=2.46x10(-8), explained variance=0.05%). Rs905938 was also associated with infant length (N=28,228; P=5.54x10(-4)) and adult height (N=127,513; P=1.45x10(-5)). DCST2 is a DC-STAMP-like protein family member and DC-STAMP is an osteoclast cell-fusion regulator. Polygenic scores based on 180 SNPs previously associated with human adult stature explained 0.13% of variance in birth length. The same SNPs explained 2.95% of the variance of infant length. Of the 180 known adult height loci, 11 were genome-wide significantly associated with infant length (SF3B4, LCORL, SPAG17, C6orf173, PTCH1, GDF5, ZNFX1, HHIP, ACAN, HLA locus and HMGA2). This study highlights that common variation in DCST2 influences variation in early growth and adult height. AU - van der Valk, R.J.* AU - Kreiner-Møller, E.* AU - Kooijman, M.N.* AU - Guxens, M.* AU - Stergiakouli, E.* AU - Saaf, A.* AU - Bradfield, J.P.* AU - Geller, F.* AU - Hayes, M.G.* AU - Cousminer, D.L.* AU - Körner, A.* AU - Thiering, E. AU - Curtin, J.A.* AU - Myhre, R.* AU - Huikari, V.* AU - Joro, R.* AU - Kerkhof, M.* AU - Warrington, N.M.* AU - Pitkänen, N.* AU - Ntalla, I.* AU - Horikoshi, M.* AU - Veijola, R.* AU - Freathy, R.M.* AU - Teo, Y.Y.* AU - Barton, S.J.* AU - Evans, D.M* AU - Kemp, J.P.* AU - St Pourcain, B.* AU - Ring, S.M.* AU - Smith, G.D.* AU - Bergström, A.* AU - Kull, I.* AU - Hakonarson, H.* AU - Mentch, F.D.* AU - Bisgaard, H.* AU - Chawes, B.* AU - Stokholm, J.* AU - Waage, J.* AU - Eriksen, P.* AU - Sevelsted, A.* AU - Melbye, M.* AU - van Duijn, C.M.* AU - Medina-Gomez, C.* AU - Hofman, A.* AU - de Jongste, J.C.* AU - Taal, H.R.* AU - Uitterlinden, A.G.* AU - Armstrong, L.L.* AU - Eriksson, J.* AU - Palotie, A.* AU - Bustamante, M.* AU - Estivill, X.* AU - Gonzalez, J.R.* AU - Llop, S.* AU - Kiess, W.* AU - Mahajan, A.* AU - Flexeder, C. AU - Tiesler, C.M. AU - Murray, C.S.* AU - Simpson, A.* AU - Magnus, P.* AU - Sengpiel, V.* AU - Hartikainen, A.L.* AU - Keinanen-Kiukaanniemi, S.* AU - Lewin, A.* AU - da Silva Couto Alves, A.* AU - Blakemore, A.I.* AU - Buxton, J.L.* AU - Kaakinen, M.* AU - Rodriguez, A.* AU - Sebert, S.* AU - Vaarasmaki, M.* AU - Lakka, T.* AU - Lindi, V.* AU - Gehring, U.* AU - Postma, D.S.* AU - Ang, W.* AU - Newnham, J.P.* AU - Lyytikäinen, L.-P.* AU - Pahkala, K.* AU - Raitakari, O.T.* AU - Panoutsopoulou, K.* AU - Zeggini, E.* AU - Boomsma, D.I.* AU - Groen-Blokhuis, M.* AU - Ilonen, J.* AU - Franke, L.* AU - Hirschhorn, J.N.* AU - Pers, T.H.* AU - Liang, L.* AU - Huang, J.* AU - Hocher, B.* AU - Knip, M.* AU - Saw, S.M.* AU - Holloway, J.W.* AU - Melén, E.* AU - Grant, S.F.* AU - Feenstra, B.* AU - Lowe, W.L.* AU - Widen, E.* AU - Sergeyev, E.* AU - Grallert, H. AU - Custovic, A.* AU - Jacobsson, B.* AU - Jarvelin, M.R.* AU - Atalay, M.* AU - Koppelman, G.H.* AU - Pennell, C.E.* AU - Niinikoski, H.* AU - Dedoussis, G.V.* AU - McCarthy, M.I.* AU - Frayling, T.M.* AU - Sunyer, J.* AU - Timpson, N.J.* AU - Rivadeneira, F.* AU - Bønnelykke, K.* AU - Jaddoe, V.W.* C1 - 32450 C2 - 35067 CY - Oxford SP - 1155-1168 TI - A novel common variant in DCST2 is associated with length in early life and height in adulthood. JO - Hum. Mol. Genet. VL - 24 IS - 4 PB - Oxford Univ Press PY - 2015 SN - 0964-6906 ER - TY - JOUR AB - Epidemiological studies have reported inconsistent associations between telomere length (TL) and risk for various cancers. These inconsistencies are likely attributable, in part, to biases that arise due to post-diagnostic and post-treatment TL measurement. To avoid such biases, we used a Mendelian randomization approach and estimated associations between nine TL-associated SNPs and risk for five common cancer types (breast, lung, colorectal, ovarian and prostate cancer, including subtypes) using data on 51,725 cases and 62,035 controls. We then used an inverse-variance weighted average of the SNP-specific associations to estimate the association between a genetic score representing long TL and cancer risk. The long TL genetic score was significantly associated with increased risk of lung adenocarcinoma (P=6.3x10(-15)), even after exclusion of a SNP residing in a known lung cancer susceptibility region (TERT-CLPTM1L) P=6.6x10(-6)). Under Mendelian randomization assumptions, the association estimate (odds ratio (OR)=2.78) is interpreted as the OR for lung adenocarcinoma corresponding to a 1000 base pair increase in TL. The weighted TL SNP score was not associated with other cancer types or subtypes. Our finding that genetic determinants of long TL increase lung adenocarcinoma risk avoids issues with reverse causality and residual confounding that arise in observational studies of TL and disease risk. Under Mendelian randomization assumptions, our finding suggests that longer TL increases lung adenocarcinoma risk. However, caution regarding this causal interpretation is warranted in light of the potential issue of pleiotropy, and a more general interpretation is that SNPs influencing telomere biology are also implicated in lung adenocarcinoma risk. AU - Zhang, C.* AU - Doherty, J.A.* AU - Burgess, S.L.* AU - Hung, R.J.* AU - Lindström, S.* AU - Kraft, P.* AU - Gong, J.* AU - Amos, C.I.* AU - Sellers, T.A.* AU - Monteiro, A.N.* AU - Chenevix-Trench, G.* AU - Bickeböller, H.* AU - Risch, A.* AU - Brennan, P.* AU - Mckay, J.* AU - Houlston, R.* AU - Landi, M.T.* AU - Timofeeva, M.* AU - Wang, Y.* AU - Heinrich, J. AU - Kote-Jarai, Z.* AU - Eeles, R.A.* AU - Muir, K.* AU - Wiklund, F.* AU - Grönberg, H.* AU - Berndt, S.I.* AU - Chanock, S.J.* AU - Schumacher, F.* AU - Haiman, C.A.* AU - Henderson, B.E.* AU - Amin Al Olama, A.* AU - Andrulis, I.L.* AU - Hopper, J.L.* AU - Chang-Claude, J.* AU - John, E.M.* AU - Malone, K.E.* AU - Gammon, M.D.* AU - Ursin, G.* AU - Whittemore, A.S.* AU - Hunter, D.J.* AU - Gruber, S.B.* AU - Knight, J.A.* AU - Hou, L.* AU - Le Marchand, L.* AU - Newcomb, P.A.* AU - Hudson, T.J.* AU - Chan, A.T.* AU - Li, L.* AU - Woods, M.O.* AU - Ahsan, H.* AU - Pierce, B.L.* C1 - 45680 C2 - 37422 SP - 5356-5366 TI - Genetic determinants of telomere length and risk of common cancers: A Mendelian randomization study. JO - Hum. Mol. Genet. VL - 24 IS - 18 PY - 2015 SN - 0964-6906 ER - TY - JOUR AB - Outer segments (OS) of rod photoreceptors are cellular compartments specialized in the conversion of light into electrical signals. This process relies on the light-triggered change in the intracellular levels of cyclic guanosine monophosphate (cGMP), which in turn controls the activity of cyclic nucleotide-gated (CNG) channels in the rod OS plasma membrane. The rod CNG channel is a macromolecular complex that in its core harbors the ion-conducting CNGA1 and CNGB1a subunits. To identify additional proteins of the complex that interact with the CNGB1a core subunit we applied affinity purification of mouse retinal proteins followed by mass spectrometry. In combination with in vitro and in vivo co-immunoprecipitation and fluorescence resonance energy transfer (FRET) we found that the tetraspanin peripherin-2 links CNGB1a to the light-detector rhodopsin. Using immunoelectron microscopy we found that this peripherin-2/rhodopsin/CNG channel complex localizes to the contact region between the disk rims and the plasma membrane. FRET measurements revealed that the fourth transmembrane domain (TM4) of peripherin-2 is required for the interaction with rhodopsin. Quantitatively, the binding affinity of the peripherin-2/rhodopsin interaction was in a similar range as that observed for rhodopsin dimers. Finally, we demonstrate that the p.G266D retinitis pigmentosa mutation found within TM4 selectively abolishes the binding of peripherin-2 to rhodopsin. This finding suggests that the specific disruption of the rhodopsin/peripherin-2 interaction in the p.G266D mutant might contribute to the pathophysiology in affected persons. AU - Becirovic, E.* AU - Nguyen, O.N.* AU - Paparizos, C.* AU - Butz, E.S.* AU - Stern-Schneider, G.* AU - Wolfrum, U.* AU - Hauck, S.M. AU - Ueffing, M. AU - Wahl-Schott, C.* AU - Michalakis, S.* AU - Biel, M.* C1 - 31684 C2 - 34707 SP - 5989-5997 TI - Peripherin-2 couples rhodopsin to the CNG channel in outer segments of rod photoreceptors. JO - Hum. Mol. Genet. VL - 23 IS - 22 PY - 2014 SN - 0964-6906 ER - TY - JOUR AB - Although over 60 loci for type 2 diabetes (T2D) have been identified, there still remains a large genetic component to be clarified. To explore unidentified loci for T2D, we performed a genome-wide association study (GWAS) of 6 209 637 single-nucleotide polymorphisms (SNPs), which were directly genotyped or imputed using East Asian references from the 1000 Genomes Project (June 2011 release) in 5976 Japanese patients with T2D and 20 829 nondiabetic individuals. Nineteen unreported loci were selected and taken forward to follow-up analyses. Combined discovery and follow-up analyses (30 392 cases and 34 814 controls) identified three new loci with genome-wide significance, which were MIR129-LEP [rs791595; risk allele = A; risk allele frequency (RAF) = 0.080; P = 2.55 × 10(-13); odds ratio (OR) = 1.17], GPSM1 [rs11787792; risk allele = A; RAF = 0.874; P = 1.74 × 10(-10); OR = 1.15] and SLC16A13 (rs312457; risk allele = G; RAF = 0.078; P = 7.69 × 10(-13); OR = 1.20). This study demonstrates that GWASs based on the imputation of genotypes using modern reference haplotypes such as that from the 1000 Genomes Project data can assist in identification of new loci for common diseases. AU - Hara, K.* AU - Fujita, H.* AU - Johnson, T.A.* AU - Yamauchi, T.* AU - Yasuda, K.* AU - Horikoshi, M.* AU - Peng, C.* AU - Hu, C.* AU - Ma, R.C.* AU - Imamura, M.* AU - Iwata, M.* AU - Tsunoda, T.* AU - Morizono, T.* AU - Shojima, N.* AU - So, W.Y.* AU - Leung, T.F.* AU - Kwan, P.* AU - Zhang, R.* AU - Wang, J.* AU - Yu, W.* AU - Maegawa, H.* AU - Hirose, H.* AU - DIAGRAM Consortium (Huth, C. AU - Gieger, C. AU - Klopp, N. AU - Meitinger, T. AU - Illig, T. AU - Grallert, H. AU - Thorand, B. AU - Wichmann, H.-E. AU - Petersen, A.-K.) AU - Kaku, K.* AU - Ito, C.* AU - Watada, H.* AU - Tanaka, Y.* AU - Tobe, K.* AU - Kashiwagi, A.* AU - Kawamori, R.* AU - Jia, W.* AU - Chan, J.C.* AU - Teo, Y.Y.* AU - Shyong, T.E.* AU - Kamatani, N.* AU - Kubo, M.* AU - Maeda, S.* AU - Kadowaki, T.* C1 - 28105 C2 - 32939 CY - Oxford SP - 239-246 TI - Genome-wide association study identifies three novel loci for type 2 diabetes. JO - Hum. Mol. Genet. VL - 23 IS - 1 PB - Oxford Univ. Press PY - 2014 SN - 0964-6906 ER - TY - JOUR AB - White blood cell (WBC) count is a common clinical measure used as a predictor of certain aspects of human health, including immunity and infection status. WBC count is also a complex trait that varies among individuals and ancestry groups. Differences in linkage disequilibrium structure and heterogeneity in allelic effects are expected to play a role in the associations observed between populations. Prior genome-wide association study (GWAS) meta-analyses have identified genomic loci associated with WBC and its subtypes, but much of the heritability of these phenotypes remains unexplained. Using GWAS summary statistics for over 50 000 individuals from three diverse populations (Japanese, African-American and European ancestry), a Bayesian model methodology was employed to account for heterogeneity between ancestry groups. This approach was used to perform a trans-ethnic meta-analysis of total WBC, neutrophil and monocyte counts. Ten previously known associations were replicated and six new loci were identified, including several regions harboring genes related to inflammation and immune cell function. Ninety-five percent credible interval regions were calculated to narrow the association signals and fine-map the putatively causal variants within loci. Finally, a conditional analysis was performed on the most significant SNPs identified by the trans-ethnic meta-analysis (MA), and nine secondary signals within loci previously associated with WBC or its subtypes were identified. This work illustrates the potential of trans-ethnic analysis and ascribes a critical role to multi-ethnic cohorts and consortia in exploring complex phenotypes with respect to variants that lie outside the European-biased GWAS pool. AU - Keller, M.F.* AU - Reiner, A.P.* AU - Okada, Y.* AU - van Rooij, F.J.* AU - Johnson, A.D.* AU - Chen, M.H.* AU - Smith, A.V.* AU - Morris, A.P.* AU - Tanaka, T.* AU - Ferrucci, L.* AU - Zonderman, A.B.* AU - Lettre, G.* AU - Harris, T.* AU - Garcia, M.* AU - Bandinelli, S.* AU - Qayyum, R.* AU - Yanek, L.R.* AU - Becker, D.M.* AU - Becker, L.C.* AU - Kooperberg, C.* AU - Keating, B.J.* AU - Reis, J.* AU - Tang, H.* AU - Boerwinkle, E.* AU - Kamatani, Y.* AU - Matsuda, K.* AU - Kamatani, N.* AU - Nakamura, Y.* AU - Kubo, M.* AU - Liu, S.* AU - Dehghan, A.* AU - Felix, J.F.* AU - Hofman, A.* AU - Uitterlinden, A.G.* AU - van Duijn, C.M.* AU - Franco, O.H.* AU - Longo, D.L.* AU - Singleton, A.B.* AU - Psaty, B.M.* AU - Evans, M.K.* AU - Cupples, L.A.* AU - Rotter, J.I.* AU - O'Donnell, C.J.* AU - Takahashi, A.* AU - Wilson, J.G.* AU - Ganesh, S.K.* AU - Nalls, M.A.* AU - CHARGE Consortium (Gieger, C. AU - Illig, T. AU - Meisinger, C. AU - Prokisch, H. AU - Wichmann, H.-E.) AU - COGENT Consortium (*) AU - RIKEN Consortium (*) C1 - 44012 C2 - 36695 SP - 6944-6960 TI - Trans-ethnic meta-analysis of white blood cell phenotypes. JO - Hum. Mol. Genet. VL - 23 IS - 25 PY - 2014 SN - 0964-6906 ER - TY - JOUR AB - Collagen type IV alpha 1 and 2 (COL4A1 and COL4A2) are present in nearly all basement membranes. COL4A1 and COL4A2 mutations are pleiotropic, affecting multiple organ systems to differing degrees, and both genetic-context and environmental factors influence this variable expressivity. Here, we report important phenotypic and molecular differences in an allelic series of Col4a1 and Col4a2 mutant mice that are on a uniform genetic background. We evaluated three organs commonly affected by COL4A1 and COL4A2 mutations and discovered allelic heterogeneity in the penetrance and severity of ocular dysgenesis, myopathy and brain malformations. Similarly, we show allelic heterogeneity in COL4A1 and COL4A2 biosynthesis. While most mutations that we examined caused increased intracellular and decreased extracellular COL4A1 and COL4A2, we identified three mutations with distinct biosynthetic signatures. Reduced temperature or presence of 4-phenylbutyrate ameliorated biosynthetic defects in primary cell lines derived from mutant mice. Together, our data demonstrate the effects and clinical implications of allelic heterogeneity in Col4a1- and Col4a2-related diseases. Understanding allelic differences will be valuable for increasing prognostic accuracy and for the development of therapeutic interventions that consider the nature of the molecular cause in patients with COL4A1 and COL4A2 mutations. AU - Kuo, D.S.* AU - Labelle-Dumais, C.* AU - Mao, M.* AU - Jeanne, M.* AU - Kauffman, W.B.* AU - Allen, J.* AU - Favor, J. AU - Gould, D.B.* C1 - 28953 C2 - 33590 CY - Oxford SP - 1709-1722 TI - Allelic heterogeneity contributes to variability in ocular dysgenesis, myopathy and brain malformations caused by Col4a1 and Col4a2 mutations. JO - Hum. Mol. Genet. VL - 23 IS - 7 PB - Oxford Univ Press PY - 2014 SN - 0964-6906 ER - TY - JOUR AB - The Genetic Investigation of Anthropometric Traits (GIANT) consortium identified 14 loci in European Ancestry (EA) individuals associated with waist-to-hip ratio (WHR) adjusted for body mass index. These loci are wide and narrowingthe signalsremains necessary. Twelve of 14 loci identified inGIANTEA samples retained strong associations with WHR in our joint EA/individuals of African Ancestry (AA) analysis (log-Bayes factor >6.1). Transethnic analysesatfiveloci (TBX15-WARS2, LYPLAL1, ADAMTS9, LY86andITPR2-SSPN)substantially narrowed the signals to smaller sets of variants, some of which are in regions that have evidence of regulatory activity. By leveraging varying linkage disequilibrium structures across different populations, single-nucleotide polymorphisms (SNPs) with strong signals and narrower credible sets from trans-ethnic meta-analysis of central obesity provide more precise localizations of potential functional variants and suggest a possible regulatory role. Meta-analysis results for WHR were obtained from 77 167 EA participants from GIANT and 23 564 AA participants from the AfricanAncestry Anthropometry Genetics Consortium. For fine mapping we interrogatedSNPs within ±250 kbflanking regionsof 14 previously reported indexSNPsfrom loci discovered in EApopulations by performing trans-ethnic meta-analysis of results from the EA and AA meta-analyses. We applied a Bayesian approach that leverages allelic heterogeneity across populations to combine meta-analysis results and aids in fine-mapping shared variants at these locations. We annotated variants using information from the ENCODE Consortium and Roadmap Epigenomics Project to prioritize variants for possible functionality. AU - Liu, C.-T.* AU - Buchkovich, M.L.* AU - Winkler, T.W.* AU - Heid, I.M. AU - African Ancestry Anthropometry Genetics Consortium (*) AU - GIANT Consortium (Albrecht, E. AU - Gieger, C. AU - Grallert, H. AU - Illig, T. AU - Müller-Nurasyid, M. AU - Peters, A. AU - Thorand, B. AU - Wichmann, H.-E.) AU - Borecki, I.B.* AU - Fox, C.S.* AU - Mohlke, K.L.* AU - North, K.E.* AU - Cupples, L.A.* C1 - 31952 C2 - 34888 CY - Oxford SP - 4738-4744 TI - Multi-ethnic fine-mapping of 14 central adiposity loci. JO - Hum. Mol. Genet. VL - 23 IS - 17 PB - Oxford Univ Press PY - 2014 SN - 0964-6906 ER - TY - JOUR AB - Parkinson's disease (PD) has a number of known genetic risk factors. Clinical and epidemiological studies have suggested the existence of intermediate factors that may be associated with additional risk of PD. We construct genetic risk profiles for additional epidemiological and clinical factors using known genome-wide association studies (GWAS) loci related to these specific phenotypes to estimate genetic comorbidity in a systematic review. We identify genetic risk profiles based on GWAS variants associated with schizophrenia and Crohn's disease as significantly associated with risk of PD. Conditional analyses adjusting for SNPs near loci associated with PD and schizophrenia or PD and Crohn's disease suggest that spatially overlapping loci associated with schizophrenia and PD account for most of the shared comorbidity, while variation outside of known proximal loci shared by PD and Crohn's disease accounts for their shared genetic comorbidity. We examine brain methylation and expression signatures proximal to schizophrenia and Crohn's disease loci to infer functional changes in the brain associated with the variants contributing to genetic comorbidity. We compare our results with a systematic review of epidemiological literature, while the findings are dissimilar to a degree; marginal genetic associations corroborate the directionality of associations across genetic and epidemiological data. We show a strong genetically defined level of comorbidity between PD and Crohn's disease as well as between PD and schizophrenia, with likely functional consequences of associated variants occurring in brain. AU - Nalls, M.A.* AU - Saad, M.* AU - Noyce, A.J.* AU - Keller, M.F.* AU - Schrag, A.* AU - Bestwick, J.P.* AU - Traynor, B.J.* AU - Gibbs, J.R.* AU - Hernandez, D.G.* AU - Cookson, M.R.* AU - Morris, H.R.* AU - Williams, N.* AU - Gasser, T.* AU - Heutink, P.* AU - Wood, N.* AU - Hardy, J.* AU - Martinez, M.* AU - Singleton, A.B.* AU - International Parkinson's Disease Genomics Consortium (IPDGC) (Illig, T. AU - Lichtner, P.) AU - Wellcome Trust Case Control Consortium 2 (WTCCC2) (*) AU - North American Brain Expression Consortium (*) AU - United Kingdom Brain Expression Consortium (UKBEC) (*) C1 - 44227 C2 - 36862 CY - Oxford SP - 831-841 TI - Genetic comorbidities in Parkinson's disease. JO - Hum. Mol. Genet. VL - 23 IS - 3 PB - Oxford Univ Press PY - 2014 SN - 0964-6906 ER - TY - JOUR AB - The length of female reproductive lifespan is associated with multiple adverse outcomes, including breast cancer, cardiovascular disease and infertility. The biological processes that govern the timing of the beginning and end of reproductive life are not well understood. Genetic variants are known to contribute to ∼50% of the variation in both age at menarche and menopause, but to date the known genes explain <15% of the genetic component. We have used genome-wide association in a bivariate meta-analysis of both traits to identify genes involved in determining reproductive lifespan. We observed significant genetic correlation between the two traits using genome-wide complex trait analysis. However, we found no robust statistical evidence for individual variants with an effect on both traits. A novel association with age at menopause was detected for a variant rs1800932 in the mismatch repair gene MSH6 (P = 1.9 × 10(-9)), which was also associated with altered expression levels of MSH6 mRNA in multiple tissues. This study contributes to the growing evidence that DNA repair processes play a key role in ovarian ageing and could be an important therapeutic target for infertility. AU - Perry, J.R.* AU - Hsu, Y.H.* AU - Chasman, D.I.* AU - Johnson, A.D.* AU - Elks, C.E.* AU - Albrecht, E. AU - Andrulis, I.L.* AU - Beesley, J.* AU - Berenson, G.S.* AU - Bergmann, S.* AU - Bojesen, S.E.* AU - Bolla, M.K.* AU - Brown, J.* AU - Buring, J.E.* AU - Campbell, H.* AU - Chang-Claude, J.* AU - Chenevix-Trench, G.* AU - Corre, T.* AU - Couch, F.J.* AU - Cox, A.* AU - Czene, K.* AU - d'Adamo, A.P.* AU - Davies, G.* AU - Deary, I.J.* AU - Dennis, J.* AU - Easton, D.F.* AU - Engelhardt, E.G.* AU - Eriksson, J.G.* AU - Esko, T.* AU - Fasching, P.A.* AU - Figueroa, J.D.* AU - Flyger, H.* AU - Fraser, A.* AU - Garcia-Closas, M.* AU - Gasparini, P.* AU - Gieger, C. AU - Giles, G.G.* AU - Guénel, P.* AU - Hägg, S.* AU - Hall, P.* AU - Hayward, C.* AU - Hopper, J.L.* AU - Ingelsson, E.* AU - kConFab Investigators () AU - Kardia, S.L.* AU - Kasiman, K.* AU - Knight, J.A.* AU - Lahti, J.* AU - Lawlor, D.A.* AU - Magnusson, P.K.* AU - Margolin, S.* AU - Marsh, J.A.* AU - Metspalu, A.* AU - Olson, J.E.* AU - Pennell, C.E.* AU - Polasek, O.* AU - Rahman, I.* AU - Ridker, P.M.* AU - Robino, A.* AU - Rudan, I.* AU - Rudolph, A.* AU - Salumets, A.* AU - Schmidt, M.K.* AU - Schoemaker, M.J.* AU - Smith, E.N.* AU - Smith, J.A.* AU - Southey, M.* AU - Stöckl, D. AU - Swerdlow, A.J.* AU - Thompson, D.J.* AU - Truong, T.* AU - Ulivi, S.* AU - Waldenberger, M. AU - Wang, Q.* AU - Wild, S.* AU - Wilson, J.F.* AU - Wright, A.F.* AU - Zgaga, L.* AU - RepoGen Consortium (*) AU - Ong, K.K.* AU - Murabito, J.M.* AU - Karasik, D.* AU - Murray, A.* C1 - 28987 C2 - 33601 CY - Oxford SP - 2490-2497 TI - DNA mismatch repair gene MSH6 implicated in determining age at natural menopause. JO - Hum. Mol. Genet. VL - 23 IS - 9 PB - Oxford Univ Press PY - 2014 SN - 0964-6906 ER - TY - JOUR AB - Previously, we reported strong influences of genetic variants on metabolic phenotypes, some of them with clinical relevance. Here we hypothesize that DNA methylation may have an important and potentially independent effect on human metabolism. To test this hypothesis we conducted what is to the best of our knowledge the first epigenome-wide association study (EWAS) between DNA methylation and metabolic traits (metabotypes) in human blood. We assess 649 blood metabolic traits from 1,814 participants of the KORA population study for association with methylation of 457,004 CpG sites, determined on the Infinium HumanMethylation450 BeadChip platform. Using the EWAS approach, we identified two types of methylome-metabotype associations. One type is driven by an underlying genetic effect; the other type is independent of genetic variation and potentially driven by common environmental and life-style dependent factors. We report eight CpG loci at genome-wide significance that have a genetic variant as confounder (p=3.9x10-20 to 2.0x10-108, r2=0.036 to 0.221). Seven loci display CpG-site-specific associations to metabotypes, but do not exhibit any underlying genetic signals (p=9.2x10-14 to 2.7x10-27, r2=0.008 to 0.107). We further identify several groups of CpG loci that associate with a same metabotype, such as 4-vinylphenol sulfate and 4-androsten-3beta,17beta-diol disulfate. In these cases the association between CpG-methylation and metabotype are likely the result of a common external environmental factor, including smoking. Our study shows that analysis of EWAS with large numbers of metabolic traits in large population cohorts are, in principle, feasible. Taken together, our data suggests that DNA methylation plays an important role in regulating human metabolism. AU - Petersen, A.-K. AU - Zeilinger, S. AU - Kastenmüller, G. AU - Römisch-Margl, W. AU - Brugger, M. AU - Peters, A. AU - Meisinger, C. AU - Strauch, K. AU - Hengstenberg, C.* AU - Pagel, P.* AU - Huber, F.* AU - Mohney, R.P.* AU - Grallert, H. AU - Illig, T.* AU - Adamski, J. AU - Waldenberger, M. AU - Gieger, C. AU - Suhre, K. C1 - 27226 C2 - 32573 CY - Oxford SP - 534-545 TI - Epigenetics meets metabolomics: An epigenome-wide association study with blood serum metabolic traits. JO - Hum. Mol. Genet. VL - 23 IS - 2 PB - Oxford Univ. Press PY - 2014 SN - 0964-6906 ER - TY - JOUR AB - Large-scale, genomic studies of specific tumors such as The Cancer Genome Atlas (TCGA) have provided a better understanding of the alterations of pathways involved in the development of solid tumors including glioblastoma, breast cancer, ovarian and endometrial cancers, colon cancer and lung squamous cell carcinoma. This tremendous effort of the scientific community has confirmed the view that Cancer actually represents a wide variety of diseases originating from different organs. These studies showed that TP53 and PI3KCA are the two most mutated genes in all types of cancers and that 30% to 70% of all solid tumors harbor potentially 'actionable' mutations that can be exploited for patient stratification or treatment optimization. Translation of this huge oncogenomic dataset to clinical application in personalized medicine programs is now the main challenge for the future. The gap between our basic knowledge and clinical application is still wide. Closing the gap will require translational personalized trials, which may initiate a radical change in our routine clinical practice in oncology. AU - Rafii, A.* AU - Touboul, C.* AU - Al Thani, H.* AU - Suhre, K. AU - Malek, J.A.* C1 - 31292 C2 - 34317 CY - Oxford SP - R69-R75 TI - Where cancer genomics should go next: A clinician's perspective. JO - Hum. Mol. Genet. VL - 23 IS - R1 PB - Oxford Univ Press PY - 2014 SN - 0964-6906 ER - TY - JOUR AB - Rolandic Epilepsy (RE) is the most common idiopathic focal childhood epilepsy. Its molecular basis is largely unknown and a complex genetic etiology is assumed in the majority of affected individuals. The present study tested whether six large recurrent CNVs at 1q21, 15q11.2, 15q13.3, 16p11.2, 16p13.11 and 22q11.2 previously associated with neurodevelopmental disorders also increase risk of RE. Our association analyses revealed a significant excess of the 600 kb genomic duplication at the 16p11.2 locus (chr16: 29.5 - 30.1 Mb) in 393 unrelated patients with typical (n=339) and atypical (ARE; n=54) RE compared with the prevalence in 65046 European population controls (5/393 cases vs 32/65046 controls; Fisher's exact test P=2.83 x 10(-6), OR=26.2, 95% CI: 7.9 - 68.2). In contrast, the 16p11.2 duplication was not detected in 1738 European epilepsy patients with either temporal lobe epilepsy (n=330) and genetic generalized epilepsies (n=1408), suggesting a selective enrichment of the 16p11.2 duplication in idiopathic focal childhood epilepsies (Fisher's exact test P=2.1 x 10(-4)). In a subsequent screen among children carrying the 16p11.2 600 kb rearrangement we identified three patients with RE-spectrum epilepsies in 117 duplication carriers (2.6%) but none in 202 carriers of the reciprocal deletion. Our results suggest that the 16p11.2 duplication represents a significant genetic risk factor for typical and atypical Rolandic epilepsy. AU - Reinthaler, E.M.* AU - Lal, D.* AU - Lebon, S.* AU - Hildebrand, M.S.* AU - Dahl, H.H.* AU - Regan, B.M.* AU - Feucht, M.* AU - Steinböck, H.* AU - Neophytou, B.* AU - Ronen, G.M.* AU - Roche, L.* AU - Gruber-Sedlmayr, U.* AU - Geldner, J.* AU - Haberlandt, E.* AU - Hoffmann, P.* AU - Herms, S.* AU - Gieger, C. AU - Waldenberger, M. AU - Franke, A.* AU - Wittig, M.* AU - Schoch, S.* AU - Becker, A.J.* AU - Hahn, A.* AU - Männik, K.* AU - Toliat, M.R.* AU - Winterer, G.* AU - Lerche, H.* AU - Nürnberg, P.* AU - Mefford, H.C.* AU - Scheffer, I.E.* AU - Berkovic, S.F.* AU - Beckmann, J.S.* AU - EPICURE Consortium (Reymond, A.*) AU - EuroEPINOMICS Consortium (Zimprich, F.*) AU - Sander, T.* AU - Jacquemont, S.* AU - Neubauer, B.A.* C1 - 31632 C2 - 34622 SP - 6069-6080 TI - 16p11.2 600 kb duplications confer risk for typical and atypical Rolandic epilepsy. JO - Hum. Mol. Genet. VL - 23 IS - 22 PY - 2014 SN - 0964-6906 ER - TY - JOUR AB - Availability of standardized metabolite panels and genome-wide single nucleotide polymorphism (SNP) data endorse the comprehensive analysis of gene-metabolite association. Currently, many studies use genome-wide association analysis to investigate the genetic effects on single metabolites (mGWAS) separately. Such studies have identified several loci that are associated not only with one but with multiple metabolites, facilitated by the fact that metabolite panels often include metabolites of the same or related pathways. Strategies that analyse several phenotypes in a combined way were shown to be able to detect additional genetic loci. One of those methods is the phenotype set enrichment analysis (PSEA) that tests sets of metabolites for enrichment at genes. Here we applied PSEA on two different panels of serum metabolites together with genome-wide data. All analyses were performed as a two-step identification-validation approach, using data from the population-based KORA cohort and the TwinsUK study. In addition to confirming genes that were already known from mGWAS, we were able to identify and validate twelve new genes. Knowledge about gene function was supported by the enriched metabolite sets. For loci with unknown gene functions, the results suggest a function that is interrelated with the metabolites, and hint at the underlying pathways. AU - Ried, J.S. AU - Shin, S.Y.* AU - Krumsiek, J. AU - Illig, T. AU - Theis, F.J. AU - Spector, T.D.* AU - Adamski, J. AU - Wichmann, H.-E. AU - Strauch, K. AU - Soranzo, N.* AU - Suhre, K. AU - Gieger, C. C1 - 31621 C2 - 34601 CY - Oxford SP - 5847-5857 TI - Novel genetic associations with serum level metabolites identified by phenotype set enrichment analyses. JO - Hum. Mol. Genet. VL - 23 IS - 21 PB - Oxford Univ Press PY - 2014 SN - 0964-6906 ER - TY - JOUR AB - Mutations in Peroxidasin (PXDN) cause severe inherited eye disorders in humans, such as congenital cataract, corneal opacity, and developmental glaucoma. The role of peroxidasin during eye development is poorly understood. Here we describe the first Pxdn mouse mutant which was induced by ENU (N-ethyl-N-nitrosourea) and led to a recessive phenotype. Sequence analysis of cDNA revealed a T3816A mutation resulting in a premature stop codon (Cys1272X) in the peroxidase domain. This mutation causes severe anterior segment dysgenesis and microphthalmia resembling the manifestations in patients with PXDN mutations. The proliferation and differentiation of the lens is disrupted in association with aberrant expression of transcription factor genes (Pax6 and Foxe3) in mutant eyes. Additionally, Pxdn is involved in the consolidation of the basement membrane and lens epithelium adhesion in the ocular lens. Lens material including γ-crystallin is extruded into the anterior and posterior chamber due to local loss of structural integrity of the lens capsule as a secondary damage to the anterior segment development leading to congenital ocular inflammation. Moreover, Pxdn mutants exhibited an early-onset glaucoma and progressive retinal dysgenesis. Transcriptome profiling revealed that peroxidasin affects the transcription of developmental and eye diseases-related genes at early eye development. These findings suggest that peroxidasin is necessary for cell proliferation and differentiation and for basement membrane consolidation during eye development. Our studies provide pathogenic mechanisms of PXDN mutation-induced congenital eye diseases. AU - Yan, X. AU - Sabrautzki, S. AU - Horsch, M. AU - Fuchs, H. AU - Gailus-Durner, V. AU - Beckers, J. AU - Hrabě de Angelis, M. AU - Graw, J. C1 - 31544 C2 - 34547 CY - Oxford SP - 5597-5614 TI - Peroxidasin is essential for eye development in the mouse. JO - Hum. Mol. Genet. VL - 23 IS - 21 PB - Oxford Univ Press PY - 2014 SN - 0964-6906 ER - TY - JOUR AB - Waist circumference (WC) and waist-to-hip ratio (WHR) are surrogate measures of central adiposity that are associated with adverse cardiovascular events, type 2 diabetes and cancer independent of body mass index (BMI). WC and WHR are highly heritable with multiple susceptibility loci identified to date. We assessed the association between SNPs and BMI-adjusted WC and WHR and unadjusted WC in up to 57 412 individuals of European descent from 22 cohorts collaborating with the NHLBI's Candidate Gene Association Resource (CARe) project. The study population consisted of women and men aged 20-80 years. Study participants were genotyped using the ITMAT/Broad/CARE array, which includes ∼50 000 cosmopolitan tagged SNPs across ∼2100 cardiovascular-related genes. Each trait was modeled as a function of age, study site and principal components to control for population stratification, and we conducted a fixed-effects meta-analysis. No new loci for WC were observed. For WHR analyses, three novel loci were significantly associated (P < 2.4 × 10(-6)). Previously unreported rs2811337-G near TMCC1 was associated with increased WHR (β ± SE, 0.048 ± 0.008, P = 7.7 × 10(-9)) as was rs7302703-G in HOXC10 (β = 0.044 ± 0.008, P = 2.9 × 10(-7)) and rs936108-C in PEMT (β = 0.035 ± 0.007, P = 1.9 × 10(-6)). Sex-stratified analyses revealed two additional novel signals among females only, rs12076073-A in SHC1 (β = 0.10 ± 0.02, P = 1.9 × 10(-6)) and rs1037575-A in ATBDB4 (β = 0.046 ± 0.01, P = 2.2 × 10(-6)), supporting an already established sexual dimorphism of central adiposity-related genetic variants. Functional analysis using ENCODE and eQTL databases revealed that several of these loci are in regulatory regions or regions with differential expression in adipose tissue. AU - Yoneyama, S.* AU - Guo, Y.* AU - Lanktree, M.B.* AU - Barnes, M.R.* AU - Elbers, C.C.* AU - Karczewski, K.J.* AU - Padmanabhan, S.* AU - Bauer, F.* AU - Baumert, J.J. AU - Beitelshees, A.L.* AU - Berenson, G.S.* AU - Boer, J.M.* AU - Burke, G.L.* AU - Cade, B.* AU - Chen, W.* AU - Cooper-DeHoff, R.M.* AU - Gaunt, T.R.* AU - Gieger, C. AU - Gong, Y.* AU - Gorski, M.* AU - Heard-Costa, N.* AU - Johnson, T.* AU - Lamonte, M.J.* AU - McDonough, C.* AU - Monda, K.L.* AU - Onland-Moret, N.C.* AU - Nelson, C.P.* AU - O'Connell, J.R.* AU - Ordovas, J.* AU - Peter, I.* AU - Peters, A. AU - Shaffer, J.* AU - Shen, H.* AU - Smith, E.* AU - Speilotes, L.* AU - Thomas, F.* AU - Thorand, B. AU - Monique Verschuren, W.M.* AU - Anand, S.S.* AU - Dominiczak, A.* AU - Davidson, K.W.* AU - Hegele, R.A.* AU - Heid, I.M. AU - Hofker, M.H.* AU - Huggins, G.S.* AU - Illig, T. AU - Johnson, J.A.* AU - Kirkland, S.A.* AU - Look AHEAD Research Group (*) AU - König, W.* AU - Langaee, T.Y.* AU - McCaffery, J.* AU - Melander, O.* AU - Mitchell, B.D.* AU - Munroe, P.* AU - Murray, S.S.* AU - Papanicolau, G.J.* AU - Redline, S.* AU - Reilly, M.* AU - Samani, N.J.* AU - Schork, N.J.* AU - van der Schouw, Y.T.* AU - Shimbo, D.* AU - Shuldiner, A.R.* AU - Tobin, M.D.* AU - Wijmenga, C.* AU - Yusuf, S.* AU - GIANT Consortium (Grallert, H. AU - Heinrich, J. AU - Thiering, E. AU - Wichmann, H.-E.) AU - CARe IBC Consortium (*) AU - Hakonarson, H.* AU - Lange, L.A.* AU - Demerath, E.W.* AU - Fox, C.S.* AU - North, K.E.* AU - Reiner, A.P.* AU - Keating, B.J.* AU - Taylor, K.C.* C1 - 28981 C2 - 33595 CY - Oxford SP - 2498-2510 TI - Gene-centric meta-analyses for central adiposity traits in up to 57412 individuals of European descent confirm known loci and reveal several novel associations. JO - Hum. Mol. Genet. VL - 23 IS - 9 PB - Oxford Univ Press PY - 2014 SN - 0964-6906 ER - TY - JOUR AB - The pubertal height growth spurt is a distinctive feature of childhood growth reflecting both the central onset of puberty and local growth factors. Although little is known about the underlying genetics, growth variability during puberty correlates with adult risks for hormone-dependent cancer and adverse cardiometabolic health. The only gene so far associated with pubertal height growth, LIN28B, pleiotropically influences childhood growth, puberty and cancer progression, pointing to shared underlying mechanisms. To discover genetic loci influencing pubertal height and growth and to place them in context of overall growth and maturation, we performed genome-wide association meta-analyses in 18 737 European samples utilizing longitudinally collected height measurements. We found significant associations (P < 1.67 × 10(-8)) at 10 loci, including LIN28B. Five loci associated with pubertal timing, all impacting multiple aspects of growth. In particular, a novel variant correlated with expression of MAPK3, and associated both with increased prepubertal growth and earlier menarche. Another variant near ADCY3-POMC associated with increased body mass index, reduced pubertal growth and earlier puberty. Whereas epidemiological correlations suggest that early puberty marks a pathway from rapid prepubertal growth to reduced final height and adult obesity, our study shows that individual loci associating with pubertal growth have variable longitudinal growth patterns that may differ from epidemiological observations. Overall, this study uncovers part of the complex genetic architecture linking pubertal height growth, the timing of puberty and childhood obesity and provides new information to pinpoint processes linking these traits. AU - Cousminer, D.L.* AU - Berry, D.J.* AU - Timpson, N.J.* AU - Ang, W.* AU - Thiering, E. AU - Byrne, E.M.* AU - Taal, H.R.* AU - Huikari, V.* AU - Bradfield, J.P.* AU - Kerkhof, M.* AU - Groen-Blokhuis, M.M.* AU - Kreiner-Møller, E.* AU - Marinelli, M.* AU - Holst, C.* AU - Leinonen, J.T.* AU - Perry, J.R.* AU - Surakka, I.* AU - Pietiläinen, O.* AU - Kettunen, J.* AU - Anttila, V.* AU - Kaakinen, M.* AU - Sovio, U.* AU - Pouta, A.* AU - Das, S.* AU - Lagou, V.* AU - Power, C.* AU - Prokopenko, I.* AU - Evans, D.M* AU - Kemp, J.P.* AU - St Pourcain, B.* AU - Ring, S.* AU - Palotie, A.* AU - Kajantie, E.* AU - Osmond, C.* AU - Lehtimäki, T.* AU - Viikari, J.S.* AU - Kähönen, M.* AU - Warrington, N.M.* AU - Lye, S.J.* AU - Palmer, L.J.* AU - Tiesler, C.M. AU - Flexeder, C. AU - Montgomery, G.W.* AU - Medland, S.E.* AU - Hofman, A.* AU - Hakonarson, H.* AU - Guxens, M.* AU - Bartels, M.* AU - Salomaa, V.* AU - RepoGen Consortium (*) AU - Murabito, J.M.* AU - Kaprio, J.* AU - Sørensen, T.I.* AU - Ballester, F.* AU - Bisgaard, H.* AU - Boomsma, D.I.* AU - Koppelman, G.H.* AU - Grant, S.F.* AU - Jaddoe, V.W.* AU - Martin, N.G.* AU - Heinrich, J. AU - Pennell, C.E.* AU - Raitakari, O.T.* AU - Eriksson, J.G.* AU - Smith, G.D.* AU - Hyppönen, E.* AU - Jarvelin, M.R.* AU - McCarthy, M.I.* AU - Ripatti, S.* AU - Widen, E.* AU - Early Growth Genetics Consortium (*) C1 - 24947 C2 - 31705 SP - 2735-2747 TI - Genome-wide association and longitudinal analyses reveal genetic loci linking pubertal height growth, pubertal timing and childhood adiposity. JO - Hum. Mol. Genet. VL - 22 IS - 13 PB - Oxford Univ. Press PY - 2013 SN - 0964-6906 ER - TY - JOUR AB - We have previously identified tagSNPs at 8q24.21 influencing glioma risk. We have sought to fine-map the location of the functional basis of this association using data from four genome-wide association studies, comprising a total of 4147 glioma cases and 7435 controls. To improve marker density across the 700 kb region, we imputed genotypes using 1000 Genomes Project data and high-coverage sequencing data generated on 253 individuals. Analysis revealed an imputed low-frequency SNP rs55705857 (P = 2.24 x 10(-38)) which was sufficient to fully capture the 8q24.21 association. Analysis by glioma subtype showed the association with rs55705857 confined to non-glioblastoma multiforme (non-GBM) tumours (P = 1.07 x 10(-67)). Validation of the non-GBM association was shown in three additional datasets (625 non-GBM cases, 2412 controls; P = 1.41 x 10(-28)). In the pooled analysis, the odds ratio for low-grade glioma associated with rs55705857 was 4.3 (P = 2.31 x 10(-94)). rs55705857 maps to a highly evolutionarily conserved sequence within the long non-coding RNA CCDC26 raising the possibility of direct functionality. These data provide additional insights into the aetiological basis of glioma development. AU - Enciso-Mora, V.* AU - Hosking, F.J.* AU - Kinnersley, B.* AU - Wang, Y.F.* AU - Shete, S.* AU - Zelenika, D.* AU - Broderick, P.* AU - Idbaih, A.* AU - Delattre, J.-Y.* AU - Hoang-Xuan, K.* AU - Marie, Y.* AU - di Stefano, A.L.* AU - Labussière, M.* AU - Dobbins, S.* AU - Boisselier, B.* AU - Ciccarino, P.* AU - Rossetto, M.* AU - Armstrong, G.* AU - Liu, Y.H.* AU - Gousias, K.* AU - Schramm, J.* AU - Lau, C.* AU - Hepworth, S.J.* AU - Strauch, K. AU - Müller-Nurasyid, M. AU - Schreiber, S.* AU - Franke, A.* AU - Moebus, S.* AU - Eisele, L.* AU - Försti, A.* AU - Hemminki, K.* AU - Tomlinson, I.P.* AU - Swerdlow, A.* AU - Lathrop, M* AU - Simon, M.* AU - Bondy, M.* AU - Sanson, M.* AU - Houlston, R.S.* C1 - 25131 C2 - 31824 SP - 2293-2302 TI - Deciphering the 8q24.21 association for glioma. JO - Hum. Mol. Genet. VL - 22 IS - 11 PB - Oxford Univ. Press PY - 2013 SN - 0964-6906 ER - TY - JOUR AB - Blood pressure (BP) is a heritable determinant of risk for cardiovascular disease (CVD). To investigate genetic associations with systolic BP (SBP), diastolic BP (DBP), mean arterial pressure (MAP) and pulse pressure (PP), we genotyped ∼50 000 single-nucleotide polymorphisms (SNPs) that capture variation in ∼2100 candidate genes for cardiovascular phenotypes in 61 619 individuals of European ancestry from cohort studies in the USA and Europe. We identified novel associations between rs347591 and SBP (chromosome 3p25.3, in an intron of HRH1) and between rs2169137 and DBP (chromosome1q32.1 in an intron of MDM4) and between rs2014408 and SBP (chromosome 11p15 in an intron of SOX6), previously reported to be associated with MAP. We also confirmed 10 previously known loci associated with SBP, DBP, MAP or PP (ADRB1, ATP2B1, SH2B3/ATXN2, CSK, CYP17A1, FURIN, HFE, LSP1, MTHFR, SOX6) at array-wide significance (P < 2.4 × 10(-6)). We then replicated these associations in an independent set of 65 886 individuals of European ancestry. The findings from expression QTL (eQTL) analysis showed associations of SNPs in the MDM4 region with MDM4 expression. We did not find any evidence of association of the two novel SNPs in MDM4 and HRH1 with sequelae of high BP including coronary artery disease (CAD), left ventricular hypertrophy (LVH) or stroke. In summary, we identified two novel loci associated with BP and confirmed multiple previously reported associations. Our findings extend our understanding of genes involved in BP regulation, some of which may eventually provide new targets for therapeutic intervention. AU - Ganesh, S.K.* AU - Tragante, V.* AU - Guo, W.* AU - Guo, Y.* AU - Lanktree, M.B.* AU - Smith, E.N.* AU - Johnson, T.* AU - Castillo, B.A.* AU - Barnard, J.* AU - Baumert, J.J. AU - Chang, Y.P.* AU - Elbers, C.C.* AU - Farrall, M.* AU - Fischer, M.E.* AU - Franceschini, N.* AU - Gaunt, T.R.* AU - Gho, J.M.* AU - Gieger, C. AU - Gong, Y.* AU - Isaacs, A.* AU - Kleber, M.E.* AU - Mateo Leach, I.* AU - McDonough, C.W.* AU - Meijs, M.F.* AU - Mellander, O.* AU - Molony, C.M.* AU - Nolte, I.M.* AU - Padmanabhan, S.* AU - Price, T.S.* AU - Rajagopalan, R.* AU - Shaffer, J.* AU - Shah, S.* AU - Shen, H.* AU - Soranzo, N.* AU - van der Most, P.J.* AU - van Iperen, E.P.* AU - van Setten, J.A.* AU - Vonk, J.M.* AU - Zhang, L.* AU - Beitelshees, A.L.* AU - Berenson, G.S.* AU - Bhatt, D.L.* AU - Boer, J.M.* AU - Boerwinkle, E.* AU - Burkley, B.* AU - Burt, A.* AU - Chakravarti, A.* AU - Chen, W.* AU - Cooper-DeHoff, R.M.* AU - Curtis, S.P.* AU - Dreisbach, A.* AU - Duggan, D.* AU - Ehret, G.B.* AU - Fabsitz, R.R.* AU - Fornage, M.* AU - Fox, E.* AU - Furlong, C.E.* AU - Gansevoort, R.T.* AU - Hofker, M.H.* AU - Hovingh, G.K.* AU - Kirkland, S.A.* AU - Kottke-Marchant, K.* AU - Kutlar, A.* AU - LaCroix, A.Z.* AU - Langaee, T.Y.* AU - Li, Y.R.* AU - Lin, H.* AU - Liu, K.* AU - Maiwald, S.* AU - Malik, R.* AU - CARDIoGRAM Consortium (Illig, T. AU - Meisinger, C. AU - Meitinger, T. AU - Peters, A. AU - Döring, A. AU - Klopp, N. AU - Wichmann, H.-E.) AU - METASTROKE Consortium (*) AU - Murugesan, G.* AU - Newton-Cheh, C.* AU - O'Connell, J.R.* AU - Onland-Moret, N.C.* AU - Ouwehand, W.H.* AU - Palmas, W.* AU - Penninx, B.W.* AU - Pepine, C.J.* AU - Pettinger, M.* AU - Polak, J.F.* AU - Ramachandran, V.S.* AU - Ranchalis, J.* AU - Redline, S.* AU - Ridker, P.M.* AU - Rose, L.M.* AU - Scharnag, H.* AU - Schork, N.J.* AU - Shimbo, D.* AU - Shuldiner, A.R.* AU - Srinivasan, S.R.* AU - Stolk, R.P.* AU - Taylor, H.A.* AU - Thorand, B. AU - Trip, M.D.* AU - van Duijn, C.M.* AU - Verschuren, W.M.* AU - Wijmenga, C.* AU - Winkelmann, B.R.* AU - Wyatt, S.* AU - Young, J.H.* AU - Boehm, B.O.* AU - Caulfield, M.J.* AU - Chasman, D.I.* AU - Davidson, K.W.* AU - Doevendans, P.A.* AU - Fitzgerald, G.A.* AU - Gums, J.G.* AU - Hakonarson, H.* AU - Hillege, H.L.* AU - Illig, T. AU - Jarvik, G.P.* AU - Johnson, J.A.* AU - Kastelein, J.J.* AU - Koenig, W.* AU - LifeLines Cohort Study (*) AU - Marz, W.* AU - Mitchell, B.D.* AU - Murray, S.S.* AU - Oldehinkel, A.J.* AU - Rader, D.J.* AU - Reilly, M.P.* AU - Reiner, A.P.* AU - Schadt, E.E.* AU - Silverstein, R.L.* AU - Snieder, H.* AU - Stanton, A.V.* AU - Uitterlinden, A.G.* AU - van der Harst, P.* AU - van der Schouw, Y.T.* AU - Samani, N.J.* AU - Johnson, A.D.* AU - Munroe, P.B.* AU - de Bakker, P.I.* AU - Zhu, X.* AU - Levy, D.* AU - Keating, B.J.* AU - Asselbergs, F.W.* C1 - 24143 C2 - 31334 SP - 1663-1678 TI - Loci influencing blood pressure identified using a cardiovascular gene-centric array. JO - Hum. Mol. Genet. VL - 22 IS - 8 PB - Oxford Univ. Press PY - 2013 SN - 0964-6906 ER - TY - JOUR AB - The peptidase CLPP is conserved from bacteria to humans. In the mitochondrial matrix, it multimerizes and forms a macromolecular proteasome-like cylinder together with the chaperone CLPX. In spite of a known relevance for the mitochondrial unfolded protein response, its substrates and tissue-specific roles are unclear in mammals. Recessive CLPP mutations were recently observed in the human Perrault variant of ovarian failure and sensorineural hearing loss. Here, a first characterization of Clpp null mice demonstrated complete female and male infertility and auditory deficits. Disrupted spermatogenesis already at the spermatid stage and ovarian follicular differentiation failure were evident. Reduced pre-/post-natal survival and marked ubiquitous growth retardation contrasted with only light impairment of movement and respiratory activities. Interestingly, the mice showed resistance to ulcerative dermatitis. Systematic expression studies detected up-regulation of other mitochondrial chaperones, accumulation of CLPX and mtDNA as well as inflammatory factors throughout tissues. T-lymphocytes in the spleen were activated. Thus, murine Clpp deletion represents a faithful Perrault model. The disease mechanism probably involves deficient clearance of mitochondrial components and inflammatory tissue destruction. AU - Gispert, S.* AU - Parganlija, D.* AU - Klinkenberg, M.* AU - Dröse, S.* AU - Wittig, I.* AU - Mittelbronn, M.* AU - Grzmil, P.* AU - Koob, S.* AU - Hamann, A.* AU - Walter, M.* AU - Buchel, F.* AU - Adler, T. AU - Hrabě de Angelis, M. AU - Busch, D.H.* AU - Zell, A.* AU - Reichert, A.S.* AU - Brandt, U.* AU - Osiewacz, H.D.* AU - Jendrach, M.* AU - Auburger, G.* C1 - 25905 C2 - 31982 SP - 4871-4887 TI - Loss of mitochondrial peptidase Clpp leads to infertility, hearing loss plus growth retardation via accumulation of CLPX, mtDNA, and inflammatory factors. JO - Hum. Mol. Genet. VL - 22 IS - 24 PB - Oxford Univ. Press PY - 2013 SN - 0964-6906 ER - TY - JOUR AB - Genetic loci for body mass index (BMI) in adolescence and young adulthood, a period of high risk for weight gain, are understudied, yet may yield important insight into the etiology of obesity and early intervention. To identify novel genetic loci and examine the influence of known loci on BMI during this critical time period in late adolescence and early adulthood, we performed a two-stage meta-analysis using 14 genome-wide association studies in populations of European ancestry with data on BMI between ages 16 and 25 in up to 29 880 individuals. We identified seven independent loci (P < 5.0 × 10⁻⁸) near FTO (P = 3.72 × 10⁻²³), TMEM18 (P = 3.24 × 10⁻¹⁷), MC4R (P = 4.41 × 10⁻¹⁷), TNNI3K (P = 4.32 × 10⁻¹¹), SEC16B (P = 6.24 × 10⁻⁹), GNPDA2 (P = 1.11 × 10⁻⁸) and POMC (P = 4.94 × 10⁻⁸) as well as a potential secondary signal at the POMC locus (rs2118404, P = 2.4 × 10⁻⁵ after conditioning on the established single-nucleotide polymorphism at this locus) in adolescents and young adults. To evaluate the impact of the established genetic loci on BMI at these young ages, we examined differences between the effect sizes of 32 published BMI loci in European adult populations (aged 18-90) and those observed in our adolescent and young adult meta-analysis. Four loci (near PRKD1, TNNI3K, SEC16B and CADM2) had larger effects and one locus (near SH2B1) had a smaller effect on BMI during adolescence and young adulthood compared with older adults (P < 0.05). These results suggest that genetic loci for BMI can vary in their effects across the life course, underlying the importance of evaluating BMI at different ages. AU - Graff, M.* AU - Ngwa, J.S.* AU - Workalemahu, T.* AU - Homuth, G.* AU - Schipf, S.* AU - Teumer, A.* AU - Völzke, H.* AU - Wallaschofski, H.* AU - Abecasis, G.R.* AU - Edward, L.* AU - Francesco, C.* AU - Sanna, S.* AU - Scheet, P.* AU - Schlessinger, D.* AU - Sidore, C.* AU - Xiao, X.* AU - Wang, Z.* AU - Chanock, S.J.* AU - Jacobs, K.B.* AU - Hayes, R.B.* AU - Hu, F.* AU - van Dam, R.M.* AU - GIANT Consortium (Heid, I.M. AU - Grallert, H. AU - Wichmann, H.-E. AU - Thiering, E. AU - Gieger, C. AU - Illig, T. AU - Heinrich, J. AU - Peters, A.) AU - Crout, R.J.* AU - Marazita, M.L.* AU - Shaffer, J.R.* AU - Atwood, L.D.* AU - Fox, C.S.* AU - Heard-Costa, N.L.* AU - White, C.* AU - Choh, A.C.* AU - Czerwinski, S.A.* AU - Demerath, E.W.* AU - Dyer, T.D.* AU - Towne, B.* AU - Amin, N.* AU - Oostra, B.A.* AU - van Duijn, C.M.* AU - Zillikens, M.C.* AU - Esko, T.* AU - Nelis, M.* AU - Nikopensius, T.* AU - Metspalu, A.* AU - Strachan, D.P.* AU - Monda, K.L.* AU - Qi, L.* AU - North, K.E.* AU - Cupples, L.A.* AU - Gordon-Larsen, P.* AU - Berndt, S.I.* C1 - 28182 C2 - 32995 SP - 3597-3607 TI - Genome-wide analysis of BMI in adolescents and young adults reveals additional insight into the effects of genetic loci over the life course. JO - Hum. Mol. Genet. VL - 22 IS - 17 PB - Oxford Univ. Press PY - 2013 SN - 0964-6906 ER - TY - JOUR AB - Recent genetic association studies have made progress in uncovering components of the genetic architecture of the body mass index (BMI). We used the ITMAT-Broad-Candidate Gene Association Resource (CARe) (IBC) array comprising up to 49 320 single nucleotide polymorphisms (SNPs) across ~2100 metabolic and cardiovascular-related loci to genotype up to 108 912 individuals of European ancestry (EA), African-Americans, Hispanics and East Asians, from 46 studies, to provide additional insight into SNPs underpinning BMI. We used a five-phase study design: Phase I focused on meta-analysis of EA studies providing individual level genotype data; Phase II performed a replication of cohorts providing summary level EA data; Phase III meta-analyzed results from the first two phases; associated SNPs from Phase III were used for replication in Phase IV; finally in Phase V, a multi-ethnic meta-analysis of all samples from four ethnicities was performed. At an array-wide significance (P < 2.40E-06), we identify novel BMI associations in loci translocase of outer mitochondrial membrane 40 homolog (yeast) - apolipoprotein E - apolipoprotein C-I (TOMM40-APOE-APOC1) (rs2075650, P = 2.95E-10), sterol regulatory element binding transcription factor 2 (SREBF2, rs5996074, P = 9.43E-07) and neurotrophic tyrosine kinase, receptor, type 2 [NTRK2, a brain-derived neurotrophic factor (BDNF) receptor gene, rs1211166, P = 1.04E-06] in the Phase IV meta-analysis. Of 10 loci with previous evidence for BMI association represented on the IBC array, eight were replicated, with the remaining two showing nominal significance. Conditional analyses revealed two independent BMI-associated signals in BDNF and melanocortin 4 receptor (MC4R) regions. Of the 11 array-wide significant SNPs, three are associated with gene expression levels in both primary B-cells and monocytes; with rs4788099 in SH2B adaptor protein 1 (SH2B1) notably being associated with the expression of multiple genes in cis. These multi-ethnic meta-analyses expand our knowledge of BMI genetics. AU - Guo, Y.* AU - Lanktree, M.B.* AU - Taylor, K.C.* AU - Hakonarson, H.* AU - Lange, L.A.* AU - Keating, B.J.* AU - IBC 50K SNP Array BMI Consortium (Baumert, J.J. AU - Gieger, C. AU - Gorski, M. AU - Heid, I.M. AU - Illig, T. AU - Peters, A. AU - Thorand, B. AU - Wichmann, H.-E.) C1 - 22464 C2 - 30872 SP - 184-201 TI - Gene-centric meta-analyses of 108912 individuals confirm known body mass index loci and reveal three novel signals. JO - Hum. Mol. Genet. VL - 22 IS - 1 PB - Oxford Univ. Press PY - 2013 SN - 0964-6906 ER - TY - JOUR AB - Parkinson's disease (PD) is the second most common neurodegenerative disease affecting 1-2% in people >60 and 3-4% in people >80. Genome-wide association (GWA) studies have now implicated significant evidence for association in at least 18 genomic regions. We have studied a large PD-meta analysis and identified a significant excess of SNPs (P < 1 × 10(-16)) that are associated with PD but fall short of the genome-wide significance threshold. This result was independent of variants at the 18 previously implicated regions and implies the presence of additional polygenic risk alleles. To understand how these loci increase risk of PD, we applied a pathway-based analysis, testing for biological functions that were significantly enriched for genes containing variants associated with PD. Analysing two independent GWA studies, we identified that both had a significant excess in the number of functional categories enriched for PD-associated genes (minimum P = 0.014 and P = 0.006, respectively). Moreover, 58 categories were significantly enriched for associated genes in both GWA studies (P < 0.001), implicating genes involved in the 'regulation of leucocyte/lymphocyte activity' and also 'cytokine-mediated signalling' as conferring an increased susceptibility to PD. These results were unaltered by the exclusion of all 178 genes that were present at the 18 genomic regions previously reported to be strongly associated with PD (including the HLA locus). Our findings, therefore, provide independent support to the strong association signal at the HLA locus and imply that the immune-related genetic susceptibility to PD is likely to be more widespread in the genome than previously appreciated. AU - Holmans, P.* AU - Moskvina, V.* AU - Jones, L.* AU - Sharma, M.* AU - International Parkinson's Disease Genomics Consortium (IPDGC) (Illig, T. AU - Lichtner, P.) AU - Vedernikov, A.* AU - Buchel, F.* AU - Saad, M.* AU - Bras, J.M.* AU - Bettella, F.* AU - Nicolaou, N.* AU - Simon-Sanchez, J.* AU - Mittag, F.* AU - Gibbs, J.R.* AU - Schulte, C.* AU - Dürr, A.* AU - Guerreiro, R.* AU - Hernandez, D.* AU - Brice, A.* AU - Stefansson, H.* AU - Majamaa, K.* AU - Gasser, T.* AU - Heutink, P.* AU - Wood, N.W.* AU - Martinez, M.* AU - Singleton, A.B.* AU - Nalls, M.A.* AU - Hardy, J.* AU - Morris, H.R.* AU - Williams, N.M.* C1 - 23004 C2 - 30980 SP - 1039-1049 TI - A pathway-based analysis provides additional support for an immune-related genetic susceptibility to Parkinson's disease. JO - Hum. Mol. Genet. VL - 22 IS - 5 PB - Oxford Univ. Press PY - 2013 SN - 0964-6906 ER - TY - JOUR AB - Uromodulin-associated kidney disease (UAKD) is a dominant heritable renal disease in humans which is caused by mutations in the uromodulin (UMOD) gene and characterized by heterogeneous clinical appearance. To get insights into possible causes of this heterogeneity of UAKD, we describe the new mutant mouse line UmodC93F, leading to disruption of a putative disulfide bond which is also absent in a known human UMOD mutation, and compare the phenotype of this new mouse line with the recently published mouse line UmodA227T. In both mutant mouse lines, which were both bred on the C3H background, the Umod mutations cause a gain-of-toxic function due to a maturation defect of the mutant uromodulin leading to a dysfunction of thick ascending limb of Henle's loop (TALH) cells of the kidney. Umod mutant mice exhibit increased plasma urea and cystatin levels, impaired urinary concentration ability, reduced fractional excretion of uric acid, and nephropathological alterations including uromodulin retention in TALH cells, interstitial fibrosis and inflammatory cell infiltrations, tubular atrophy, and occasional glomerulo- und tubulocystic changes, a phenotype highly similar to UAKD in humans. The maturation defect of mutant uromodulin leads to the accumulation of immature uromodulin in the endoplasmic reticulum (ER) and to ER hyperplasia. Further, this study was able to demonstrate for the first time in vivo that the severity of the uromodulin maturation defect as well as onset and speed of progression of renal dysfunction and morphological alterations are strongly dependent on the particular Umod mutation itself and the zygosity status. AU - Kemter, E.* AU - Prueckl, P.* AU - Sklenak, S.* AU - Rathkolb, B. AU - Habermann, F.A.* AU - Hans, W. AU - Gailus-Durner, V. AU - Fuchs, H. AU - Hrabě de Angelis, M. AU - Wolf, E.* AU - Aigner, B.* AU - Wanke, R.* C1 - 24845 C2 - 31707 SP - 4148-4163 TI - Type of uromodulin mutation and allelic status influence onset and severity of uromodulin-associated kidney disease in mice. JO - Hum. Mol. Genet. VL - 22 IS - 20 PB - Oxford Univ. Press PY - 2013 SN - 0964-6906 ER - TY - JOUR AB - Genetic variations in FTO, a well-replicated gene locus of obesity, appear to be associated also with reduced regional brain volumes in elderly. Here, we examined whether FTO is associated with total brain-volume in adolescence, thus exploring possible developmental effects of FTO. We studied a population-based sample of 598 adolescents recruited from the French-Canadian founder population in whom we measured brain volume by magnetic resonance imaging. Total fat mass was assessed with bioimpedance and body mass index was determined with anthropometry. Genotype-phenotype associations were tested with Merlin under an additive model. We found that the G allele of fto (rs9930333) was associated with higher total body fat (p=0.002) and lower brain volume (p=0.005). The same allele was also associated with higher lean body mass (p=0.03) and no difference in height (p=0.99). Principal component analysis identified a shared inverse variance between the brain volume and total body fat, which was associated with FTO at p=5.5x10(-6). These results were replicated in two independent samples of 413 and 718 adolescents; in a meta-analysis of all three samples (n=1,729 adolescents), FTO was associated with this shared inverse variance at p=1.3x10(-9). Co-expression networks analysis supported the possibility that the underlying FTO effects may occur during embryogenesis. In conclusion, FTO is associated with shared inverse variance between body adiposity and brain volume, suggesting that this gene may exert inverse effects on adipose and brain tissues. Given the completion of the overall brain growth in early childhood, these effects may have their origins during early development. AU - Melka, M.G.* AU - Gillis, J.* AU - Bernard, M.* AU - Abrahamowicz, M.* AU - Chakravarty, M.M.* AU - Leonard, G.T.* AU - Perron, M.* AU - Richer, L.* AU - Veillette, S.* AU - Banaschewski, T.* AU - Barker, G.J.* AU - Büchel, C.* AU - Conrod, P.* AU - Flor, H.* AU - Heinz, A.* AU - Garavan, H.* AU - Brühl, R.* AU - Mann, K.* AU - Artiges, E.* AU - Lourdusamy, A.* AU - Lathrop, M* AU - Loth, E.* AU - Schwartz, Y.* AU - Frouin, V.* AU - Rietschel, M.* AU - Smolka, M.N.* AU - Ströhle, A.* AU - Gallinat, J.* AU - Struve, M.* AU - Lattka, E. AU - Waldenberger, M. AU - Schumann, G.* AU - Pavlidis, P.* AU - Gaudet, D.* AU - Paus, T.* AU - Pausova, Z.* C1 - 11406 C2 - 30652 SP - 1050-1058 TI - FTO, obesity and the adolescent brain. JO - Hum. Mol. Genet. VL - 22 IS - 5 PB - Oxford Univ. Press PY - 2013 SN - 0964-6906 ER - TY - JOUR AB - Increased systemic levels of myeloperoxidase (MPO) are associated with the risk of coronary artery disease (CAD). To identify the genetic factors that are associated with circulating MPO levels, we carried out a genome-wide association study (GWAS) and a gene-centric analysis in subjects of European ancestry and African Americans (AAs). A locus on chromosome 1q31.1 containing the complement factor H (CFH) gene was strongly associated with serum MPO levels in 9305 subjects of European ancestry (lead SNP rs800292; P = 4.89 × 10(-41)) and in 1690 AA subjects (rs505102; P = 1.05 × 10(-8)). Gene-centric analyses in 8335 subjects of European ancestry additionally identified two rare MPO coding sequence variants that were associated with serum MPO levels (rs28730837, P = 5.21 × 10(-12); rs35897051, P = 3.32 × 10(-8)). A GWAS for plasma MPO levels in 9260 European ancestry subjects identified a chromosome 17q22 region near MPO that was significantly associated (lead SNP rs6503905; P = 2.94 × 10(-12)), but the CFH locus did not exhibit evidence of association with plasma MPO levels. Functional analyses revealed that rs800292 was associated with levels of complement proteins in serum. Variants at chromosome 17q22 also had pleiotropic cis effects on gene expression. In a case-control analysis of ∼80 000 subjects from CARDIoGRAM, none of the identified single-nucleotide polymorphisms (SNPs) were associated with CAD. These results suggest that distinct genetic factors regulate serum and plasma MPO levels, which may have relevance for various acute and chronic inflammatory disorders. The clinical implications for CAD and a better understanding of the functional basis for the association of CFH and MPO variants with circulating MPO levels require further study. AU - Reiner, A.P.* AU - Hartiala, J.* AU - Zeller, T.* AU - Bis, J.C.* AU - Dupuis, J.* AU - Fornage, M.* AU - Baumert, J.J. AU - Kleber, M.E.* AU - Wild, P.S.* AU - Baldus, S.* AU - Bielinski, S.J.* AU - Fontes, J.D.* AU - Illig, T. AU - Keating, B.J.* AU - Lange, L.A.* AU - Ojeda, F.* AU - Müller-Nurasyid, M. AU - Munzel, T.F.* AU - Psaty, B.M.* AU - Rice, K.* AU - Rotter, J.I.* AU - Schnabel, R.B.* AU - Tang, W.H.* AU - Thorand, B. AU - Erdmann, J.* AU - CARDIoGRAM Consortium (Wichmann, H.-E. AU - Illig, T. AU - Klopp, N. AU - Meitinger, T. AU - Peters, A. AU - Meisinger, C. AU - Döring, A.) AU - Jacobs, D.R.* AU - Wilson, J.G.* AU - Koenig, W.* AU - Tracy, R.P.* AU - Blankenberg, S.* AU - Marz, W.* AU - Gross, M.D.* AU - Benjamin, E.J.* AU - Hazen, S.L.* AU - Allayee, H.* C1 - 26613 C2 - 32302 SP - 3381-3393 TI - Genome-wide and gene-centric analyses of circulating myeloperoxidase levels in the charge and care consortia. JO - Hum. Mol. Genet. VL - 22 IS - 16 PB - Oxford Univ. Press PY - 2013 SN - 0964-6906 ER - TY - JOUR AB - Visual refractive errors (REs) are complex genetic traits with a largely unknown etiology. To date, genome-wide association studies (GWASs) of moderate size have identified several novel risk markers for RE, measured here as mean spherical equivalent (MSE). We performed a GWAS using a total of 7280 samples from five cohorts: the Age-Related Eye Disease Study (AREDS); the KORA study ('Cooperative Health Research in the Region of Augsburg'); the Framingham Eye Study (FES); the Ogliastra Genetic Park-Talana (OGP-Talana) Study and the Multiethnic Study of Atherosclerosis (MESA). Genotyping was performed on Illumina and Affymetrix platforms with additional markers imputed to the HapMap II reference panel. We identified a new genome-wide significant locus on chromosome 16 (rs10500355, P = 3.9 × 10(-9)) in a combined discovery and replication set (26 953 samples). This single nucleotide polymorphism (SNP) is located within the RBFOX1 gene which is a neuron-specific splicing factor regulating a wide range of alternative splicing events implicated in neuronal development and maturation, including transcription factors, other splicing factors and synaptic proteins. AU - Stambolian, D.* AU - Wojciechowski, R.* AU - Oexle, K.* AU - Pirastu, M.* AU - Li, X.* AU - Raffel, L.J.* AU - Cotch, M.F.* AU - Chew, E.Y.* AU - Klein, B.* AU - Klein, R.* AU - Wong, T.Y.* AU - Simpson, C.L.* AU - Klaver, C.C.* AU - van Duijn, C.M.* AU - Verhoeven, V.J.* AU - Baird, P.N.* AU - Vitart, V.* AU - Paterson, A.D.* AU - Mitchell, P.* AU - Saw, S.M.* AU - Fossarello, M.* AU - Kazmierkiewicz, K.* AU - Murgia, F.* AU - Portas, L.* AU - Schache, M.* AU - Richardson, A.* AU - Xie, J.* AU - Wang, J.J.* AU - Rochtchina, E.* AU - DCCT/EDIC Research Group (*) AU - Viswanathan, A.C.* AU - Hayward, C.* AU - Wright, A.F.* AU - Polasek, O.* AU - Campbell, H.* AU - Rudan, I.* AU - Oostra, B.A.* AU - Uitterlinden, A.G.* AU - Hofman, A.* AU - Rivadeneira, F.* AU - Amin, N.* AU - Karssen, L.C.* AU - Vingerling, J.R.* AU - Hosseini, S.M.* AU - Döring, A. AU - Bettecken, T. AU - Vatavuk, Z.* AU - Gieger, C. AU - Wichmann, H.-E. AU - Wilson, J.F.* AU - Fleck, B.* AU - Foster, P.J.* AU - Topouzis, F.* AU - McGuffin, P.* AU - Sim, X.* AU - Inouye, M.* AU - Holliday, E.G.* AU - Attia, J.* AU - Scott, R.J.* AU - Rotter, J.I.* AU - Meitinger, T. AU - Bailey-Wilson, J.E.* C1 - 25234 C2 - 31853 SP - 2754-2764 TI - Meta-analysis of genome-wide association studies in five cohorts reveals common variants in RBFOX1, a regulator of tissue-specific splicing, associated with refractive error. JO - Hum. Mol. Genet. VL - 22 IS - 13 PB - Oxford Univ. Press PY - 2013 SN - 0964-6906 ER - TY - JOUR AB - Atopic dermatitis (AD) is the most common dermatological disease of childhood. Many children with AD have asthma and AD shares regions of genetic linkage with psoriasis, another chronic inflammatory skin disease. We present here a genome-wide association study (GWAS) of childhood-onset AD in 1563 European cases with known asthma status and 4054 European controls. Using Illumina genotyping followed by imputation, we generated 268 034 consensus genotypes and in excess of 2 million single nucleotide polymorphisms (SNPs) for analysis. Association signals were assessed for replication in a second panel of 2286 European cases and 3160 European controls. Four loci achieved genome-wide significance for AD and replicated consistently across all cohorts. These included the epidermal differentiation complex (EDC) on chromosome 1, the genomic region proximal to LRRC32 on chromosome 11, the RAD50/IL13 locus on chromosome 5 and the major histocompatibility complex (MHC) on chromosome 6; reflecting action of classical HLA alleles. We observed variation in the contribution towards co-morbid asthma for these regions of association. We further explored the genetic relationship between AD, asthma and psoriasis by examining previously identified susceptibility SNPs for these diseases. We found considerable overlap between AD and psoriasis together with variable coincidence between allergic rhinitis (AR) and asthma. Our results indicate that the pathogenesis of AD incorporates immune and epidermal barrier defects with combinations of specific and overlapping effects at individual loci. AU - Weidinger, S.* AU - Willis-Owen, S.A.* AU - Kamatani, Y.* AU - Baurecht, H.* AU - Morar, N.* AU - Liang, L.* AU - Edser, P.* AU - Street, T.* AU - Rodriguez, E.* AU - O'Regan, G.M.* AU - Beattie, P.* AU - Fölster-Holst, R.* AU - Franke, A.* AU - Novak, N.* AU - Fahy, C.M.* AU - Winge, M.C.G.* AU - Kabesch, M.* AU - Illig, T. AU - Heath, S.* AU - Söderhäll, C.* AU - Melén, E.* AU - Pershagen, G.* AU - Kere, J.* AU - Bradley, M.* AU - Liedén, A.* AU - Nordenskjöld, M.* AU - Harper, J.I.* AU - McLean, W.H.* AU - Brown, S.J.* AU - Cookson, W.O.* AU - Lathrop, G.M.* AU - Irvine, A.D.* AU - Moffatt, M.F.* C1 - 28492 C2 - 33426 SP - 4841-4856 TI - A genome-wide association study of atopic dermatitis identifies loci with overlapping effects on asthma and psoriasis. JO - Hum. Mol. Genet. VL - 22 IS - 23 PB - Oxford Univ. Press PY - 2013 SN - 0964-6906 ER - TY - JOUR AB - The male-to-female sex ratio at birth is constant across world populations with an average of 1.06 (106 male to 100 female live births) for populations of European descent. The sex ratio is considered to be affected by numerous biological and environmental factors and to have a heritable component. The aim of this study was to investigate the presence of common allele modest effects at autosomal and chromosome X variants that could explain the observed sex ratio at birth. We conducted a large-scale genome-wide association scan (GWAS) meta-analysis across 51 studies, comprising overall 114 863 individuals (61 094 women and 53 769 men) of European ancestry and 2 623 828 common (minor allele frequency >0.05) single-nucleotide polymorphisms (SNPs). Allele frequencies were compared between men and women for directly-typed and imputed variants within each study. Forward-time simulations for unlinked, neutral, autosomal, common loci were performed under the demographic model for European populations with a fixed sex ratio and a random mating scheme to assess the probability of detecting significant allele frequency differences. We do not detect any genome-wide significant (P < 5 × 10(-8)) common SNP differences between men and women in this well-powered meta-analysis. The simulated data provided results entirely consistent with these findings. This large-scale investigation across ∼115 000 individuals shows no detectable contribution from common genetic variants to the observed skew in the sex ratio. The absence of sex-specific differences is useful in guiding genetic association study design, for example when using mixed controls for sex-biased traits. AU - Boraska, V.* AU - Jeroncic, A.* AU - Colonna, V.* AU - Southam, L.* AU - Nyholt, D.R.* AU - William Rayner, N.* AU - Perry, J.R.* AU - Toniolo, D.* AU - Albrecht, E. AU - Ang, W.* AU - Bandinelli, S.* AU - Barbalic, M.* AU - Barroso, I.* AU - Beckmann, J.S.* AU - Biffar, R.* AU - Boomsma, D.* AU - Campbell, H.* AU - Corre, T.* AU - Erdmann, J.* AU - Esko, T.* AU - Fischer, K.* AU - Franceschini, N.* AU - Frayling, T.M.* AU - Girotto, G.* AU - Gonzalez, J.R.* AU - Harris, T.B.* AU - Heath, A.C.* AU - Heid, I.M. AU - Hoffmann, W.* AU - Hofman, A.* AU - Horikoshi, M.* AU - Hua Zhao, J.* AU - Jackson, A.U.* AU - Hottenga, J.J.* AU - Jula, A.* AU - Kähönen, M.* AU - Khaw, K.T.* AU - Kiemeney, L.A.* AU - Klopp, N.* AU - Kutalik, Z.* AU - Lagou, V.* AU - Launer, L.J.* AU - Lehtimäki, T.* AU - Lemire, M.* AU - Lokki, M.L.* AU - Loley, C.* AU - Luan, J.* AU - Mangino, M.* AU - Mateo Leach, I.* AU - Medland, S.E.* AU - Mihailov, E.* AU - Montgomery, G.W.* AU - Navis, G.* AU - Newnham, J.* AU - Nieminen, M.S.* AU - Palotie, A.* AU - Panoutsopoulou, K.* AU - Peters, A.* AU - Pirastu, N.* AU - Polasek, O.* AU - Rehnström, K.* AU - Ripatti, S.* AU - Ritchie, G.R.* AU - Rivadeneira, F.* AU - Robino, A.* AU - Samani, N.J.* AU - Shin, S.Y.* AU - Sinisalo, J.* AU - Smit, J.H.* AU - Soranzo, N.* AU - Stolk, L.* AU - Swinkels, D.W.* AU - Tanaka, T.* AU - Teumer, A.* AU - Tönjes, A.* AU - Traglia, M.* AU - Tuomilehto, J.* AU - Valsesia, A.* AU - van Gilst, W.H.* AU - van Meurs, J.B.* AU - Smith, A.V.* AU - Viikari, J.* AU - Vink, J.M.* AU - Waeber, G.* AU - Warrington, N.M.* AU - Widen, E.* AU - Willemsen, G.* AU - Wright, A.F.* AU - Zanke, B.W.* AU - Zgaga, L.* AU - Wellcome Trust Case Consortium (WTCCC) (*) AU - Boehnke, M.* AU - d'Adamo, A.P.* AU - de Geus, E.* AU - Demerath, E.W.* AU - den Heijer, M.* AU - Eriksson, J.G.* AU - Ferrucci, L.* AU - Gieger, C.* AU - Gudnason, V.* AU - Hayward, C.* AU - Hengstenberg, C.* AU - Hudson, T.J.* AU - Jarvelin, M.R.* AU - Kogevinas, M.* AU - Loos, R.J.* AU - Martin, N.G.* AU - Metspalu, A.* AU - Pennell, C.E.* AU - Penninx, B.W.* AU - Perola, M.* AU - Raitakari, O.* AU - Salomaa, V.* AU - Schreiber, S.* AU - Schunkert, H.* AU - Spector, T.D.* AU - Stumvoll, M.* AU - Uitterlinden, A.G.* AU - Ulivi, S.* AU - van der Harst, P.* AU - Vollenweider, P.* AU - Völzke, H.* AU - Wareham, N.J.* AU - Wichmann, H.-E. AU - Wilson, J.F.* AU - Rudan, I.* AU - Xue, Y.* AU - Zeggini, E.* C1 - 11210 C2 - 30550 SP - 4805-4815 TI - Genome-wide meta-analysis of common variant differences between men and women. JO - Hum. Mol. Genet. VL - 21 IS - 21 PB - Oxford Univ. Press PY - 2012 SN - 0964-6906 ER - TY - JOUR AB - In conducting genome-wide association studies (GWAS), analytical approaches leveraging biological information may further understanding of the pathophysiology of clinical traits. To discover novel associations with estimated glomerular filtration rate (eGFR), a measure of kidney function, we developed a strategy for integrating prior biological knowledge into the existing GWAS data for eGFR from the CKDGen Consortium. Our strategy focuses on single nucleotide polymorphism (SNPs) in genes that are connected by functional evidence, determined by literature mining and gene ontology (GO) hierarchies, to genes near previously validated eGFR associations. It then requires association thresholds consistent with multiple testing, and finally evaluates novel candidates by independent replication. Among the samples of European ancestry, we identified a genome-wide significant SNP in FBXL20 (P 5.6 10(9)) in meta-analysis of all available data, and additional SNPs at the INHBC, LRP2, PLEKHA1, SLC3A2 and SLC7A6 genes meeting multiple-testing corrected significance for replication and overall P-values of 4.5 10(4)2.2 10(7). Neither the novel PLEKHA1 nor FBXL20 associations, both further supported by association with eGFR among African Americans and with transcript abundance, would have been implicated by eGFR candidate gene approaches. LRP2, encoding the megalin receptor, was identified through connection with the previously known eGFR gene DAB2 and extends understanding of the megalin system in kidney function. These findings highlight integration of existing genome-wide association data with independent biological knowledge to uncover novel candidate eGFR associations, including candidates lacking known connections to kidney-specific pathways. The strategy may also be applicable to other clinical phenotypes, although more testing will be needed to assess its potential for discovery in general. AU - Chasman, D.I.* AU - Fuchsberger, C.* AU - Pattaro, C.* AU - Teumer, A.* AU - Böger, C.A.* AU - Endlich, K.* AU - Olden, M.* AU - Chen, M.-H.* AU - Tin, A.* AU - Taliun, D.* AU - Li, M.* AU - Gao, X.Y.* AU - Gorski, M.* AU - Yang, Q.* AU - Hundertmark, C.* AU - Foster, M.C.* AU - O'Seaghdha, C.M.* AU - Glazer, N.* AU - Isaacs, A.* AU - Liu, C.-T.* AU - Smith, A.V.* AU - O'Connell, J.R.* AU - Struchalin, M.* AU - Tanaka, T.* AU - Li, G.* AU - Johnson, A.D.* AU - Gierman, H.J.* AU - Feitosa, M.F.* AU - Hwang, S.-J.* AU - Atkinson, E.J.* AU - Lohman, K.* AU - Cornelis, M.C.* AU - Johansson, A.* AU - Tönjes, A.* AU - Dehghan, A.* AU - Lambert, J.-C.* AU - Holliday, E.G.* AU - Sorice, R.* AU - Kutalik, Z.* AU - Lehtimäki, T.* AU - Esko, T.* AU - Deshmukh, H.* AU - Ulivi, S.* AU - Chu, A.Y.* AU - Murgia, F.* AU - Trompet, S.* AU - Imboden, M.* AU - Coassin, S.* AU - Pistis, G.* AU - Harris, T.B.* AU - Launer, L.J.* AU - Aspelund, T.* AU - Eiriksdottir, G.* AU - Mitchell, B.D.* AU - Boerwinkle, E.* AU - Schmidt, H.* AU - Cavalieri, M.* AU - Rao, M.* AU - Hu, F.* AU - Demirkan, A.* AU - Oostra, B.A.* AU - de Andrade, M.* AU - Turner, S.T.* AU - Ding, J.Z.* AU - Andrews, J.S.* AU - Freedman, B.I.* AU - Giulianini, F.* AU - Koenig, W.* AU - Illig, T. AU - Meisinger, C. AU - Gieger, C. AU - Zgaga, L.* AU - Zemunik, T.* AU - Boban, M.* AU - Minelli, C.* AU - Wheeler, H.E.* AU - Igl, W.* AU - Zaboli, G.* AU - Wild, S.H.* AU - Wright, A.F.* AU - Campbell, H.* AU - Ellinghaus, D.* AU - Nöthlings, U.* AU - Jacobs, G.* AU - Biffar, R.* AU - Ernst, F.* AU - Homuth, G.* AU - Kroemer, H.K.* AU - Nauck, M.* AU - Stracke, S.* AU - Völker, U.* AU - Völzke, H.* AU - Kovacs, P.* AU - Stumvoll, M.* AU - Mägi, R.* AU - Hofman, A.* AU - Uitterlinden, A.G.* AU - Rivadeneira, F.* AU - Aulchenko, Y.S.* AU - Polasek, O.* AU - Hastie, N.* AU - Vitart, V.* AU - Helmer, C.* AU - Wang, J.J.* AU - Stengel, B.* AU - Ruggiero, D.* AU - Bergmann, S.* AU - Kähönen, M.* AU - Viikari, J.* AU - Nikopensius, T.* AU - Province, M.* AU - Ketkar, S.* AU - Colhoun, H.* AU - Doney, A.* AU - Robino, A.* AU - Krämer, B.K.* AU - Portas, L.* AU - Ford, I.* AU - Buckley, B.M.* AU - Adam, M.* AU - Thun, G.-A.* AU - Paulweber, B.* AU - Haun, M.* AU - Sala, C.* AU - Mitchell, P.* AU - Ciullo, M.* AU - Kim, S.K.* AU - Vollenweider, P.* AU - Raitakari, O.* AU - Metspalu, A.* AU - Palmer, C.* AU - Gasparini, P.* AU - Pirastu, M.* AU - Jukema, J.W.* AU - Probst-Hensch, N.M.* AU - Kronenberg, F.* AU - Toniolo, D.* AU - Gudnason, V.* AU - Shuldiner, A.R.* AU - Coresh, J.* AU - Schmidt, R.* AU - Ferrucci, L.* AU - Siscovick, D.S.* AU - van Duijn, C.M.* AU - Borecki, I.B.* AU - Kardia, S.L.R.* AU - Liu, Y.M.* AU - Curhan, G.C.* AU - Rudan, I.* AU - Gyllensten, U.* AU - Wilson, J.F.* AU - Franke, A.* AU - Pramstaller, P.P.* AU - Rettig, R.* AU - Prokopenko, I.* AU - Witteman, J.* AU - Hayward, C.* AU - Ridker, P.M.* AU - Parsa, A.* AU - Bochud, M.* AU - Heid, I.M. AU - Kao, W.H.L.* AU - Fox, C.S.* AU - Köttgen, A.* C1 - 11534 C2 - 30686 SP - 5329-5343 TI - Integration of genome-wide association studies with biological knowledge identifies six novel genes related to kidney function. JO - Hum. Mol. Genet. VL - 21 IS - 24 PB - Oxford Univ. Press PY - 2012 SN - 0964-6906 ER - TY - JOUR AB - To identify a novel susceptibility locus for type 2 diabetes, we performed an imputation-based, genome-wide association study (GWAS) in a Japanese population using newly obtained imputed-genotype data for 2 229 890 single-nucleotide polymorphisms (SNPs) estimated from previously reported, directly genotyped GWAS data in the same samples (stage 1: 4470 type 2 diabetes versus 3071 controls). We directly genotyped 43 new SNPs with P-values of <10(-4) in a part of stage-1 samples (2692 type 2 diabetes versus 3071 controls), and the associations of validated SNPs were evaluated in another 11 139 Japanese individuals (stage 2: 7605 type 2 diabetes versus 3534 controls). Combined meta-analysis using directly genotyped data for stages 1 and 2 revealed that rs515071 in ANK1 and rs7656416 near MGC21675 were associated with type 2 diabetes in the Japanese population at the genome-wide significant level (P < 5 × 10(-8)). The association of rs515071 was also observed in European GWAS data (combined P for all populations = 6.14 × 10(-10)). Rs7656416 was in linkage disequilibrium to rs6815464, which had recently been identified as a top signal in a meta-analysis of East Asian GWAS for type 2 diabetes (r(2) = 0.76 in stage 2). The association of rs7656416 with type 2 diabetes disappeared after conditioning on rs6815464. These results indicate that the ANK1 locus is a new, common susceptibility locus for type 2 diabetes across different ethnic groups. The signal of association was weaker in the directly genotyped data, so the improvement in signal indicates the importance of imputation in this particular case. AU - Imamura, M.* AU - Maeda, S.* AU - Yamauchi, T.* AU - Hara, K.* AU - Yasuda, K.* AU - Morizono, T.* AU - Takahashi, A.* AU - Horikoshi, M.* AU - Nishimura, M.* AU - Fujita, H.* AU - Tsunoda, T.* AU - Kubo, M.* AU - Watada, H.* AU - Maegawa, H.* AU - Okada-Iwabu, M.* AU - Iwabu, M.* AU - Shojima, N.* AU - Ohshige, T.* AU - Omori, S.* AU - Iwata, M.* AU - Hirose, H.* AU - Kaku, K.* AU - Ito, C.* AU - Tanaka, Y.* AU - Tobe, K.* AU - Kashiwagi, A.* AU - Kawamori, R.* AU - DIAGRAM Consortium (Huth, C. AU - Grallert, H. AU - Gieger, C. AU - Klopp, N. AU - Meitinger, T. AU - Petersen, A.-K. AU - Thorand, B. AU - Wichmann, H.-E. AU - Illig, T.) AU - Kasuga, M.* AU - Kamatani, N.* C1 - 10839 C2 - 30392 SP - 3042-3049 TI - A single-nucleotide polymorphism in ANK1 is associated with susceptibility to type 2 diabetes in Japanese populations. JO - Hum. Mol. Genet. VL - 21 IS - 13 PB - Oxford Univ. Press PY - 2012 SN - 0964-6906 ER - TY - JOUR AB - Genome-wide association studies (GWASs) have been successful at identifying single-nucleotide polymorphisms (SNPs) highly associated with common traits; however, a great deal of the heritable variation associated with common traits remains unaccounted for within the genome. Genome-wide complex trait analysis (GCTA) is a statistical method that applies a linear mixed model to estimate phenotypic variance of complex traits explained by genome-wide SNPs, including those not associated with the trait in a GWAS. We applied GCTA to 8 cohorts containing 7096 case and 19 455 control individuals of European ancestry in order to examine the missing heritability present in Parkinson's disease (PD). We meta-analyzed our initial results to produce robust heritability estimates for PD types across cohorts. Our results identify 27% (95% CI 17-38, P = 8.08E - 08) phenotypic variance associated with all types of PD, 15% (95% CI -0.2 to 33, P = 0.09) phenotypic variance associated with early-onset PD and 31% (95% CI 17-44, P = 1.34E - 05) phenotypic variance associated with late-onset PD. This is a substantial increase from the genetic variance identified by top GWAS hits alone (between 3 and 5%) and indicates there are substantially more risk loci to be identified. Our results suggest that although GWASs are a useful tool in identifying the most common variants associated with complex disease, a great deal of common variants of small effect remain to be discovered. AU - Keller, M.F.* AU - Saad, M.* AU - Bras, J.* AU - Bettella, F.* AU - Nicolaou, N.* AU - Simon-Sanchez, J.* AU - Mittag, F.* AU - Buchel, F.* AU - Sharma, M.* AU - Gibbs, J.R.* AU - Schulte, C.* AU - Moskvina, V.* AU - Dürr, A.* AU - Holmans, P.* AU - Kilarski, L.L.* AU - Guerreiro, R.* AU - Hernandez, D.G.* AU - Brice, A.* AU - Ylikotila, P.* AU - Stefansson, H.* AU - Majamaa, K.* AU - Morris, H.R.* AU - Williams, N.* AU - Gasser, T.* AU - Heutink, P.* AU - Wood, N.W.* AU - Hardy, J.* AU - Martinez, M.* AU - Singleton, A.B.* AU - Nalls, M.A.* AU - International Parkinson's Disease Genomics Consortium (IPDGC) (Illig, T. AU - Lichtner, P.) AU - Wellcome Trust Case Control Consortium 2 (WTCCC2) (*) C1 - 26402 C2 - 32212 SP - 4996-5009 TI - Using genome-wide complex trait analysis to quantify 'missing heritability' in Parkinson's disease. JO - Hum. Mol. Genet. VL - 21 IS - 22 PB - Oxord Univ. Press PY - 2012 SN - 0964-6906 ER - TY - JOUR AB - Prion diseases are fatal neurodegenerative diseases of humans and animals caused by the misfolding and aggregation of prion protein (PrP). Mammalian prion diseases are under strong genetic control but few risk factors are known aside from the PrP gene locus (PRNP). No genome-wide association study (GWAS) has been done aside from a small sample of variant Creutzfeldt-Jakob disease (CJD). We conducted GWAS of sporadic CJD (sCJD), variant CJD (vCJD), iatrogenic CJD, inherited prion disease, kuru and resistance to kuru despite attendance at mortuary feasts. After quality control, we analysed 2000 samples and 6015 control individuals (provided by the Wellcome Trust Case Control Consortium and KORA-gen) for 491032-511862 SNPs in the European study. Association studies were done in each geographical and aetiological group followed by several combined analyses. The PRNP locus was highly associated with risk in all geographical and aetiological groups. This association was driven by the known coding variation at rs1799990 (PRNP codon 129). No non-PRNP loci achieved genome-wide significance in the meta-analysis of all human prion disease. SNPs at the ZBTB38-RASA2 locus were associated with CJD in the UK (rs295301, P = 3.13 × 10(-8); OR, 0.70) but these SNPs showed no replication evidence of association in German sCJD or in Papua New Guinea-based tests. A SNP in the CHN2 gene was associated with vCJD [P = 1.5 × 10(-7); odds ratio (OR), 2.36], but not in UK sCJD (P = 0.049; OR, 1.24), in German sCJD or in PNG groups. In the overall meta-analysis of CJD, 14 SNPs were associated (P < 10(-5); two at PRNP, three at ZBTB38-RASA2, nine at nine other independent non-PRNP loci), more than would be expected by chance. None of the loci recently identified as genome-wide significant in studies of other neurodegenerative diseases showed any clear evidence of association in prion diseases. Concerning common genetic variation, it is likely that the PRNP locus contains the only strong risk factors that act universally across human prion diseases. Our data are most consistent with several other risk loci of modest overall effects which will require further genetic association studies to provide definitive evidence. AU - Mead, S.* AU - Uphill, J.* AU - Beck, J.* AU - Poulter, M.* AU - Campbell, T.* AU - Lowe, J.* AU - Adamson, G.* AU - Hummerich, H.* AU - Klopp, N. AU - Rückert, I.-M. AU - Wichmann, H.-E. AU - Azazi, D.* AU - Plagnol, V.* AU - Pako, W.H.* AU - Whitfield, J.* AU - Alpers, M.P.* AU - Whittaker, J.* AU - Balding, D.J.* AU - Zerr, I.* AU - Kretzschmar, H.* AU - Collinge, J.* C1 - 7489 C2 - 29749 SP - 1897-1906 TI - Genome-wide association study in multiple human prion diseases suggests genetic risk factors additional to PRNP. JO - Hum. Mol. Genet. VL - 21 IS - 8 PB - Oxford Univ. Press PY - 2012 SN - 0964-6906 ER - TY - JOUR AB - Adverse levels of lipoproteins are highly heritable and constitute risk factors for cardiovascular outcomes. Hitherto, genome-wide association studies revealed 95 lipid-associated loci. However, due to the small effect sizes of these associations large sample numbers (>100 000 samples) were needed. Here we show that analyzing more refined lipid phenotypes, namely lipoprotein subfractions, can increase the number of significantly associated loci compared with bulk high-density lipoprotein and low-density lipoprotein analysis in a study with identical sample numbers. Moreover, lipoprotein subfractions provide novel insight into the human lipid metabolism. We measured 15 lipoprotein subfractions (L1-L15) in 1791 samples using (1)H-NMR (nuclear magnetic resonance) spectroscopy. Using cluster analyses, we quantified inter-relationships among lipoprotein subfractions. Additionally, we analyzed associations with subfractions at known lipid loci. We identified five distinct groups of subfractions: one (L1) was only marginally captured by serum lipids and therefore extends our knowledge of lipoprotein biochemistry. During a lipid-tolerance test, L1 lost its special position. In the association analysis, we found that eight loci (LIPC, CETP, PLTP, FADS1-2-3, SORT1, GCKR, APOB, APOA1) were associated with the subfractions, whereas only four loci (CETP, SORT1, GCKR, APOA1) were associated with serum lipids. For LIPC, we observed a 10-fold increase in the variance explained by our regression models. In conclusion, NMR-based fine mapping of lipoprotein subfractions provides novel information on their biological nature and strengthens the associations with genetic loci. Future clinical studies are now needed to investigate their biomedical relevance. AU - Petersen, A.-K. AU - Stark, K.* AU - Musameh, M.D.* AU - Nelson, C.P.* AU - Römisch-Margl, W. AU - Kremer, W.* AU - Raffler, J. AU - Krug, S.* AU - Skurk, T.* AU - Rist, M.J.* AU - Daniel, H.* AU - Hauner, H.* AU - Adamski, J. AU - Tomaszewski, M.* AU - Döring, A. AU - Peters, A. AU - Wichmann, H.-E. AU - Kaess, B.M.* AU - Kalbitzer, H.R.* AU - Huber, F.* AU - Pfahlert, V.* AU - Samani, N.J.* AU - Kronenberg, F.* AU - Dieplinger, H.* AU - Illig, T. AU - Hengstenberg, C.* AU - Suhre, K. AU - Gieger, C. AU - Kastenmüller, G. C1 - 7272 C2 - 29691 SP - 1433-1443 TI - Genetic associations with lipoprotein subfractions provide information on their biological nature. JO - Hum. Mol. Genet. VL - 21 IS - 6 PB - Oxford Univ. Press PY - 2012 SN - 0964-6906 ER - TY - JOUR AB - Thyroid hormones play key roles in cellular growth, development and metabolism. Although there is a strong genetic influence on thyroid hormone levels, the genes involved are widely unknown. The levels of circulating thyroid hormones are tightly regulated by thyrotropin (TSH), which also represents the most important diagnostic marker for thyroid function. Therefore, in order to identify genetic loci associated with TSH levels, we performed a discovery meta-analysis of two genome-wide association studies including two cohorts from Germany, KORA (n 1287) and SHIP (n 2449), resulting in a total sample size of 3736. Four genetic loci at 5q13.3, 1p36, 16q23 and 4q31 were associated with serum TSH levels. The lead single-nucleotide polymorphisms of these four loci were located within PDE8B encoding phosphodiesterase 8B, upstream of CAPZB that encodes the -subunit of the barbed-end F-actin-binding protein, in a former ogene desert' that was recently demonstrated to encode a functional gene (LOC440389) associated with thyroid volume, and upstream of NR3C2 encoding the mineralocorticoid receptor. The latter association for the first time suggests the modulation of thyroid function by mineral corticoids. All four loci were replicated in three additional cohorts: the HUNT study from Norway (n 1487) and the two German studies CARLA (CARLA, n 1357) and SHIP-TREND (n 883). Together, these four quantitative trait loci accounted for approximate to 3.3 of the variance in TSH serum levels. These results contribute to our understanding of genetic factors and physiological mechanisms mediating thyroid function. AU - Rawal, R. AU - Teumer, A.* AU - Völzke, H.* AU - Wallaschofski, H.* AU - Ittermann, T.* AU - Asvold, B.O.* AU - Bjoro, T.* AU - Greiser, K.H.* AU - Tiller, D.* AU - Werdan, K.* AU - zu Schwabedissen, H.E.M.* AU - Döring, A. AU - Illig, T. AU - Gieger, C. AU - Meisinger, C. AU - Homuth, G.* C1 - 8188 C2 - 30011 SP - 3275-3282 TI - Meta-analysis of two genome-wide association studies identifies four genetic loci associated with thyroid function. JO - Hum. Mol. Genet. VL - 21 IS - 14 PB - Oxford Univ. Press PY - 2012 SN - 0964-6906 ER - TY - JOUR AB - Genome-wide association studies (GWAS) of breast cancer defined by hormone receptor status have revealed loci contributing to susceptibility of estrogen receptor (ER)-negative subtypes. To identify additional genetic variants for ER-negative breast cancer, we conducted the largest meta-analysis of ER-negative disease to date, comprising 4754 ER-negative cases and 31 663 controls from three GWAS: NCI Breast and Prostate Cancer Cohort Consortium (BPC3) (2188 ER-negative cases; 25 519 controls of European ancestry), Triple Negative Breast Cancer Consortium (TNBCC) (1562 triple negative cases; 3399 controls of European ancestry) and African American Breast Cancer Consortium (AABC) (1004 ER-negative cases; 2745 controls). We performed in silico replication of 86 SNPs at P 1 10(-5) in an additional 11 209 breast cancer cases (946 with ER-negative disease) and 16 057 controls of Japanese, Latino and European ancestry. We identified two novel loci for breast cancer at 20q11 and 6q14. SNP rs2284378 at 20q11 was associated with ER-negative breast cancer (combined two-stage OR 1.16; P 1.1 10(8)) but showed a weaker association with overall breast cancer (OR 1.08, P 1.3 10(6)) based on 17 869 cases and 43 745 controls and no association with ER-positive disease (OR 1.01, P 0.67) based on 9965 cases and 22 902 controls. Similarly, rs17530068 at 6q14 was associated with breast cancer (OR 1.12; P 1.1 10(9)), and with both ER-positive (OR 1.09; P 1.5 10(5)) and ER-negative (OR 1.16, P 2.5 10(7)) disease. We also confirmed three known loci associated with ER-negative (19p13) and both ER-negative and ER-positive breast cancer (6q25 and 12p11). Our results highlight the value of large-scale collaborative studies to identify novel breast cancer risk loci. AU - Siddiq, A.* AU - Couch, F.J.* AU - Chen, G.K.* AU - Lindström, S.* AU - Eccles, D.* AU - Millikan, R.C.* AU - Michailidou, K.* AU - Stram, D.O.* AU - Beckmann, L.* AU - Rhie, S.K.* AU - Ambrosone, C.B.* AU - Aittomäki, K.* AU - Amiano, P.* AU - Apicella, C.* AU - Baglietto, L.* AU - Bandera, E.V.* AU - Beckmann, M.W.* AU - Berg, C.D.* AU - Bernstein, L.* AU - Blomqvist, C.* AU - Brauch, H.* AU - Brinton, L.* AU - Bui, Q.M.* AU - Buring, J.E.* AU - Buys, S.S.* AU - Campa, D.* AU - Carpenter, J.E.* AU - Chasman, D.I.* AU - Chang-Claude, J.* AU - Chen, C.* AU - Clavel-Chapelon, F.* AU - Cox, A.* AU - Cross, S.S.* AU - Czene, K.* AU - Deming, S.L.* AU - Diasio, R.B.* AU - Diver, W.R.* AU - Dunning, A.M.* AU - Durcan, L.* AU - Ekici, A.B.* AU - Fasching, P.A.* AU - Feigelson, H.S.* AU - Fejerman, L.* AU - Figueroa, J.D.* AU - Fletcher, O.* AU - Flesch-Janys, D.* AU - Gaudet, M.M.* AU - Gerty, S.M.* AU - Rodriguez-Gil, J.L.* AU - Giles, G.G.* AU - van Gils, C.H.* AU - Godwin, A.K.* AU - Graham, N.* AU - Greco, D.* AU - Hall, P.* AU - Hankinson, S.E.* AU - Hartmann, A.* AU - Hein, R.* AU - Heinz, J.* AU - Hoover, R.N.* AU - Hopper, J.L.* AU - Hu, J.J.* AU - Huntsman, S.* AU - Ingles, S.A.* AU - Irwanto, A.* AU - Isaacs, C.* AU - Jacobs, K.B.* AU - John, E.M.* AU - Justenhoven, C.* AU - Kaaks, R.* AU - Kolonel, L.N.* AU - Coetzee, G.A.* AU - Lathrop, M* AU - Marchand, L.* AU - Lee, A.M.* AU - Lee, I.M.* AU - Lesnick, T.* AU - Lichtner, P. AU - Liu, J.J.* AU - Lund, E.* AU - Makalic, E.* AU - Martin, N.G.* AU - McLean, C.A.* AU - Meijers-Heijboer, H.* AU - Meindl, A.* AU - Miron, P.* AU - Monroe, K.R.* AU - Montgomery, G.W.* AU - Müller-Myhsok, B.* AU - Nickels, S.* AU - Nyante, S.J.* AU - Olswold, C.* AU - Overvad, K.* AU - Palli, D.* AU - Park, D.J.* AU - Palmer, J.R.* AU - Pathak, H.* AU - Peto, J.* AU - Pharoah, P.* AU - Rahman, N.* AU - Rivadeneira, F.* AU - Schmidt, D.F.* AU - Schmutzler, R.K.* AU - Slager, S.* AU - Southey, M.C.* AU - Stevens, K.N.* AU - Sinn, H.P.* AU - Press, M.F.* AU - Ross, E.* AU - Riboli, E.* AU - Ridker, P.M.* AU - Schumacher, F.R.* AU - Severi, G.* AU - Silva, I.D.* AU - Stone, J.* AU - Sund, M.* AU - Tapper, W.J.* AU - Thun, M.J.* AU - Travis, R.C.* AU - Turnbull, C.* AU - Uitterlinden, A.G.* AU - Waisfisz, Q.* AU - Wang, X.S.* AU - Wang, Z.M.* AU - Weaver, J.* AU - Schulz-Wendtland, R.* AU - Wilkens, L.R.* AU - van Den Berg, D.* AU - Zheng, W.* AU - Ziegler, R.G.* AU - Ziv, E.* AU - Nevanlinna, H.* AU - Easton, D.F.* AU - Hunter, D.J.* AU - Henderson, B.E.* AU - Chanock, S.J.* AU - Garcia-Closas, M.* AU - Kraft, P.* AU - Haiman, C.A.* AU - Vachon, C.M.* C1 - 11533 C2 - 30724 SP - 5373-5384 TI - A meta-analysis of genome-wide association studies of breast cancer identifies two novel susceptibility loci at 6q14 and 20q11. JO - Hum. Mol. Genet. VL - 21 IS - 24 PB - Oxford Univ. Press PY - 2012 SN - 0964-6906 ER - TY - JOUR AB - Genetic generalized epilepsies (GGEs) have a lifetime prevalence of 0.3 and account for 2030 of all epilepsies. Despite their high heritability of 80, the genetic factors predisposing to GGEs remain elusive. To identify susceptibility variants shared across common GGE syndromes, we carried out a two-stage genome-wide association study (GWAS) including 3020 patients with GGEs and 3954 controls of European ancestry. To dissect out syndrome-related variants, we also explored two distinct GGE subgroups comprising 1434 patients with genetic absence epilepsies (GAEs) and 1134 patients with juvenile myoclonic epilepsy (JME). Joint Stage-1 and 2 analyses revealed genome-wide significant associations for GGEs at 2p16.1 (rs13026414, P-meta 2.5 10(9), OR[T] 0.81) and 17q21.32 (rs72823592, P-meta 9.3 10(9), OR[A] 0.77). The search for syndrome-related susceptibility alleles identified significant associations for GAEs at 2q22.3 (rs10496964, P-meta 9.1 10(9), OR[T] 0.68) and at 1q43 for JME (rs12059546, P-meta 4.1 10(8), OR[G] 1.42). Suggestive evidence for an association with GGEs was found in the region 2q24.3 (rs11890028, P-meta 4.0 10(6)) nearby the SCN1A gene, which is currently the gene with the largest number of known epilepsy-related mutations. The associated regions harbor high-ranking candidate genes: CHRM3 at 1q43, VRK2 at 2p16.1, ZEB2 at 2q22.3, SCN1A at 2q24.3 and PNPO at 17q21.32. Further replication efforts are necessary to elucidate whether these positional candidate genes contribute to the heritability of the common GGE syndromes. AU - Steffens, M.* AU - Leu, C.* AU - Ruppert, A.K.* AU - Zara, F.* AU - Striano, P.* AU - Robbiano, A.* AU - Capovilla, G.* AU - Tinuper, P.* AU - Gambardella, A.* AU - Bianchi, A.* AU - La Neve, A.* AU - Crichiutti, G.* AU - de Kovel, C.G.F.* AU - Trenite, D.K.N.* AU - de Haan, G.J.* AU - Lindhout, D.* AU - Gaus, V.* AU - Schmitz, B.* AU - Janz, D.* AU - Weber, Y.G.* AU - Becker, F.* AU - Lerche, H.* AU - Steinhoff, B.J.* AU - Kleefuss-Lie, A.A.* AU - Kunz, W.S.* AU - Surges, R.* AU - Elger, C.E.* AU - Muhle, H.* AU - von Spiczak, S.* AU - Ostertag, P.* AU - Helbig, I.* AU - Stephani, U.* AU - Moller, R.S.* AU - Hjalgrim, H.* AU - Dibbens, L.M.* AU - Bellows, S.* AU - Oliver, K.* AU - Mullen, S.* AU - Scheffer, I.E.* AU - Berkovic, S.F.* AU - Everett, K.V.* AU - Gardiner, M.R.* AU - Marini, C.* AU - Guerrini, R.* AU - Lehesjoki, A.E.* AU - Siren, A.* AU - Guipponi, M.* AU - Malafosse, A.* AU - Thomas, P.* AU - Nabbout, R.* AU - Baulac, S.* AU - Leguern, E.* AU - Guerrero, R.* AU - Serratosa, J.M.* AU - Reif, P.S.* AU - Rosenow, F.* AU - Morzinger, M.* AU - Feucht, M.* AU - Zimprich, F.* AU - Kapser, C.* AU - Schankin, C.J.* AU - Suls, A.* AU - Smets, K.* AU - de Jonghe, P.* AU - Jordanova, A.* AU - Caglayan, H.* AU - Yapici, Z.* AU - Yalcin, D.A.* AU - Baykan, B.* AU - Bebek, N.* AU - Ozbek, U.* AU - Gieger, C. AU - Wichmann, H.-E. AU - Balschun, T.* AU - Ellinghaus, D.* AU - Franke, A.* AU - Meesters, C.* AU - Becker, T.* AU - Wienker, T.F.* AU - Hempelmann, A.* AU - Schulz, S.* AU - Ruschendorf, F.* AU - Leber, M.* AU - Pauck, S.M.* AU - Trucks, H.* AU - Toliat, M.R.* AU - Nürnberg, P.* AU - Avanzini, G.* AU - Koeleman, B.P.C.* AU - Sander, T.* AU - EPICURE Consortium (*) AU - EMINet Consortium (*) C1 - 11535 C2 - 30723 SP - 5359-5372 TI - Genome-wide association analysis of genetic generalized epilepsies implicates susceptibility loci at 1q43, 2p16.1, 2q22.3 and 17q21.32. JO - Hum. Mol. Genet. VL - 21 IS - 24 PB - Oxford Univ. Press PY - 2012 SN - 0964-6906 ER - TY - JOUR AB - Osteogenesis imperfecta (OI) is an inherited connective tissue disorder with skeletal dysplasia of varying severity, predominantly caused by mutations in the collagen I genes (COL1A1/COL1A2). Extraskeletal findings such as cardiac and pulmonary complications are generally considered to be significant secondary features. Aga2, a murine model for human OI, was systemically analyzed in the German Mouse Clinic by means of in vivo and in vitro examinations of the cardiopulmonary system, to identify novel mechanisms accounting for perinatal lethality. Pulmonary and, especially, cardiac fibroblast of perinatal lethal Aga2/+ animals display a strong down-regulation of Col1a1 transcripts in vivo and in vitro, resulting in a loss of extracellular matrix integrity. In addition, dysregulated gene expression of Nppa, different types of collagen and Agt in heart and lung tissue support a bone-independent vicious cycle of heart dysfunction, including hypertrophy, loss of myocardial matrix integrity, pulmonary hypertension, pneumonia and hypoxia leading to death in Aga2. These murine findings are corroborated by a pediatric OI cohort study, displaying significant progressive decline in pulmonary function and restrictive pulmonary disease independent of scoliosis. Most participants show mild cardiac valvular regurgitation, independent of pulmonary and skeletal findings. Data obtained from human OI patients and the mouse model Aga2 provide novel evidence for primary effects of type I collagen mutations on the heart and lung. The findings will have potential benefits of anticipatory clinical exams and early intervention in OI patients. AU - Thiele, F. AU - Cohrs, C.M. AU - Flor, A.* AU - Lisse, T.S. AU - Przemeck, G.K.H. AU - Horsch, M. AU - Schrewe, A. AU - Gailus-Durner, V. AU - Ivandic, B.* AU - Katus, H.A.* AU - Wurst, W. AU - Reisenberg, C.* AU - Chaney, H.* AU - Fuchs, H. AU - Hans, W. AU - Beckers, J. AU - Marini, J.C.* AU - Hrabě de Angelis, M. C1 - 8201 C2 - 30050 SP - 3535-3545 TI - Cardiopulmonary dysfunction in the osteogenesis imperfecta mouse model Aga2 and human patients are caused by bone-independent mechanisms. JO - Hum. Mol. Genet. VL - 21 IS - 16 PB - Oxford Univ. Press PY - 2012 SN - 0964-6906 ER - TY - JOUR AB - Recent genome-wide association studies (GWASs) have identified common genetic variants at 5p15.33, 6p216p22 and 15q25.1 associated with lung cancer risk. Several other genetic regions including variants of CHEK2 (22q12), TP53BP1 (15q15) and RAD52 (12p13) have been demonstrated to influence lung cancer risk in candidate- or pathway-based analyses. To identify novel risk variants for lung cancer, we performed a meta-analysis of 16 GWASs, totaling 14 900 cases and 29 485 controls of European descent. Our data provided increased support for previously identified risk loci at 5p15 (P 7.2 10(16)), 6p21 (P 2.3 10(14)) and 15q25 (P 2.2 10(63)). Furthermore, we demonstrated histology-specific effects for 5p15, 6p21 and 12p13 loci but not for the 15q25 region. Subgroup analysis also identified a novel disease locus for squamous cell carcinoma at 9p21 (CDKN2A/p16(INK4A)/p14(ARF)/CDKN2B/p15(INK4B)/ANRIL; rs1333040, P 3.0 10(7)) which was replicated in a series of 5415 Han Chinese (P 0.03; combined analysis, P 2.3 10(8)). This large analysis provides additional evidence for the role of inherited genetic susceptibility to lung cancer and insight into biological differences in the development of the different histological types of lung cancer. AU - Timofeeva, M.N.* AU - Hung, R.J.* AU - Rafnar, T.* AU - Christiani, D.C.* AU - Field, J.K.* AU - Bickeböller, H.* AU - Risch, A.* AU - McKay, J.D.* AU - Wang, Y.F.* AU - Dai, J.C.* AU - Gaborieau, V.* AU - McLaughlin, J.* AU - Brenner, D.* AU - Narod, S.A.* AU - Caporaso, N.E.* AU - Albanes, D.* AU - Thun, M.* AU - Eisen, T.* AU - Wichmann, H.-E. AU - Rosenberger, A.* AU - Han, Y.H.* AU - Chen, W.* AU - Zhu, D.K.* AU - Spitz, M.* AU - Wu, X.F.* AU - Pande, M.* AU - Zhao, Y.* AU - Zaridze, D.* AU - Szeszenia-Dabrowska, N.* AU - Lissowska, J.* AU - Rudnai, P.* AU - Fabianova, E.* AU - Mates, D.* AU - Bencko, V.* AU - Foretova, L.* AU - Janout, V.* AU - Krokan, H.E.* AU - Gabrielsen, M.E.* AU - Skorpen, F.* AU - Vatten, L.* AU - Njolstad, I.* AU - Chen, C.* AU - Goodman, G.* AU - Lathrop, M* AU - Benhamou, S.* AU - Vooder, T.* AU - Välk, K.* AU - Nelis, M.* AU - Metspalu, A.* AU - Raji, O.* AU - Chen, Y.* AU - Gosney, J.* AU - Liloglou, T.* AU - Muley, T.* AU - Dienemann, H.* AU - Thorleifsson, G.* AU - Shen, H.B.* AU - Stefansson, K.* AU - Brennan, P.* AU - Amos, C.I.* AU - Houlston, R.* AU - Landi, M.T.* C1 - 11096 C2 - 30559 SP - 4980-4995 TI - Influence of common genetic variation on lung cancer risk: Meta-analysis of 14900 cases and 29485 controls. JO - Hum. Mol. Genet. VL - 21 IS - 22 PB - Oxford Univ. Press PY - 2012 SN - 0964-6906 ER - TY - JOUR AB - Autosomal dominant cerebellar ataxia, deafness and narcolepsy (ADCA-DN) is characterized by late onset (30-40 years old) cerebellar ataxia, sensory neuronal deafness, narcolepsy-cataplexy and dementia. We performed exome sequencing in five individuals from three ADCA-DN kindreds and identified DNMT1 as the only gene with mutations found in all five affected individuals. Sanger sequencing confirmed the de novo mutation p.Ala570Val in one family, and showed co-segregation of p.Val606Phe and p.Ala570Val, with the ADCA-DN phenotype, in two other kindreds. An additional ADCA-DN kindred with a p.GLY605Ala mutation was subsequently identified. Narcolepsy and deafness were the first symptoms to appear in all pedigrees, followed by ataxia. DNMT1 is a widely expressed DNA methyltransferase maintaining methylation patterns in development, and mediating transcriptional repression by direct binding to HDAC2. It is also highly expressed in immune cells and required for the differentiation of CD4+ into T regulatory cells. Mutations in exon 20 of this gene were recently reported to cause hereditary sensory neuropathy with dementia and hearing loss (HSAN1). Our mutations are all located in exon 21 and in very close spatial proximity, suggesting distinct phenotypes depending on mutation location within this gene. AU - Winkelmann, J. AU - Lin, L.* AU - Schormair, B. AU - Kornum, B.R.* AU - Faraco, J.* AU - Plazzi, G.* AU - Melberg, A.* AU - Cornelio, F.* AU - Urban, A.E.* AU - Pizza, F.* AU - Poli, F.* AU - Grubert, F.* AU - Wieland, T. AU - Graf, E. AU - Hallmayer, J.* AU - Strom, T.M. AU - Mignot, E.* C1 - 7505 C2 - 29764 SP - 2205-2210 TI - Mutations in DNMT1 cause autosomal dominant cerebellar ataxia, deafness and narcolepsy. JO - Hum. Mol. Genet. VL - 21 IS - 10 PB - Oxford Univ. Press PY - 2012 SN - 0964-6906 ER - TY - JOUR AB - Renal cell carcinoma (RCC) is the most lethal urologic cancer. Only two common susceptibility loci for RCC have been confirmed to date. To identify additional RCC common susceptibility loci, we conducted an independent genome-wide association study (GWAS). We analyzed 533 191 single nucleotide polymorphisms (SNPs) for association with RCC in 894 cases and 1516 controls of European descent recruited from MD Anderson Cancer Center in the primary scan, and validated the top 500 SNPs in silico in 3772 cases and 8505 controls of European descent involved in the only published GWAS of RCC. We identified two common variants in linkage disequilibrium, rs718314 and rs1049380 (r(2) = 0.64, D ' = 0.84), in the inositol 1,4,5-triphosphate receptor, type 2 (ITPR2) gene on 12p11.23 as novel susceptibility loci for RCC (P = 8.89 × 10(-10) and P = 6.07 × 10(-9), respectively, in meta-analysis) with an allelic odds ratio of 1.19 [95% confidence interval (CI): 1.13-1.26] for rs718314 and 1.18 (95% CI: 1.12-1.25) for rs1049380. It has been recently identified that rs718314 in ITPR2 is associated with waist-hip ratio (WHR) phenotype. To our knowledge, this is the first genetic locus associated with both cancer risk and WHR. AU - Wu, X.* AU - Scelo, G.* AU - Purdue, M.P.* AU - Rothman, N.* AU - Johansson, M.* AU - Ye, Y.* AU - Wang, Z.* AU - Zelenika, D.* AU - Moore, L.E.* AU - Wood, C.G.* AU - Prokhortchouk, E.* AU - Gaborieau, V.* AU - Jacobs, K.B.* AU - Chow, W.H.* AU - Toro, J.R.* AU - Zaridze, D.* AU - Lin, J.* AU - Lubinski, J.* AU - Trubicka, J.* AU - Szeszenia-Dabrowska, N.* AU - Lissowska, J.* AU - Rudnai, P.* AU - Fabianova, E.* AU - Mates, D.* AU - Jinga, V.* AU - Bencko, V.* AU - Slamova, A.* AU - Holcatova, I.* AU - Navratilova, M.* AU - Janout, V.* AU - Boffetta, P.* AU - Colt, J.S.* AU - Davis, F.G.* AU - Schwartz, K.L.* AU - Banks, R.E.* AU - Selby, P.J.* AU - Harnden, P.* AU - Berg, C.D.* AU - Hsing, A.W.* AU - Grubb, R.L.* AU - Boeing, H.* AU - Vineis, P.* AU - Clavel-Chapelon, F.* AU - Palli, D.* AU - Tumino, R.* AU - Krogh, V.* AU - Panico, S.* AU - Duell, E.J.* AU - Quirós, J.R.* AU - Sánchez, M.J.* AU - Navarro, C.* AU - Ardanaz, E.* AU - Dorronsoro, M.* AU - Khaw, K.T.* AU - Allen, N.E.* AU - Bueno-de-Mesquita, H.B.* AU - Peeters, P.H.* AU - Trichopoulos, D.* AU - Linseisen, J. AU - Ljungberg, B.* AU - Overvad, K.* AU - Tjønneland, A.* AU - Romieu, I.* AU - Riboli, E.* AU - Stevens, V.L.* AU - Thun, M.J.* AU - Diver, W.R.* AU - Gapstur, S.M.* AU - Pharoah, P.D.* AU - Easton, D.F.* AU - Albanes, D.* AU - Virtamo, J.* AU - Vatten, L.* AU - Hveem, K.* AU - Fletcher, T.* AU - Koppova, K.* AU - Cussenot, O.* AU - Cancel-Tassin, G.* AU - Benhamou, S.* AU - Hildebrandt, M.A.* AU - Pu, X.* AU - Foglio, M.* AU - Lechner, D.* AU - Hutchinson, A.* AU - Yeager, M.* AU - Fraumeni, J.F.* AU - Lathrop, M* AU - Skryabin, K.G.* AU - McKay, J.D.* AU - Gu, J.* AU - Brennan, P.* AU - Chanock, S.J.* C1 - 7207 C2 - 29559 SP - 456-462 TI - A genome-wide association study identifies a novel susceptibility locus for renal cell carcinoma on 12p11.23. JO - Hum. Mol. Genet. VL - 21 IS - 2 PB - Oxford Univ. Press PY - 2012 SN - 0964-6906 ER - TY - JOUR AB - Mutations in the DELTA-LIKE 3 (DLL3) gene cause the congenital abnormal vertebral segmentation syndrome, spondylocostal dysostosis (SCD). DLL3 is a divergent member of the DSL family of Notch ligands that does not activate signalling in adjacent cells, but instead inhibits signalling when expressed in the same cell as the Notch receptor. Targeted deletion of Dll3 in the mouse causes a developmental defect in somite segmentation, and consequently vertebral formation is severely disrupted, closely resembling human SCD. In contrast to the canonical Notch signalling pathway, very little is known about the mechanism of cis-inhibition by DSL ligands. Here, we report that Dll3 is not presented on the surface of presomitic mesoderm (PSM) cells in vivo, but instead interacts with Notch1 in the late endocytic compartment. This suggests for the first time a mechanism for Dll3-mediated cis-inhibition of Notch signalling, with Dll3 targeting newly synthesized Notch1 for lysosomal degradation prior to post-translational processing and cell surface presentation of the receptor. An inhibitory role for Dll3 in vivo is further supported by the juxtaposition of Dll3 protein and Notch1 signalling in the PSM. Defining a mechanism for cis-inhibition of Notch signalling by Dll3 not only contributes greatly to our understanding of this ligand's function during the formation of the vertebral column, but also provides a paradigm for understanding how other ligands of Notch cis-inhibit signalling. AU - Chapman, G.* AU - Sparrow, D.B.* AU - Kremmer, E. AU - Dunwoodie, S.L.* C1 - 5706 C2 - 28089 SP - 905-916 TI - Notch inhibition by the ligand Delta-Like 3 defines the mechanism of abnormal vertebral segmentation in spondylocostal dysostosis. JO - Hum. Mol. Genet. VL - 20 IS - 5 PB - Oxford Univ. Press PY - 2011 SN - 0964-6906 ER - TY - JOUR AB - Recent studies have established ciliary dysfunction as the underlying cause of a broad range of multi-organ phenotypes, known as 'ciliopathies'. Ciliopathy-associated proteins have a common site of action in the cilium, however, their overall importance for ciliary function differs, as implied by the extreme variability in ciliopathy phenotypes. The aim of this study was to gain more insight in the function of two ciliopathy-associated protein homologs, RPGR interacting protein 1 (RPGRIP1) and RPGRIP1-like protein (RPGRIP1L). Mutations in RPGRIP1 lead to the eye-restricted disease Leber congenital amaurosis, while mutations in RPGRIP1L are causative for Joubert and Meckel syndrome, which affect multiple organs and are at the severe end of the ciliopathy spectrum. Using tandem affinity purification in combination with mass spectrometry, we identified Nek4 serine/threonine kinase as a prominent component of both the RPGRIP1- as well as the RPGRIP1L-associated protein complex. In ciliated cells, this kinase localized to basal bodies, while in ciliated organs, the kinase was predominantly detected at the ciliary rootlet. Down-regulation of NEK4 in ciliated cells led to a significant decrease in cilium assembly, pointing to a role for Nek4 in cilium dynamics. We now hypothesize that RPGRIP1 and RPGRIP1L function as cilium-specific scaffolds that recruit a Nek4 signaling network which regulates cilium stability. Our data are in line with previously established roles in the cilium of other members of the Nek protein family and define NEK4 as a ciliopathy candidate gene. AU - Coene, K.L.* AU - Mans, D.A.* AU - Boldt, K. AU - Gloeckner, C.J. AU - van Reeuwijk, J.* AU - Bolat, E.* AU - Roosing, S.* AU - Letteboer, S.J.* AU - Peters, T.A.* AU - Cremers, F.P.* AU - Ueffing, M. AU - Roepman, R.* C1 - 6167 C2 - 28988 CY - Oxford, UK SP - 3592-3605 TI - The ciliopathy-associated protein homologs RPGRIP1 and RPGRIP1L are linked to cilium integrity through interaction with Nek4 serine/threonine kinase. JO - Hum. Mol. Genet. VL - 20 IS - 18 PB - Oxford Univ. Press PY - 2011 SN - 0964-6906 ER - TY - JOUR AB - Renal-coloboma syndrome, also known as papillorenal syndrome, is an autosomal dominant human disorder in which optic disc coloboma is associated with kidney abnormalities. Mutations in the paired domain transcription factor PAX2 have been found to be the underlying cause of this disease. Disease severity varies between patients, and in some cases, renal hypoplasia has been found in the absence of any retinal defects. Here we report an N-ethyl-N-nitrosourea-induced mouse mutation, Opdc, which is an isoleucinetothreonine missense mutation, I40T, in the first α-helix of the Pax2 paired domain. The mutant protein binds target DNA sequences less strongly than the wild-type protein and acts poorly to transactivate target promoters in culture. The phenotypic consequence of this mutation on the development of the eye and ear is similar to that reported for null alleles of Pax2. However, in homozygotes, cerebellar development is normal on a genetic background in which loss of Pax2 results in failure of cerebellar formation. Moreover, there is a genetic background effect on the heterozygous phenotype such that on some strain backgrounds, kidney development is unaffected. Opdc is the first hypomorphic mutation reported for Pax2 that differs in phenotype from loss-of-function mutations. These results suggest that PAX2 is a strong candidate gene for cases in which human patients have optic disc coloboma not associated with renal dysplasia. AU - Cross, S.H.* AU - McKie, L.* AU - West, K.* AU - Coghill, E.L.* AU - Favor, J. AU - Bhattacharya, S.* AU - Brown, S.D.* AU - Jackson, I.J.* C1 - 816 C2 - 28013 SP - 223-234 TI - The Opdc missense mutation of Pax2 has a milder than loss-of-function phenotype. JO - Hum. Mol. Genet. VL - 20 IS - 2 PB - Oxford Univ. Press PY - 2011 SN - 0964-6906 ER - TY - JOUR AB - High blood concentration of the N-terminal cleavage product of the B-type natriuretic peptide (NT-proBNP) is strongly associated with cardiac dysfunction and is increasingly used for heart failure diagnosis. To identify genetic variants associated with NT-proBNP level, we performed a genome-wide association analysis in 1325 individuals from South Tyrol, Italy, and followed up the most significant results in 1746 individuals from two German population-based studies. A genome-wide significant signal in the MTHFR-CLCN6-NPPA-NPPB gene cluster was replicated, after correction for multiple testing (replication one-sided P-value = 8.4 × 10(-10)). A conditional regression analysis of 128 single-nucleotide polymorphisms in the region of interest identified novel variants in the CLCN6 gene as independently associated with NT-proBNP. In this locus, four haplotypes were associated with increased NT-proBNP levels (haplotype-specific combined P-values from 8.3 × 10(-03) to 9.3 × 10(-11)). The observed increase in the NT-proBNP level was proportional to the number of haplotype copies present (i.e. dosage effect), with an increase associated with two copies that varied between 20 and 100 pg/ml across populations. The identification of novel variants in the MTHFR-CLCN6-NPPA-NPPB cluster provides new insights into the biological mechanisms of cardiac dysfunction. AU - Del Greco, M, F.* AU - Pattaro, C.* AU - Luchner, A.* AU - Pichler, I.* AU - Winkler, T.* AU - Hicks, A.A.* AU - Fuchsberger, C.* AU - Franke, A.* AU - Melville, SA.* AU - Peters, A. AU - Wichmann, H.-E. AU - Schreiber, S.* AU - Heid, I.M. AU - Krawczak, M.* AU - Minelli, C.* AU - Wiedermann, C.J.* AU - Pramstaller, P.P.* C1 - 6324 C2 - 28506 CY - Oxford SP - 1660-1671 TI - Genome-wide association analysis and fine mapping of NT-proBNP level provide novel insight into the role of the MTHFR-CLCN6-NPPA-NPPB gene cluster. JO - Hum. Mol. Genet. VL - 20 IS - 8 PB - Oxford Univ. Press PY - 2011 SN - 0964-6906 ER - TY - JOUR AB - CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) is the most common monogenic cause of stroke and vascular dementia. Accumulation and deposition of the NOTCH3 (N3) extracellular domain in small blood vessels has been recognized as a central pathological feature of the disease. Recent experiments suggested enhanced formation of higher order multimers for mutant N3 compared with wild-type (WT). However, the mechanisms and consequences of N3 multimerization are still poorly understood, in part because of the lack of an appropriate in vitro aggregation assay. We therefore developed and validated a robust assay based on recombinant N3 fragments purified from cell culture supernatants. Using single-molecule analysis techniques such as scanning for intensely fluorescent targets and single-particle fluorescence resonance energy transfer, we show that spontaneous aggregation is limited to CADASIL-mutant N3, recapitulating a central aspect of CADASIL pathology in vitro. N3 aggregation requires no co-factor and is facilitated by sulfhydryl crosslinking. Although WT N3 does not exhibit multimerization itself, it can participate in aggregates of mutant N3. Furthermore, we demonstrate that thrombospondin-2, a known interaction partner of N3, co-aggregates with mutant N3. Sequestration of WT N3 and other proteins into aggregates represents a potentially important disease mechanism. These findings in combination with a new assay for single-molecule aggregation analysis provide novel opportunities for the development of therapeutic strategies. AU - Duering, M.* AU - Karpinska, A.* AU - Rosner, S.* AU - Hopfner, F.* AU - Zechmeister, M.* AU - Peters, N.* AU - Kremmer, E. AU - Haffner, C.* AU - Giese, A.* AU - Dichgans, M.* AU - Opherk, C.* C1 - 6488 C2 - 28765 CY - Oxford, UK SP - 3256-3265 TI - Co-aggregate formation of CADASIL-mutant NOTCH3: A single-particle analysis. JO - Hum. Mol. Genet. VL - 20 IS - 16 PB - Oxford Univ. Press PY - 2011 SN - 0964-6906 ER - TY - JOUR AB - The prevalence of hypertension in African Americans (AAs) is higher than in other US groups; yet, few have performed genome-wide association studies (GWASs) in AA. Among people of European descent, GWASs have identified genetic variants at 13 loci that are associated with blood pressure. It is unknown if these variants confer susceptibility in people of African ancestry. Here, we examined genome-wide and candidate gene associations with systolic blood pressure (SBP) and diastolic blood pressure (DBP) using the Candidate Gene Association Resource (CARe) consortium consisting of 8591 AAs. Genotypes included genome-wide single-nucleotide polymorphism (SNP) data utilizing the Affymetrix 6.0 array with imputation to 2.5 million HapMap SNPs and candidate gene SNP data utilizing a 50K cardiovascular gene-centric array (ITMAT-Broad-CARe [IBC] array). For Affymetrix data, the strongest signal for DBP was rs10474346 (P= 3.6 × 10(-8)) located near GPR98 and ARRDC3. For SBP, the strongest signal was rs2258119 in C21orf91 (P= 4.7 × 10(-8)). The top IBC association for SBP was rs2012318 (P= 6.4 × 10(-6)) near SLC25A42 and for DBP was rs2523586 (P= 1.3 × 10(-6)) near HLA-B. None of the top variants replicated in additional AA (n = 11 882) or European-American (n = 69 899) cohorts. We replicated previously reported European-American blood pressure SNPs in our AA samples (SH2B3, P= 0.009; TBX3-TBX5, P= 0.03; and CSK-ULK3, P= 0.0004). These genetic loci represent the best evidence of genetic influences on SBP and DBP in AAs to date. More broadly, this work supports that notion that blood pressure among AAs is a trait with genetic underpinnings but also with significant complexity. AU - Fox, E.R.* AU - Young, J.H.* AU - Li, Y.* AU - Dreisbach, A.W.* AU - Keating, B.J.* AU - Musani, S.K.* AU - Liu, K.* AU - Morrison, A.C.* AU - Ganesh, S.* AU - Kutlar, A.* AU - Ramachandran, V.S.* AU - Polak, J.F.* AU - Fabsitz, R.R.* AU - Dries, D.L.* AU - Farlow, D.N.* AU - Redline, S.* AU - Adeyemo, A.* AU - Hirschhorn, J.N.* AU - Sun, Y.V.* AU - Wyatt, S.B.* AU - Penman, A.D.* AU - Palmas, W.* AU - Rotter, J.I.* AU - Townsend, R.R.* AU - Doumatey, A.P.* AU - Tayo, B.O.* AU - Mosley, T.H Jr.* AU - Lyon, H.N.* AU - Kang, S.J.* AU - Rotimi, C.N.* AU - Cooper, R.S.* AU - Franceschini, N.* AU - Curb, J.D.* AU - Martin, L.W.* AU - Eaton, C.B.* AU - Kardia, S.L.* AU - Taylor, H.A.* AU - Caulfield, M.J.* AU - Ehret, GB.* AU - Johnson, T.* AU - ICBP Consortium (Meitinger, T. AU - Wichmann, H.-E.) AU - Chakravarti, A.* AU - Zhu, X.* AU - Levy, D.* C1 - 6483 C2 - 28759 CY - Oxford, UK SP - 2273-2284 TI - Association of genetic variation with systolic and diastolic blood pressure among African Americans: The Candidate Gene Association Resource study. JO - Hum. Mol. Genet. VL - 20 IS - 11 PB - Oxford Univ. Press PY - 2011 SN - 0964-6906 ER - TY - JOUR AB - Insulin-like growth factor-I (IGF-I) and insulin-like growth factor-binding protein-3 (IGFBP-3) are involved in cell replication, proliferation, differentiation, protein synthesis, carbohydrate homeostasis and bone metabolism. Circulating IGF-I and IGFBP-3 concentrations predict anthropometric traits and risk of cancer and cardiovascular disease. In a genome-wide association study of 10 280 middle-aged and older men and women from four community-based cohort studies, we confirmed a known association of single nucleotide polymorphisms in the IGFBP3 gene region on chromosome 7p12.3 with IGFBP-3 concentrations using a significance threshold of P < 5 × 10(-8) (P = 3.3 × 10(-101)). Furthermore, the same IGFBP3 gene locus (e.g. rs11977526) that was associated with IGFBP-3 concentrations was also associated with the opposite direction of effect, with IGF-I concentration after adjustment for IGFBP-3 concentration (P = 1.9 × 10(-26)). A novel and independent locus on chromosome 7p12.3 (rs700752) had genome-wide significant associations with higher IGFBP-3 (P = 4.4 × 10(-21)) and higher IGF-I (P = 4.9 × 10(-9)) concentrations; when the two measurements were adjusted for one another, the IGF-I association was attenuated but the IGFBP-3 association was not. Two additional loci demonstrated genome-wide significant associations with IGFBP-3 concentration (rs1065656, chromosome 16p13.3, P = 1.2 × 10(-11), IGFALS, a confirmatory finding; and rs4234798, chromosome 4p16.1, P = 4.5 × 10(-10), SORCS2, a novel finding). Together, the four genome-wide significant loci explained 6.5% of the population variation in IGFBP-3 concentration. Furthermore, we observed a borderline statistically significant association between IGF-I concentration and FOXO3 (rs2153960, chromosome 6q21, P = 5.1 × 10(-7)), a locus associated with longevity. These genetic loci deserve further investigation to elucidate the biological basis for the observed associations and clarify their possible role in IGF-mediated regulation of cell growth and metabolism. AU - Kaplan, R.C.* AU - Petersen, A.-K. AU - Chen, M.H.* AU - Teumer, A.* AU - Glazer, N.L.* AU - Döring, A. AU - Lam, C.S.* AU - Friedrich, N.* AU - Newman, A.* AU - Müller, M. AU - Yang, Q.* AU - Homuth, G.* AU - Cappola, A.* AU - Klopp, N. AU - Smith, H.* AU - Ernst, F.* AU - Psaty, B.M.* AU - Wichmann, H.-E. AU - Sawyer, D.B.* AU - Biffar, R.* AU - Rotter, J.I.* AU - Gieger, C. AU - Sullivan, L.S.* AU - Völzke, H.* AU - Rice, K.* AU - Spyroglou, A.* AU - Kroemer, H.K.* AU - Ida, Chen, Y.D.* AU - Manolopoulou, J.* AU - Nauck, M.* AU - Strickler, H.D.* AU - Goodarzi, M.O.* AU - Reincke, M.* AU - Pollak, M.N.* AU - Bidlingmaier, M.* AU - Vasan, R.S.* AU - Wallaschofski, H. C1 - 6026 C2 - 28529 SP - 1241-1251 TI - A genome-wide association study identifies novel loci associated with circulating IGF-I and IGFBP-3. JO - Hum. Mol. Genet. VL - 20 IS - 6 PB - Oxford Univ Press PY - 2011 SN - 0964-6906 ER - TY - JOUR AB - The level of body iron storage and the erythropoietic need for iron are indicated by the serum levels of ferritin and soluble transferrin receptor (sTfR), respectively. A meta-analysis of five genome-wide association studies on sTfR and ferritin revealed novel association to the PCSK7 and TMPRSS6 loci for sTfR and the HFE locus for both parameters. The PCSK7 association was the most significant (rs236918, P = 1.1 × 10E-27) suggesting that proprotein convertase 7, the gene product of PCSK7, may be involved in sTfR generation and/or iron homeostasis. Conditioning the sTfR analyses on transferrin saturation abolished the HFE signal and substantially diminished the TMPRSS6 signal while the PCSK7 association was unaffected, suggesting that the former may be mediated by transferrin saturation whereas the PCSK7-associated effect on sTfR generation appears to be more direct. AU - Oexle, K.* AU - Ried, J.S. AU - Hicks, A.A.* AU - Tanaka, T.* AU - Hayward, C.* AU - Bruegel, M.* AU - Gögele, M.* AU - Lichtner, P. AU - Müller-Myhsok, B.* AU - Döring, A. AU - Illig, T. AU - Schwienbacher, C.* AU - Minelli, C.* AU - Pichler, I.* AU - Fiedler, G.M.* AU - Thiery, J.* AU - Rudan, I.* AU - Wright, A.F.* AU - Campbell, H.* AU - Ferrucci, L.* AU - Bandinelli, S.* AU - Pramstaller, P.P.* AU - Wichmann, H.-E. AU - Gieger, C. AU - Winkelmann, J.* AU - Meitinger, T. C1 - 6314 C2 - 28479 SP - 1042-1047 TI - Novel association to the proprotein convertase PCSK7 gene locus revealed by analysing soluble transferrin receptor (sTfR) levels. JO - Hum. Mol. Genet. VL - 20 IS - 5 PB - Oxford Univ Press PY - 2011 SN - 0964-6906 ER - TY - JOUR AB - While gliomas are the most common primary brain tumors, their etiology is largely unknown. To identify novel risk loci for glioma, we conducted genome-wide association (GWA) analysis of two case-control series from France and Germany (2269 cases and 2500 controls). Pooling these data with previously reported UK and US GWA studies provided data on 4147 glioma cases and 7435 controls genotyped for 424 460 common tagging single-nucleotide polymorphisms. Using these data, we demonstrate two statistically independent associations between glioma and rs11979158 and rs2252586, at 7p11.2 which encompasses the EGFR gene (population-corrected statistics, P(c) = 7.72 × 10(-8) and 2.09 × 10(-8), respectively). Both associations were independent of tumor subtype, and were independent of EGFR amplification, p16INK4a deletion and IDH1 mutation status in tumors; compatible with driver effects of the variants on glioma development. These findings show that variation in 7p11.2 is a determinant of inherited glioma risk. AU - Sanson, M.* AU - Hosking, F.J.* AU - Shete, S.* AU - Zelenika, D.* AU - Dobbins, S.E.* AU - Ma, Y.* AU - Enciso-Mora, V.* AU - Idbaih, A.* AU - Delattre, JY.* AU - Hoang-Xuan, K.* AU - Marie, Y.* AU - Boisselier, B.* AU - Carpentier, C.* AU - Wang, X.W.* AU - Di, Stefano, A.L.* AU - Labussière, M.* AU - Gousias, K.* AU - Schramm, J.* AU - Boland, A.* AU - Lechner, D.* AU - Gut, I.* AU - Armstrong, G.* AU - Liu, Y.* AU - Yu, R.* AU - Lau, C.* AU - Di, Bernardo, M.C.* AU - Robertson, L.B.* AU - Muir, K.* AU - Hepworth, S.* AU - Swerdlow, A.* AU - Schoemaker, MJ.* AU - Wichmann, H.-E. AU - Müller, M. AU - Schreiber, S.* AU - Franke, A.* AU - Moebus, S.* AU - Eisele, L.* AU - Försti, A.* AU - Hemminki, K.* AU - Lathrop, M* AU - Bondy, M.* AU - Houlston, R.S.* AU - Simon, M.* C1 - 6499 C2 - 28817 CY - Oxford, UK SP - 2897-2904 TI - Chromosome 7p11.2 (EGFR) variation influences glioma risk. JO - Hum. Mol. Genet. VL - 20 IS - 14 PB - Oxford Univ. Press PY - 2011 SN - 0964-6906 ER - TY - JOUR AB - P-selectin and intercellular adhesion molecule-1 (ICAM-1) participate in inflammatory processes by promoting adhesion of leukocytes to vascular wall endothelium. Their soluble levels have been associated with adverse cardiovascular events. To identify loci affecting soluble levels of P-selectin (sP-selectin) and ICAM-1 (sICAM-1), we performed a genome-wide association study in a sample of 4115 (sP-selectin) and 9813 (sICAM-1) individuals of European ancestry as a part of The Cohorts for Heart and Aging Research in Genome Epidemiology consortium. The most significant SNP association for sP-selectin was within the SELP gene (rs6136, P = 4.05 x 10(-61)) and for sICAM-1 levels within the ICAM-1 gene (rs3093030, P = 3.53 x 10(-23)). Both sP-selectin and sICAM-1 were associated with ABO gene variants (rs579459, P = 1.86 x 10(-41) and rs649129, P = 1.22 x 10(-15), respectively) and in both cases the observed associations could be accounted for by the A1 allele of the ABO blood group. The absence of an association between ABO blood group and platelet-bound P-selectin levels in an independent subsample (N = 1088) from the ARIC study, suggests that the ABO blood group may influence cleavage of the P-selectin protein from the cell surface or clearance from the circulation, rather than its production and cellular presentation. These results provide new insights into adhesion molecule biology. AU - Barbalic, M.* AU - Dupuis, J.* AU - Dehghan, A.* AU - Bis, J.C.* AU - Hoogeveen, R.C.* AU - Schnabel, R.B.* AU - Nambi, V.* AU - Bretler, M.* AU - Smith, N.L.* AU - Peters, A. AU - Lu, C.* AU - Tracy, R.P.* AU - Aleksic, N.* AU - Heeriga, J.* AU - Keaney, J.F.* AU - Rice, K.* AU - Lip, G.Y.H.* AU - Vasan, R.S.* AU - Glazer, N.L.* AU - Larson, M.G.* AU - Uitterlinden, A.G.* AU - Yamamoto, J.* AU - Durda, P.* AU - Haritunians, T.* AU - Psaty, B.M.* AU - Boerwinkle, E.* AU - Hofman, A.* AU - Koenig, W.* AU - Jenny, N.S.* AU - Witteman, J.C.* AU - Ballantyne, C.* AU - Benjamin, E.J.* C1 - 3232 C2 - 27297 SP - 1863-1872 TI - Large-scale genomic studies reveal central role of ABO in sP-selectin and sICAM-1 levels. JO - Hum. Mol. Genet. VL - 19 IS - 9 PB - Oxford Univ. Press PY - 2010 SN - 0964-6906 ER - TY - JOUR AB - The mitochondrial chaperone mortalin has been linked to neurodegeneration in Parkinson's disease (PD) based on reduced protein levels in affected brain regions of PD patients and its interaction with the PD-associated protein DJ-1. Recently, two amino acid exchanges in the ATPase domain (R126W) and the substrate-binding domain (P509S) of mortalin were identified in Spanish PD patients. Here, we identified a separate and novel variant (A476T) in the substrate-binding domain of mortalin in German PD patients. To define a potential role as a susceptibility factor in PD, we characterized the functions of all three variants in different cellular models. In vitro import assays revealed normal targeting of all mortalin variants. In neuronal and non-neuronal human cell lines, the disease-associated variants caused a mitochondrial phenotype of increased reactive oxygen species and reduced mitochondrial membrane potential, which were exacerbated upon proteolytic stress. These functional impairments correspond with characteristic alterations of the mitochondrial network in cells overexpressing mutant mortalin compared with wild-type (wt), which were confirmed in fibroblasts from a carrier of the A476T variant. In line with a loss of function hypothesis, knockdown of mortalin in human cells caused impaired mitochondrial function that was rescued by wt mortalin, but not by the variants. Our genetic and functional studies of novel disease-associated variants in the mortalin gene define a loss of mortalin function, which causes impaired mitochondrial function and dynamics. Our results support the role of this mitochondrial chaperone in neurodegeneration and underscore the concept of impaired mitochondrial protein quality control in PD. AU - Burbulla, L.F.* AU - Schelling, C.* AU - Kato, H.* AU - Rapaport, D.* AU - Woitalla, D.* AU - Schiesling, C.* AU - Schulte, C.* AU - Sharma, M.* AU - Illig, T. AU - Bauer, P.* AU - Jung, S.* AU - Nordheim, A.* AU - Schöls, L.* AU - Riess, O.* AU - Kruger, R.* C1 - 6091 C2 - 28053 SP - 4437-4452 TI - Dissecting the role of the mitochondrial chaperone mortalin in Parkinson's disease: Functional impact of disease-related variants on mitochondrial homeostasis. JO - Hum. Mol. Genet. VL - 19 IS - 22 PB - Oxford Univ. Press PY - 2010 SN - 0964-6906 ER - TY - JOUR AB - Higher resting heart rate is associated with increased cardiovascular disease and mortality risk. Though heritable factors play a substantial role in population variation, little is known about specific genetic determinants. This knowledge can impact clinical care by identifying novel factors that influence pathologic heart rate states, modulate heart rate through cardiac structure and function or by improving our understanding of the physiology of heart rate regulation. To identify common genetic variants associated with heart rate, we performed a meta-analysis of 15 genome-wide association studies (GWAS), including 38,991 subjects of European ancestry, estimating the association between age-, sex- and body mass-adjusted RR interval (inverse heart rate) and approximately 2.5 million markers. Results with P < 5 × 10(-8) were considered genome-wide significant. We constructed regression models with multiple markers to assess whether results at less stringent thresholds were likely to be truly associated with RR interval. We identified six novel associations with resting heart rate at six loci: 6q22 near GJA1; 14q12 near MYH7; 12p12 near SOX5, c12orf67, BCAT1, LRMP and CASC1; 6q22 near SLC35F1, PLN and c6orf204; 7q22 near SLC12A9 and UfSp1; and 11q12 near FADS1. Associations at 6q22 400 kb away from GJA1, at 14q12 MYH6 and at 1q32 near CD34 identified in previously published GWAS were confirmed. In aggregate, these variants explain approximately 0.7% of RR interval variance. A multivariant regression model including 20 variants with P < 10(-5) increased the explained variance to 1.6%, suggesting that some loci falling short of genome-wide significance are likely truly associated. Future research is warranted to elucidate underlying mechanisms that may impact clinical care. AU - Eijgelsheim, M.* AU - Newton-Cheh, C.* AU - Sotoodehnia, N.* AU - de Bakker, P.I.W.* AU - Müller, M. AU - Morrison, A.C.* AU - Smith, A.V.* AU - Isaacs, A.* AU - Sanna, S.* AU - Dörr, M.* AU - Navarro, P.* AU - Fuchsberger, C.* AU - Nolte, I.M.* AU - de Geus, E.J.* AU - Estrada, K.* AU - Hwang, S.J.* AU - Bis, J.C.* AU - Rückert, I.-M.* AU - Alonso, A.* AU - Launer, L.J.* AU - Hottenga, J.J.* AU - Rivadeneira, F.* AU - Noseworthy, P.A.* AU - Rice, K.M.* AU - Perz, S. AU - Arking, D.E.* AU - Spector, T.D.* AU - Kors, J.A.* AU - Aulchenko, Y.S.* AU - Tarasov, K.V.* AU - Homuth, G.* AU - Wild, S.H.* AU - Marroni, F.* AU - Gieger, C.* AU - Licht, C.M.* AU - Prineas, R.J.* AU - Hofman, A.* AU - Rotter, J.I.* AU - Hicks, A.A.* AU - Ernst, F.* AU - Najjar, S.S.* AU - Wright, A.F.* AU - Peters, A.* AU - Fox, E.R.* AU - Oostra, B.A.* AU - Kroemer, H.K.* AU - Couper, D.* AU - Völzke, H.* AU - Campbell, H.* AU - Meitinger, T. AU - Uda, M.* AU - Witteman, J.C.M.* AU - Psaty, B.M.* AU - Wichmann, H.-E. AU - Harris, T.B.* AU - Kääb, S. AU - Siscovick, D.S.* AU - Jamshidi, Y.* AU - Uitterlinden, A.G.* AU - Folsom, A.R.* AU - Larson, M.G.* AU - Wilson, J.F.* AU - Penninx, B.W.* AU - Snieder, H.* AU - Pramstaller, P.P.* AU - van Duijn, C.M.* AU - Lakatta, E.G.* AU - Felix, S.B.* AU - Gudnason, V.* AU - Pfeufer, A. AU - Heckbert, S.R.* AU - Stricker, B.H.C.* AU - Boerwinkle, E.* AU - O'Donnell, C.J.* C1 - 4656 C2 - 27547 SP - 3885-3894 TI - Genome-wide association analysis identifies multiple loci related to resting heart rate. JO - Hum. Mol. Genet. VL - 19 IS - 19 PB - Oxford Univ. Press PY - 2010 SN - 0964-6906 ER - TY - JOUR AB - The global prevalence of obesity has increased significantly in recent decades, mainly due to excess calorie intake and increasingly sedentary lifestyle. Here, we test the association between obesity measured by body mass index (BMI) and one of the best-known genetic variants showing strong selective pressure: the functional variant in the cis-regulatory element of the lactase gene. We tested this variant since it is presumed to provide nutritional advantage in specific physical and cultural environments. We genetically defined lactase persistence (LP) in 31 720 individuals from eight European population-based studies and one family study by genotyping or imputing the European LP variant (rs4988235). We performed a meta-analysis by pooling the beta-coefficient estimates of the relationship between rs4988235 and BMI from the nine studies and found that the carriers of the allele responsible for LP among Europeans showed higher BMI (P = 7.9 x 10(-5)). Since this locus has been shown to be prone to population stratification, we paid special attention to reveal any population substructure which might be responsible for the association signal. The best evidence of exclusion of stratification came from the Dutch family sample which is robust for stratification. In this study, we highlight issues in model selection in the genome-wide association studies and problems in imputation of these special genomic regions. AU - Kettunen, J.* AU - Silander, K.* AU - Saarela, O.* AU - Amin, N.* AU - Müller, M. AU - Timpson, N.* AU - Surakka, I.* AU - Ripatti, S.* AU - Laitinen, J.* AU - Hartikainen, A.L.* AU - Pouta, A.* AU - Lahermo, P.* AU - Anttila, V.* AU - Männistö, S.* AU - Jula, A.* AU - Virtamo, J.* AU - Salomaa, V.* AU - Lehtimäki, T.* AU - Raitakari, O.* AU - Gieger, C. AU - Wichmann, H.-E. AU - van Duijn, C.M.* AU - Smith, G.D.* AU - McCarthy, M.I.* AU - Jarvelin, M.R.* AU - Perola, M.* AU - Peltonen, L.* C1 - 1402 C2 - 27293 SP - 1129-1136 TI - European lactase persistence genotype shows evidence of association with increase in body mass index. JO - Hum. Mol. Genet. VL - 19 IS - 6 PB - Oxford Univ. Press PY - 2010 SN - 0964-6906 ER - TY - JOUR AB - Epidemiological studies consistently show that circulating sex hormone binding globulin (SHBG) levels are lower in type 2 diabetes patients than non-diabetic individuals, but the causal nature of this association is controversial. Genetic studies can help dissect causal directions of epidemiological associations because genotypes are much less likely to be confounded, biased or influenced by disease processes. Using this Mendelian randomization principle, we selected a common single nucleotide polymorphism (SNP) near the SHBG gene, rs1799941, that is strongly associated with SHBG levels. We used data from this SNP, or closely correlated SNPs, in 27 657 type 2 diabetes patients and 58 481 controls from 15 studies. We then used data from additional studies to estimate the difference in SHBG levels between type 2 diabetes patients and controls. The SHBG SNP rs1799941 was associated with type 2 diabetes [odds ratio (OR) 0.94, 95% CI: 0.91, 0.97; P = 2 x 10(-5)], with the SHBG raising allele associated with reduced risk of type 2 diabetes. This effect was very similar to that expected (OR 0.92, 95% CI: 0.88, 0.96), given the SHBG-SNP versus SHBG levels association (SHBG levels are 0.2 standard deviations higher per copy of the A allele) and the SHBG levels versus type 2 diabetes association (SHBG levels are 0.23 standard deviations lower in type 2 diabetic patients compared to controls). Results were very similar in men and women. There was no evidence that this variant is associated with diabetes-related intermediate traits, including several measures of insulin secretion and resistance. Our results, together with those from another recent genetic study, strengthen evidence that SHBG and sex hormones are involved in the aetiology of type 2 diabetes. AU - Perry, J.R.B.* AU - Weedon, M.N.* AU - Langenberg, C.* AU - Jackson, A.U.* AU - Lyssenko, V.* AU - Sparso, T.* AU - Thorleifsson, G.* AU - Grallert, H. AU - Ferrucci, L.* AU - Maggio, M.* AU - Paolisso, G.* AU - Walker, M.* AU - Palmer, C.N.A.* AU - Payne, F.* AU - Young, E.* AU - Herder, C.* AU - Narisu, N.* AU - Morken, M.A.* AU - Bonnycastle, L.L.* AU - Owen, K.R.* AU - Shields, B.* AU - Knight, B.* AU - Bennett, A.* AU - Groves, C.J.* AU - Ruokonen, A.* AU - Jarvelin, M.R.* AU - Pearson, E.* AU - Pascoe, L.* AU - Ferrannini, E.* AU - Bornstein, S.R.* AU - Stringham, H.M.* AU - Scott, L.J.* AU - Kuusisto, J.* AU - Nilsson, P.* AU - Neptin, M.* AU - Gjesing, A.P.* AU - Pisinger, C.* AU - Lauritzen, T.* AU - Sandbaek, A.* AU - Sampson, M.* AU - Magic, E.Z.* AU - Lindgren, C.M.* AU - Steinthorsdottir, V.* AU - Thorsteinsdottir, U.* AU - Hansen, T.* AU - Schwarz, P.* AU - Illig, T. AU - Laakso, M.* AU - Stefansson, K.* AU - Morris, A.D.* AU - Groop, L.* AU - Pedersen, O.* AU - Boehnke, M.* AU - Barroso, I.* AU - Wareham, N.J.* AU - Hattersley, A.T.* AU - McCarthy, M.I.* AU - Frayling, T.M.* C1 - 699 C2 - 27112 SP - 535-544 TI - Genetic evidence that raised sex hormone binding globulin (SHBG) levels reduce the risk of type 2 diabetes. JO - Hum. Mol. Genet. VL - 19 IS - 3 PB - Oxford Univ. Press PY - 2010 SN - 0964-6906 ER - TY - JOUR AB - To identify type 2 diabetes (T2D) susceptibility loci, we conducted genome-wide association (GWA) scans in nested case-control samples from two prospective cohort studies, including 2591 patients and 3052 controls of European ancestry. Validation was performed in 11 independent GWA studies of 10,870 cases and 73,735 controls. We identified significantly associated variants near RBMS1 and ITGB6 genes at 2q24, best-represented by SNP rs7593730 (combined OR=0.90, 95% CI=0.86-0.93; P=3.7x10(-8)). The frequency of the risk-lowering allele T is 0.23. Variants in this region were nominally related to lower fasting glucose and HOMA-IR in the MAGIC consortium (P<0.05). These data suggest that the 2q24 locus may influence the T2D risk by affecting glucose metabolism and insulin resistance. AU - Qi, L.* AU - Cornelis, M.C.* AU - Kraft, P.* AU - Stanya, K.J.* AU - Kao, W.H.L.* AU - Pankow, J.S.* AU - Dupuis, J.* AU - Florez, J.C* AU - Fox, C.S.* AU - Paré, G.* AU - Sun, Q.* AU - Girman, C.J.* AU - Laurie, C.C.* AU - Mirel, D.B.* AU - Manolio, T.A.* AU - Chasman, D.I.* AU - Boerwinkle, E.* AU - Ridker, P.M.* AU - Hunter, D.J.* AU - Meigs, J.B.* AU - Lee, C.H.* AU - van Dam, R.M.* AU - Hu, F.B.* C1 - 6096 C2 - 27925 SP - 2706-2715 TI - Genetic variants at 2q24 are associated with susceptibility to type 2 diabetes. JO - Hum. Mol. Genet. VL - 19 IS - 13 PB - Oxford Univ. Press PY - 2010 SN - 0964-6906 ER - TY - JOUR AB - The cause of sporadic amyotrophic lateral sclerosis (ALS) is largely unknown, but genetic factors are thought to play a significant role in determining susceptibility to motor neuron degeneration. To identify genetic variants altering risk of ALS, we undertook a two-stage genome-wide association study (GWAS): we followed our initial GWAS of 545 066 SNPs in 553 individuals with ALS and 2338 controls by testing the 7600 most associated SNPs from the first stage in three independent cohorts consisting of 2160 cases and 3008 controls. None of the SNPs selected for replication exceeded the Bonferroni threshold for significance. The two most significantly associated SNPs, rs2708909 and rs2708851 [odds ratio (OR) = 1.17 and 1.18, and P-values = 6.98 x 10(-7) and 1.16 x 10(-6)], were located on chromosome 7p13.3 within a 175 kb linkage disequilibrium block containing the SUNC1, HUS1 and C7orf57 genes. These associations did not achieve genome-wide significance in the original cohort and failed to replicate in an additional independent cohort of 989 US cases and 327 controls (OR = 1.18 and 1.19, P-values = 0.08 and 0.06, respectively). Thus, we chose to cautiously interpret our data as hypothesis-generating requiring additional confirmation, especially as all previously reported loci for ALS have failed to replicate successfully. Indeed, the three loci (FGGY, ITPR2 and DPP6) identified in previous GWAS of sporadic ALS were not significantly associated with disease in our study. Our findings suggest that ALS is more genetically and clinically heterogeneous than previously recognized. Genotype data from our study have been made available online to facilitate such future endeavors. AU - Chio, A.* AU - Schymick, J.C.* AU - Restagno, G.* AU - Scholz, S.W.* AU - Lombardo, F.* AU - Lai, S.L.* AU - Mora, G.* AU - Fung, H.C.* AU - Britton, A.* AU - Arepalli, S.* AU - Gibbs, J.R.* AU - Nalls, M.* AU - Berger, S.* AU - Kwee, L.C.* AU - Oddone, E.Z.* AU - Ding, J.H.* AU - Crews, C.* AU - Rafferty, I.* AU - Washecka, N.* AU - Hernandez, D.* AU - Ferrucci, L.* AU - Bandinelli, S.* AU - Guralnik, J.* AU - Macciardi, F.* AU - Torri, F.* AU - Lupoli, S.* AU - Chanock, S.J.* AU - Thomas, G.* AU - Hunter, D.J.* AU - Gieger, C. AU - Wichmann, H.-E. AU - Calvo, A.* AU - Mutani, R.* AU - Battistini, S.* AU - Giannini, F.* AU - Caponnetto, C.* AU - Mancardi, G.L.* AU - La Bella, V.* AU - Valentino, F.* AU - Monsurro, M.R.* AU - Tedeschi, G.* AU - Marinou, K.* AU - Sabatelli, M.* AU - Conte, A.* AU - Mandrioli, J.* AU - Sola, P.* AU - Salvi, F.* AU - Bartolomei, I.* AU - Siciliano, G.* AU - Carlesi, C.* AU - Orrell, R.W.* AU - Talbot, K.* AU - Simmons, Z.* AU - Connor, J.* AU - Pioro, E.P.* AU - Dunkley, T.* AU - Stephan, D.A.* AU - Kasperaviciute, D.* AU - Fisher, E.M.* AU - Jabonka, S.* AU - Sendtner, M.* AU - Beck, M.* AU - Bruijn, L.* AU - Rothstein, J.* AU - Schmidt, S.* AU - Singleton, A.* AU - Hardy, J.* AU - Traynor, B.J.* C1 - 2243 C2 - 26141 SP - 1524-1532 TI - A two-stage genome-wide association study of sporadic amyotrophic lateral sclerosis. JO - Hum. Mol. Genet. VL - 18 IS - 8 PB - Oxford Univ. Press PY - 2009 SN - 0964-6906 ER - TY - JOUR AB - Recent evidence suggests a close association between extracellular E-cadherin mutation in diffuse-type gastric carcinoma and the acquisition of a migratory phenotype of tumour cells. To characterise the cellular machinery that mediates the gain of motility of tumour cells with mutant E-cadherin, we turned to the small Rho GTPases Rac1 and Rho because they have been implicated in pathological processes including tumour cell migration and invasion. In the present study, we analyse the activity of Rac1 and Rho in relation to E-cadherin harbouring an in-frame deletion of exon 8, and prove for the first time that the mutation reduces the ability of E-cadherin to activate Rac1 and to inhibit Rho. We provide evidence that the lack of Rac1 activation observed in response to mutant E-cadherin influences the downstream signalling of Rac1, as is shown by the decrease in the binding of the Rac1 effector protein IQGAP1 to Rac1-GTP. Moreover, reduced membranous localisation of p120-catenin in mutant E-cadherin-expressing cells provides an explanation for the lack of negative regulation of Rho by mutant E-cadherin. Further, we show by time-lapse laser-scanning microscopy and invasion assay that the enhanced motility and invasion associated with mutant E-cadherin is sensitive to the inhibition of Rac1 and Rho. Together, these findings present evidence that the mutation of E-cadherin influences Rac1 and Rho activation in opposite directions, and that Rac1 and Rho are involved in the establishment of the migratory and invasive phenotype of tumour cells that have an E-cadherin mutation. AU - Deplazes, J.* AU - Fuchs, M.* AU - Rauser, S. AU - Genth, H.* AU - Lengyel, E.* AU - Busch, R.* AU - Luber, B.* C1 - 1188 C2 - 26360 SP - 3632-3644 TI - Rac1 and Rho contribute to the migratory and invasive phenotype associated with somatic E-cadherin mutation. JO - Hum. Mol. Genet. VL - 18 IS - 19 PB - Oxford Univ. Press PY - 2009 SN - 0964-6906 ER - TY - JOUR AB - Genes for height have gained interest for decades, but only recently have candidate genes started to be identified. We have performed linkage analysis and genome-wide association for height in approximately 4000 individuals from five European populations. A total of five chromosomal regions showed suggestive linkage and in one of these regions, two SNPs (rs849140 and rs1635852) were associated with height (nominal P = 7.0 x 10(-8) and P = 9.6 x 10(-7), respectively). In total, five SNPs across the genome showed an association with height that reached the threshold of genome-wide significance (nominal P < 1.6 x 10(-7)). The association with height was replicated for two SNPs (rs1635852 and rs849140) using three independent studies (n = 31 077, n=1268 and n = 5746) with overall meta P-values of 9.4 x 10(-10) and 5.3 x 10(-8). These SNPs are located in the JAZF1 gene, which has recently been associated with type II diabetes, prostate and endometrial cancer. JAZF1 is a transcriptional repressor of NR2C2, which results in low IGF1 serum concentrations, perinatal and early postnatal hypoglycemia and growth retardation when knocked out in mice. Both the linkage and association analyses independently identified the JAZF1 region affecting human height. We have demonstrated, through replication in additional independent populations, the consistency of the effect of the JAZF1 SNPs on height. Since this gene also has a key function in the metabolism of growth, JAZF1 represents one of the strongest candidates influencing human height identified so far. AU - Johansson, A.* AU - Marroni, F.* AU - Hayward, C.* AU - Franklin, C.S.* AU - Kirichenko, A.V.* AU - Jonasson, I.* AU - Hicks, A.A.* AU - Vitart, V.* AU - Isaacs, A.* AU - Axenovich, T.* AU - Campbell, S.* AU - Dunlop, M.G* AU - Floyd, J.* AU - Hastie, N.* AU - Hofman, A.* AU - Knott, S.* AU - Kolcic, I.* AU - Pichler, I.* AU - Polasek, O.* AU - Rivadeneira, F.* AU - Tenesa, A.* AU - Uitterlinden, A.G.* AU - Wild, S.H.* AU - Zorkoltseva, I.V.* AU - Meitinger, T. AU - Wilson, J.F.* AU - Rudan, I.* AU - Campbell, H.* AU - Pattaro, C.* AU - Pramstaller, P.* AU - Oostra, B.A.* AU - Wright, A.F.* AU - van Duijn, C.M.* AU - Aulchenko, Y.S.* AU - Gyllensten, U.* C1 - 329 C2 - 26264 SP - 373-380 TI - Common variants in the JAZF1 gene associated with height identified by linkage and genome-wide association analysis. JO - Hum. Mol. Genet. VL - 18 IS - 2 PB - Oxford Univ. Press PY - 2009 SN - 0964-6906 ER - TY - JOUR AB - Adiponutrin (PNPLA3) is a predominantly liver-expressed transmembrane protein with phospholipase activity that is regulated by fasting and feeding. Recent genome-wide association studies identified PNPLA3 to be associated with hepatic fat content and liver function, thus pointing to a possible involvement in the hepatic lipoprotein metabolism. The aim of this study was to examine the association between two common variants in the adiponutrin gene and parameters of lipoprotein metabolism in 23 274 participants from eight independent West-Eurasian study populations including six population-based studies [Bruneck (n = 800), KORA S3/F3 (n = 1644), KORA S4/F4 (n = 1814), CoLaus (n = 5435), SHIP (n = 4012), Rotterdam (n = 5967)], the SAPHIR Study as a healthy working population (n = 1738) and the Utah Obesity Case-Control Study including a group of 1037 severely obese individuals (average BMI 46 kg/m(2)) and 827 controls from the same geographical region of Utah. We observed a strong additive association of a common non-synonymous variant within adiponutrin (rs738409) with age-, gender-, and alanine-aminotransferase-adjusted lipoprotein concentrations: each copy of the minor allele decreased levels of total cholesterol on average by 2.43 mg/dl (P = 8.87 x 10(-7)), non-HDL cholesterol levels by 2.35 mg/dl (P = 2.27 x 10(-6)) and LDL cholesterol levels by 1.48 mg/dl (P = 7.99 x 10(-4)). These associations remained significant after correction for multiple testing. We did not observe clear evidence for associations with HDL cholesterol or triglyceride concentrations. In conclusion, our study suggests that adiponutrin is involved in the metabolism of apoB-containing lipoproteins. AU - Kollerits, B.* AU - Coassin, S.* AU - Beckmann, N.D.* AU - Teumer, A.* AU - Kiechl, S.* AU - Döring, A. AU - Kavousi, M.* AU - Hunt, S.C.* AU - Lamina, C. AU - Paulweber, B.* AU - Kutalik, Z.* AU - Nauck, M.* AU - van Duijn, C.M.* AU - Heid, I.M. AU - Willeit, J.* AU - Brandstatter, A.* AU - Adams, T.D.* AU - Mooser, V.* AU - Aulchenko, Y.S.* AU - Völzke, H.* AU - Kronenberg, F.* C1 - 1300 C2 - 26492 SP - 4669-4676 TI - Genetic evidence for a role of adiponutrin in the metabolism of apolipoprotein b-containing lipoproteins. JO - Hum. Mol. Genet. VL - 18 IS - 23 PB - Oxford Univ. Press PY - 2009 SN - 0964-6906 ER - TY - JOUR AB - Hypertension is a complex disease that affects a large proportion of adult population. Although approximately half of the inter-individual variance in blood pressure (BP) level is heritable, identification of genes responsible for its regulation has remained challenging. Genome-wide association study (GWAS) is a novel approach to search for genetic variants contributing to complex diseases. We conducted GWAS for three BP traits [systolic and diastolic blood pressure (SBP and DBP); hypertension (HYP)] in the Kooperative Gesundheitsforschung in der Region Augsburg (KORA) S3 cohort (n = 1644) recruited from general population in Southern Germany. GWAS with 395 912 single nucleotide polymorphisms (SNPs) identified an association between BP traits and a common variant rs11646213 (T/A) upstream of the CDH13 gene at 16q23.3. The initial associations with HYP and DBP were confirmed in two other European population-based cohorts: KORA S4 (Germans) and HYPEST (Estonians). The associations between rs11646213 and three BP traits were replicated in combined analyses (dominant model: DBP, P = 5.55 x 10(-5), effect -1.40 mmHg; SBP, P = 0.007, effect -1.56 mmHg; HYP, P = 5.30 x 10(-8), OR = 0.67). Carriers of the minor allele A had a decreased risk of hypertension. A non-significant trend for association was also detected with severe family based hypertension in the BRIGHT sample (British). The novel susceptibility locus, CDH13, encodes for an adhesion glycoprotein T-cadherin, a regulator of vascular wall remodeling and angiogenesis. Its function is compatible with the BP biology and may improve the understanding of the pathogenesis of hypertension. AU - Org, E.* AU - Eyheramendy, S. AU - Juhanson, P.* AU - Gieger, C. AU - Lichtner, P. AU - Klopp, N. AU - Veldre, G.* AU - Döring, A. AU - Viigimaa, M.* AU - Sõber, S.* AU - Tomberg, K.* AU - Eckstein, G. AU - Kelgo, P.* AU - Rebane, T.* AU - Shaw-Hawkins, S.* AU - Howard, P.* AU - Onipinla, A. AU - Dobson, R.J.* AU - Newhouse, S.J.* AU - Brown, M.* AU - Dominiczak, A.* AU - Connell, J.* AU - Samani, N.* AU - Farrall, M.* AU - Caulfield, M.J.* AU - Munroe, P.B.* AU - Illig, T. AU - Wichmann, H.-E. AU - Meitinger, T. AU - Laan, M.* C1 - 1917 C2 - 26166 SP - 2288-2296 TI - Genome-wide scan identifies CDH13 as a novel susceptibility locus contributing to blood pressure determination in two European populations. JO - Hum. Mol. Genet. VL - 18 IS - 12 PB - Oxford Univ. Press PY - 2009 SN - 0964-6906 ER - TY - JOUR AB - Embryonic stem (ES) cells are pluripotent and permanent cell lines which can differentiate into cell types of all the three germ layers. These features imply multiple opportunities for clinical applications in tissue engineering and regenerative medicine. Most of our knowledge on the biology and technology of ES cells is derived from studies with mouse ES cells. While appropriate for proof-of-principle studies, the mouse model has limitations in its application in translational, pre-clinical studies. This is particularly true for studies evaluating the safety and efficacy of stem cell therapies. For this purpose, large animal models more closely mimicking important aspects of human anatomy, physiology and pathology than mouse models are urgently needed. In this context, the dog is an excellent candidate: the plethora of different dog breeds offer a large phenotypic and genetic variability, which can be exploited increasingly well due to the advanced status of the dog genome project and the rapidly growing box of genomic tools. Recently, the first pluripotent canine embryo-derived stem cells have been described, further increasing the potential of the dog as a model system for regenerative medicine. Although these cells express alkaline phosphatase, NANOG and OCT4, and can be differentiated in vitro towards endoderm-, mesoderm- and ectoderm-lineages (typical features of human and mouse ES cells), their in vivo differentiation capability, i.e. formation of teratomas in immunodeficient mice or contribution to chimeric animals, remains to be demonstrated. Here, we discuss the features of reported canine embryo-derived cells and their potential applications in basic and translational biomedical research. AU - Schneider, M.R.* AU - Wolf, E.* AU - Braun, J.* AU - Kolb, H.-J. AU - Adler, H. C1 - 2614 C2 - 25361 SP - R42-R47 TI - Canine embryo-derived stem cells and models for human diseases. JO - Hum. Mol. Genet. VL - 17 IS - R1 PB - Oxford Univ. Press PY - 2008 SN - 0964-6906 ER - TY - JOUR AB - Data from both experimental models and humans provide evidence that ghrelin and its receptor, the growth hormone secretagogue receptor (ghrelin receptor, GHSR), possess a variety of cardiovascular effects. Thus, we hypothesized that genetic variants within the ghrelin system (ligand ghrelin and its receptor GHSR) are associated with susceptibility to myocardial infarction (MI) and coronary artery disease (CAD). Seven single nucleotide polymorphisms (SNPs) covering the GHSR region as well as eight SNPs across the ghrelin gene (GHRL) region were genotyped in index MI patients (864 Caucasians, ‘index MI cases’) from the German MI family study and in matched controls without evidence of CAD (864 Caucasians, ‘controls’, MONICA Augsburg). In addition, siblings of these MI patients with documented severe CAD (826 ‘affected sibs’) were matched likewise with controls (n = 826 Caucasian ‘controls’) and used for verification. The effect of interactions between genetic variants of both genes of the ghrelin system was explored by conditional classification tree models. We found association of several GHSR SNPs with MI [best SNP odds ratio (OR) 1.7 (1.2–2.5); P = 0.002] using a recessive model. Moreover, we identified a common GHSR haplotype which significantly increases the risk for MI [multivariate adjusted OR for homozygous carriers 1.6 (1.1–2.5) and CAD OR 1.6 (1.1–2.5)]. In contrast, no relationship between genetic variants and the disease could be revealed for GHRL. However, the increase in MI/CAD frequency related to the susceptible GHSR haplotype was abolished when it coincided with a common GHRL haplotype. Multivariate adjustments as well as permutation-based methods conveyed the same results. These data are the first to demonstrate an association of SNPs and haplotypes within important genes of the ghrelin system and the susceptibility to MI, whereas association with MI/CAD could be identified for genetic variants across GHSR, no relationship could be revealed for GHRL itself. However, we found an effect of GHRL dependent upon the presence of a common, MI and CAD susceptible haplotype of GHSR. Thus, our data suggest that specific haplotypes of the ghrelin ligand and its receptor act epistatically to affect susceptibility or tolerance to MI and/or CAD. AU - Baessler, A.* AU - Fischer, M.* AU - Mayer, B.* AU - Koehler, M.* AU - Wiedmann, S.* AU - Stark, K.* AU - Döring, A. AU - Erdmann, J.* AU - Riegger, G.* AU - Schunkert, H.* AU - Kwitek, A.E.* AU - Hengstenberg, C.* C1 - 2067 C2 - 24613 SP - 887-899 TI - Epistatic interaction between haplotypes of the ghrelin ligand and receptor genes influence susceptibility to myocardial infarction and coronary artery disease. JO - Hum. Mol. Genet. VL - 16 IS - 8 PB - Oxford Univ. Press PY - 2007 SN - 0964-6906 ER - TY - JOUR AB - Single-nucleotide polymorphisms within the BAT1-NFKBIL1-LTA genomic region (6p21.3) and the LGALS2 gene (22q13.1), encoding a regulator for lymphotoxin-alpha, the product of the LTA gene, have been reported to be linked with the risk of myocardial infarction in Japanese. We employed nine polymorphisms from the BAT1-NFKBIL1-LTA region and one polymorphism from the LGALS2 gene, and investigated whether such associations were also present in Europeans. The study included 3657 patients with myocardial infarction and 1211 control individuals with angiographically normal coronary arteries. Minor homozygous genotypes of polymorphisms in BAT1 (rs2239527, -23C/G), NFKBIL1 (rs2071592, -63T/A) and LTA (rs1800683, -162G/A; rs909253, 252G/A; rs1041981, Thr26Asn) were associated with moderately protective effects against myocardial infarction (P AU - Koch, W.* AU - Hoppmann, P.* AU - Michou, E.* AU - Jung, V.* AU - Pfeufer, A. AU - Mueller, J.C.* AU - Gieger, C. AU - Wichmann, H.-E. AU - Meitinger, T. AU - Schömig, A.* AU - Kastrati, A.* C1 - 2775 C2 - 24780 SP - 1821-1827 TI - Association of variants in the BAT1-NFKBIL1-LTA genomic region with protection against myocardial infarction in Europeans. JO - Hum. Mol. Genet. VL - 16 IS - 15 PB - Oxford Univ. Press PY - 2007 SN - 0964-6906 ER - TY - JOUR AB - MAF, one of a family of large Maf bZIP transcription factors, is mutated in human developmental ocular disorders that include congenital cataract, microcornea, coloboma and anterior segment dysgenesis. Expressed early in the developing lens vesicle, it is central to regulation of lens crystallin gene expression. We report a semi-dominant mouse c-Maf mutation recovered after ENU mutatgenesis which results in the substitution, D90V, at a highly conserved residue within the N-terminal 35 amino-acid minimal transactivation domain (MTD). Unlike null and loss-of-function c-Maf mutations, which cause severe runting and renal abnormalities, the phenotype caused by the D90V mutation is isolated cataract. In reporter assays, D90V results in increased promoter activation, a situation similar to MTD mutations of NRL that also cause human disease. In contrast to wild-type protein, the c-Maf D90V mutant protein is not inhibited by protein kinase A-dependent pathways. The MTD of large Maf proteins has been shown to interact with the transcriptional co-activator p300 and we demonstrate that c-Maf D90V enhances p300 recruitment in a cell-type dependent manner. We observed the same for the pathogenic human NRL MTD mutation S50T, which suggests a common mechanism of action. AU - Perveen, R.* AU - Favor, J. AU - Jamieson, R.V.* AU - Ray, D.W.* AU - Black, G.C.* C1 - 3785 C2 - 24783 SP - 1030-1038 TI - A heterozygous c-Maf transactivation domain mutation causes congenital cataract and enhances target gene activation. JO - Hum. Mol. Genet. VL - 16 IS - 9 PB - Oxford Univ. Press PY - 2007 SN - 0964-6906 ER - TY - JOUR AB - Mutations in the leucine-rich repeat kinase 2 gene (LRRK2) have been recently identified in families with autosomal dominant late-onset Parkinson disease (PD). The LRRK2 protein consists of multiple domains and belongs to the Roco family, a novel group of the Ras/GTPase superfamily. Besides the GTPase (Roc) domain, it contains a predicted kinase domain, with homology to MAP kinase kinase kinases. Using cell fractionation and immunofluorescence microscopy, we show that LRRK2 is localized in the cytoplasm and is associated with cellular membrane structures. The purified LRRK2 protein demonstrates autokinase activity. The disease-associated I2020T mutant shows a significant increase in autophosphorylation of similar to 40% in comparison to wild-type protein in vitro. This suggests that the pathology of PD caused by the I2020T mutation is associated with an increase rather than a loss in LRRK2 kinase activity. AU - Gloeckner, C.J. AU - Kinkl, N. AU - Schumacher, A. AU - Braun, R.J. AU - O'Neill, E.* AU - Meitinger, T. AU - Kolch, W.* AU - Prokisch, H. AU - Ueffing, M. C1 - 4256 C2 - 23475 SP - 223-232 TI - The parkinson disease causing LRRK2 mutation I2020T is associated with increased kinase activity. JO - Hum. Mol. Genet. VL - 15 IS - 2 PB - Oxford Univ. Press PY - 2006 SN - 0964-6906 ER - TY - JOUR AB - Nance-Horan syndrome (NHS) is an X-linked disorder characterized by congenital cataracts, dental anomalies, dysmorphic features and mental retardation. A recent report suggests that the novel gene NHS1 is involved in this disorder due to the presence of point mutations in NHS patients. A possible mouse model for NHS, Xcat, was mapped to a 2.11 Mb interval on the X-chromosome. Sequence and FISH analysis of the X-chromosome region containing the Xcat mutation reveal a large insertion between exons 1 and 2 of the mouse Nhs1 gene. The insertion inhibits the expression of the Nhs1 isoform containing exon 1 and results in exclusive expression of the alternative isoform containing exon 1A. Quantitative RT-PCR of Xcat cDNA shows reduced levels of Nhs1 transcripts. The Nhs1 protein is strongly expressed within the cytoplasm of elongating lens fiber cells from wild-type neonate lens, but is significantly reduced within the Xcat lens. Transient transfection studies of CHO cells with Nhs1-GFP fusion proteins were done to determine whether the amino acids encoded by exon 1 were critical for protein localization. We found the presence of Nhs1 exon 1 critical for localization of the fusion protein to the cytoplasm, whereas fusion proteins lacking Nhs1 exon 1 are predominantly nuclear. These results indicate that the first exon of Nhs1 contains crucial information required for the proper expression and localization of Nhs1 protein. Inhibition of expression of the exon 1 containing isoform results in the abnormal phenotype of Xcat. AU - Huang, K.M.* AU - Wu, J.* AU - Duncan, M.K.* AU - Moy, C.* AU - Dutra, A.* AU - Favor, J. AU - Da, T.* AU - Stambolian, D.* C1 - 3773 C2 - 23666 SP - 319-327 TI - Xcat, a novel mouse model for Nance-Horan syndrome inhibits expression of the cytoplasmic-targeted Nhs1 isoform. JO - Hum. Mol. Genet. VL - 15 IS - 2 PB - Oxford Univ. Press PY - 2006 SN - 0964-6906 ER - TY - JOUR AB - A number of susceptibility loci for Alzheimer's disease (AD) have been identified including a region on Chromosome 10q21-q22. Within this region the plasminogen activator urokinase gene (PLAU) was considered as a reasonable candidate from its functional implication in plasmin generation, a serine protease capable of degrading beta-Amyloid (A beta) protein. We screened 56 single nucleotide polymorphisms (SNPs) around PLAU using 1751 individuals from four independent case-control samples (Munich, N=679; Bonn N=282; Brescia (Italy) N=219; Perth (Australia) N=557 and one discordant sib-pair sample (Munich N=622). In brain tissue samples of neuropathologically confirmed cases with AD (N=33) we analyzed plaque counts according to the risk allele. We identified that one functional exonic SNP (rs2227564) is associated with development of AD using the four independent case-control samples (Munich, P=0.02; Bonn, P=0.005; Brescia (Italy), P=0.001; Perth (Australia), P=0.03) and the discordant sib-pair sample (P=0.001). In brain tissue, from neuropathologically confirmed cases with AD, we identified significantly higher plaque counts in carriers of the risk allele (N=6; 60.3 +/- 16.9) compared with non-carriers (N=9; 26.3 +/- 8.8; P=0.007). This study provides compelling evidence of a genetic and functional involvement of a common PLAU variant into the pathogenesis of AD. Further functional investigations are warranted to elucidate the specific role of PLAU, respectively, PLAU variants in the metabolism of A beta proteins. AU - Riemenschneider, M.* AU - Konta, L.* AU - Friedrich, P.* AU - Schwarz, S.* AU - Taddei, K.* AU - Neff, F.* AU - Padovani, A.* AU - Kölsch, H.* AU - Laws, S.M.* AU - Klopp, N. AU - Bickeböller, H.* AU - Wagenpfeil, S.* AU - Mueller, J.C.* AU - Rosenberger, A.* AU - Diehl-Schmid, J.* AU - Archetti, S.* AU - Lautenschlager, N.* AU - Borroni, B.* AU - Müller, U.* AU - Illig, T. AU - Heun, R.* AU - Egensperger, R.* AU - Schlegel, J.* AU - Förstl, H.* AU - Martins, R.N.* AU - Kurz, A.* C1 - 3114 C2 - 23790 SP - 2446-2456 TI - A functional polymorphism within plasminogen activator urokinase (PLAU) is associated with Alzheimer's disease. JO - Hum. Mol. Genet. VL - 15 IS - 16 PB - Oxford Univ. Press PY - 2006 SN - 0964-6906 ER - TY - JOUR AB - Fatty acid composition in membranes plays an important role in cellular processes and has shown to be associated with the aetiology of several complex diseases in humans. We report strong associations between variants in the human delta-5 and delta-6 desaturase genes FADS1 FADS2 and fatty acid composition in serum phospholipids. Eighteen polymorphisms located in this gene cluster were genotyped in 727 adults from Erfurt, a German centre of the European Community Respiratory Health Survey. The cluster is located at chromosome 11q12-11q13.1, a region repeatedly found to be linked with atopy and other complex diseases. Polymorphisms and statistically reconstructed haplotypes of FADS1 and the upstream region of FADS2 showed strongest associations with the level of the direct precursor of inflammatory eicosanoids, the n-6 fatty acid arachidonic acid (C20:4n-6), also strong associations with levels of the n-6 fatty acids C18:2n-6, C18:3n-6, C20:2n-6, C20:3n-6, C22:4n-6 and of the n-3 fatty acids C18:3n-3, C20:5n-3 and C22:5n-3 (P-values < 1.0x10(-13)). Carriers of the rare alleles of several SNPs and their respective haplotypes had a lower prevalence of allergic rhinitis and atopic eczema. No association was found for total and specific IgE levels. AU - Schaeffer, L. AU - Gohlke, H. AU - Müller, M. AU - Heid, I.M. AU - Palmer, L.J.* AU - Kompauer, I. AU - Demmelmair, H.* AU - Illig, T. AU - Koletzko, B.* AU - Heinrich, J. C1 - 2776 C2 - 23704 SP - 1745-1756 TI - Common genetic variants of the FADS1 FADS2 gene cluster and their reconstructed haplotypes are associated with the fatty acid composition in phospholipids JO - Hum. Mol. Genet. VL - 15 IS - 11 PB - Oxford Univ. Press PY - 2006 SN - 0964-6906 ER - TY - JOUR AB - Familial tumoral calcinosis (FTC) is an autosomal recessive disorder characterized by ectopic calcifications and elevated serum phosphate levels. Recently, mutations in the GALNT3 gene have been described to cause FTC. The FTC phenotype is regarded as the metabolic mirror image of hypophosphatemic conditions, where causal mutations are known in genes FGF23 or PHEX. We investigated an individual with FTC who was negative for GALNT3 mutations. Sequencing revealed a homozygous missense mutation in the FGF23 gene (p.S71G) at an amino acid position which is conserved from fish to man. Wild-type FGF23 is secreted as intact protein and processed N-terminal and C-terminal fragments. Expression of the mutated protein in HEK293 cells showed that only the C-terminal fragment is secreted, whereas the intact protein is retained in the Golgi complex. In addition, determination of circulating FGF23 in the affected individual showed a marked increase in the C-terminal fragment. These results suggest that the FGF23 function is decreased by absent or extremely reduced secretion of intact FGF23. We conclude that FGF23 mutations in hypophosphatemic rickets and FTC have opposite effects on phosphate homeostasis. AU - Benet-Pagès, A. AU - Orlik, P.* AU - Strom, T.M. AU - Lorenz-Depiereux, B. C1 - 831 C2 - 22835 SP - 385-390 TI - An FGF23 missense mutation causes familial tumoral calcinosis with hyperphosphatemia. JO - Hum. Mol. Genet. VL - 14 IS - 3 PB - Oxford Univ. Press PY - 2005 SN - 0964-6906 ER - TY - JOUR AB - Asthma is a familial inflammatory disease of the airways of the lung. Microbial exposures in childhood protect against asthma through unknown mechanisms. The innate immune system is able to identify microbial components through a variety of pattern-recognition receptors (PRRs). NOD1 is an intracellular PRR that initiates inflammation in response to bacterial diaminopimelic acid (iE-DAP). The NOD1 gene is on chromosome 7p14, in a region that has been genetically linked to asthma. We carried out a systematic search for polymorphism in the gene. We found an insertion-deletion polymorphism (ND1+32656) near the beginning of intron IX that accounted for similar to 7% of the variation in IgE in two panels of families (P < 0.0005 in each). Allele*2 (the insertion) was associated with high IgE levels. The same allele was strongly associated with asthma in an independent study of 600 asthmatic children and 1194 super-normal controls [odds ratio (OR) 6.3; 95% confidence interval (CI) 1.4-28.3, dominant model]. Differential binding of the two ND1+32656 alleles was observed to a protein from nuclei of the Calu 3 epithelial cell line. In an accompanying study, the deletion allele (ND1+32656*1) was found to be associated with inflammatory bowel disease. The results indicate that intracellular recognition of specific bacterial products affects the presence of childhood asthma. AU - Hysi, P.* AU - Kabesch, M.* AU - Moffatt, M.F.* AU - Schedel, M.* AU - Carr, D.* AU - Zhang, Y.* AU - Boardman, B.* AU - von Mutius, E.* AU - Weiland, S.K.* AU - Leupold, W.* AU - Fritzsch, C.* AU - Klopp, N. AU - Musk, A.W.* AU - James, A.* AU - Nunez, G.* AU - Inohara, N.* AU - Cookson, W.O.* C1 - 3393 C2 - 22986 SP - 935-941 TI - NOD1 variation, immunoglobulin E and asthma. JO - Hum. Mol. Genet. VL - 14 IS - 7 PB - Oxford Univ. Press PY - 2005 SN - 0964-6906 ER - TY - JOUR AB - Age-related macular degeneration (AMD) is a multifactorial disease and a prevalent cause of visual impairment in developed countries. Risk factors include environmental components and genetic determinants. The complement factor H (CFH) has been the first major susceptibility gene for AMD identified within 1q32. Here, we focused on a second region of interest in 10q26 where a recent meta-analysis revealed strongest evidence for linkage to AMD at a genome-wide significance level. Within an interval of 22 Mb, we have analyzed 93 single nucleotide polymorphisms for allelic association with AMD in two independent case-control cohorts of German origin (AMD(combined) n=1166; controls(combined) n=945). Significant association was found across a 60 kb region of high linkage disequilibrium harboring two genes PLEKHA1 and hypothetical LOC387715. The strongest association (P=10(-34)) centered over a frequent coding polymorphism, Ala69Ser, at LOC387715, strongly implicating this gene in the pathogenesis of AMD. Besides abundant expression in placenta, we demonstrate weak expression of LOC387715 in the human retina. At present, however, there is no functional information on this gene, which appears to have evolved recently within the primate lineage. The joint contribution of the common risk allele at LOC387715, Ala69Ser, and at CFH, Tyr402His, was assessed in our case-control population, which suggests an additive model indicating an independent contribution of the two gene loci to disease risk. Our data show a disease odds ratio of 57.6 (95% CI: 37.2, 89.0) conferred by homozygosity for risk alleles at both CFH and LOC387715 when compared with the baseline non-risk genotype. AU - Rivera, A.* AU - Fisher, S.A.* AU - Fritsche, L.G.* AU - Keilhauer, C.N.* AU - Lichtner, P. AU - Meitinger, T. AU - Weber, B.H.F.* C1 - 4480 C2 - 23185 SP - 3227-3236 TI - Hypoethical LOC387715 is a second major susceptibility gene for age-related macular degeneration, contributing independently of complement factor H to disease risk. JO - Hum. Mol. Genet. VL - 14 IS - 21 PB - Oxford Univ. Press PY - 2005 SN - 0964-6906 ER - TY - JOUR AB - YT521-B is a ubiquitously expressed nuclear protein that changes alternative splice site usage in a concentration dependent manner. YT521-B is located in a dynamic nuclear compartment, the YT body. We show that YT521-B is tyrosine phosphorylated by c-Abl in the nucleus. The protein shuttles between nucleus and cytosol, where it can be phosphorylated by c-Src or p59(fyn). Tyrosine phosphorylation causes dispersion of YT521-B from YT bodies to the nucleoplasm. Whereas YT bodies are soluble in non-denaturing buffers, the phosphorylated, dispersed form is non-soluble. Non-phosphorylated YT521-B changes alternative splice site selection of the IL-4 receptor, CD44 and SRp20, but phosphorylation of c-Abl minimizes this concentration dependent effect. We propose that tyrosine phosphorylation causes sequestration of YT521-B in an insoluble nuclear form, which abolishes the ability of YT521-B to change alternative splice sites. AU - Rafalska, I.* AU - Zhang, Z.* AU - Benderska, N.* AU - Wolff, H. AU - Hartmann, A.M.* AU - Brack-Werner, R. AU - Stamm, S.* C1 - 3086 C2 - 22365 SP - 1535-1549 TI - The intranuclear localization and function of YT521-B is regulated by tyrosine phosphorylation. JO - Hum. Mol. Genet. VL - 13 IS - 15 PB - Oxford Univ. Press PY - 2004 SN - 0964-6906 ER - TY - JOUR AB - Mutations in the human PANK2 gene have been shown to occur in autosomal-recessive pantothenate kinase-associated neurodegeneration, a syndrome originally described by Hallervorden and Spatz. The kinase catalyses the first and rate-limiting step in the biosynthesis of coenzyme A, a key molecule in energy metabolism. We have determined the exon-intron structure of the hPANK2 gene and identified two alternatively used first exons. The resulting transcripts encode distinct isoforms of hPANK2, one of which carries an N-terminal extension with a predicted mitochondrial targeting signal. An in vitro import assay and in vivo immunolocalization experiments demonstrate a mitochondrial localization of this isoform. We conclude that the symptoms observed in pantothenate kinase-associated neurodegeneration are caused by a deficiency of the mitochondrial isoform and postulate the existence of a complete intramitochondrial pathway for de novo synthesis of coenzyme A. AU - Hörtnagel, K. AU - Prokisch, H.* AU - Meitinger, T. C1 - 23560 C2 - 31368 SP - 321-327 TI - An isoform of hPANK2, deficient in pantothenate kinase-associated neurodegeneration, localizes to mitochondria. JO - Hum. Mol. Genet. VL - 12 IS - 3 PB - Oxford Univ. Press PY - 2003 SN - 0964-6906 ER - TY - JOUR AB - The human signal transducer and activator of transcription 6 (STAT6) gene represents one of the most promising candidate genes for asthma and other inflammatory diseases on the chromosomal region 12q13-q24. Therefore we screened all 23 exons, including parts of the neighbouring introns, as well as the promoter region for common polymorphisms and tested them for linkage/association with asthma and related traits (total serum IgE level, eosinophil cell count and SLOPE of the dose-response curve after bronchial challenge) in a Caucasian sib-pair study (108 families with at least two affected children). We could identify 13 single nucleotide polymorphisms (SNPs), which are all non-coding. A recently described dinucleotide (GT) repeat in exon 1 was also examined. Besides the confirmation of the four alleles described elsewhere we could identify a new one, named allele A5. Neither the SNPs nor the GT repeat showed linkage/association to asthma. Two intronic SNPs and one SNP in the 3'untranslated region of the gene showed weak association to total IgE levels (P = 0.0200, 0.0260 and 0.0280, respectively), whereas a significant association was found between a SNP in intron 18 and an increase in total IgE levels (P = 0.0070). However, the most promising effect was seen between allele A4 of the GT repeat polymorphism and an increase in eosinophil cell count (P = 0.0010). From these findings we conclude that the human STAT6 gene is rather involved in the development of eosinophilia and changes in total IgE levels than contributing to the pathogenesis of asthma. AU - Duetsch, G. AU - Illig, T. AU - Loesgen, S. AU - Rohde-Zimmermann, K.* AU - Klopp, N. AU - Herbon, N. AU - Gohlke, H. AU - Altmüller, J. AU - Wjst, M. C1 - 9530 C2 - 20703 SP - 613-621 TI - STAT6 as an asthma candidate gene : Polymorphism-screening, association and haplotype analysis in a Caucasian sib-pair study. JO - Hum. Mol. Genet. VL - 11 IS - 6 PB - Oxford Univ. Press PY - 2002 SN - 0964-6906 ER - TY - JOUR AB - Asthma is a common, complex human disease. Gene discovery in asthma has been complicated by substantial etiological heterogeneity, the possibility of genes of small effect and the concomitant requirement for large sample sizes. Linkage to asthma phenotypes has been investigated most intensively in the 5q chromosomal region, although results have been inconsistent across studies and all studies have had modest sample sizes. One potential solution to these issues is to combine data from multiple studies in a retrospective meta-analysis by pooling either summary statistics or raw data. The International Consortium on Asthma Genetics combined data from 11 data sets (n = 6277 subjects) to investigate evidence for linkage of 35 markers spanning the cytokine cluster on chromosome 5q31–33 to 'asthma' dichotomy and total serum immunoglobulin E (IgE) levels. Chromosome 5q markers typed in different centers were integrated into a consensus map to facilitate effective data pooling. Multipoint linkage analyses using a new Haseman–Elston method were performed with all data sets pooled together, and also separately with the resulting linkage statistics pooled by meta-analytic methods. Our results did not provide any evidence significant at the 5% level that loci conferring susceptibility to asthma or atopy are present in the 5q31–33 region; however, there was some weak evidence (empirical P = 0.077) of linkage to asthma affection. This study suggests that loci in 5q31–33 have at most a modest effect on susceptibility to asthma or total serum IgE levels, may not be detectable or present in all human populations and are difficult to detect even using combined linkage evidence from 2400–2600 full sibling pairs. AU - Palmer, L.J.* AU - Barnes, K.C.* AU - Burton, P.R* AU - Chen, H.* AU - Cookson, W.O.C.M.* AU - Deichmann, K.A.* AU - Elston, R.C.* AU - Holloway, J.W.* AU - Jacobs, K.B.* AU - Laitinen, T.* AU - Wjst, M. AU - Collaborative Study on the Genetics of Asthma* C1 - 21825 C2 - 19863 SP - 891-899 TI - Meta-analysis for linkage to asthma and atopy in the chromosome 5q31-33 candidate region. JO - Hum. Mol. Genet. VL - 10 PY - 2001 SN - 0964-6906 ER - TY - JOUR AU - Grimm, C. AU - Spörle, R. AU - Schmid, T.E. AU - Adler, I.-D. AU - Adamski, J. AU - Schughart, K. AU - Graw, J. C1 - 20844 C2 - 18900 SP - 697-710 TI - Isolation and embryonic expression of the novel mouse gene Hic1, the homologue of HIC1, a canditate gene for the Miller-Dieker syndrome. JO - Hum. Mol. Genet. VL - 8 PY - 1999 SN - 0964-6906 ER - TY - JOUR AU - Becker, K.-F. AU - Atkinson, M.J. AU - Reich, U. AU - Huang, H.-H. AU - Nekarda, H. AU - Siewert, J.R. AU - Höfler, H. C1 - 20369 C2 - 13565 SP - 803-804 TI - Exon Skipping in the E-Cadherin Gene Transcript in Metastatic Human Gastric Carcinomas. JO - Hum. Mol. Genet. VL - 2 PY - 1993 SN - 0964-6906 ER - TY - JOUR AU - Becker, K.F. AU - Atkinson, M.J. AU - Reich, U. AU - Huang, H.H.* AU - Nekarda, H.* AU - Siewert., J.R.* AU - Höfler, H. C1 - 40310 C2 - 40074 SP - 803-804 TI - Exon skipping in the E-cadherin gene transcript in metastatic human gastric carcinomas. JO - Hum. Mol. Genet. VL - 2 IS - 6 PY - 1993 SN - 0964-6906 ER - TY - JOUR AB - In about 80% of Burkitt's lymphoma cases, the tumour cell harbours a reciprocal chromosomal translocation which invariably transposes the coding exons 2 and 3 of c-myc from chromosome 8 to the immunoglobulin heavy chain locus on chromosome 14. Those t(8;14) translocations which disrupt chromosome 8 within or close to the c-myc gene are well documented. In this study we have focussed on t(8;14) translocations with the chromosomal breakpoint far upstream of c-myc. We analyzed the breakpoint position in 44 BL cell lines with t(8;14) translocations of different geographical origin and identified 9 cell lines with the breakpoint more than 14 kb upstream of c-myc. In these cell lines the positions of the translocation junctions on the derivative chromosomes 8q- and 14q+ were mapped by pulsed field gel electrophoresis and multicolour fluorescence in situ hybridization. The breakpoints occur at distances between 55 and more than 340 kb upstream of c-myc with no preferential site on chromosome 8. On chromosome 14, however, the translocation breakpoints are clustered in a narrow region 5′ of the intron enhancer of the immunoglobulin heavy chain gene. In 7 of 9 cases, the enhancer is fused to the c-myc bearing sequences of chromosome 8. In two cases, the translocation has occurred in switch μ and downstream of Cμ, respectively. The impact of these results with respect to the hypothesis, that cisregulatory sequences from the immunoglobulin heavy chain locus can deregulate c-myc expression in a manner sufficient for tumour formation, is discussed. AU - Joos, S. AU - Falk, M.H. AU - Lichtner, P.* AU - Haluska, F.G.* AU - Henglein, B.* AU - Lenoir, G.M.* AU - Bornkamm, G.W. C1 - 40592 C2 - 13733 SP - 625-632 TI - Variable breakpoints in Burkitt lymphoma cells with chromosomal t(8;14) translocation separate c-myc and the IgH locus up to several hundred kb. JO - Hum. Mol. Genet. VL - 1 IS - 8 PY - 1992 SN - 0964-6906 ER -