TY  - JOUR
AB  - BACKGROUND: Alterations in the effects of glucocorticoids have been implicated in mediating some of the negative health effects associated with chronic stress, including increased risk for psychiatric disorders as well as cardiovascular and metabolic diseases. This study investigates how genetic variants influence gene expression and DNA methylation (DNAm) in response to glucocorticoid receptor (GR)-activation, and their association with disease risk. METHODS: We measured DNAm (n=199) and gene expression (n=297) in peripheral blood before and after GR-activation with dexamethasone, with matched genotype data available for all samples. A comprehensive molecular quantitative trait locus (QTL) analysis was conducted, mapping GR-response methylation (me)QTLs, GR-response expression (e)QTLs, and GR-response expression quantitative trait methylation (eQTM). A multi-level network analysis was employed to map the complex relationships between the transcriptome, epigenome, and genetic variation. RESULTS: We identified 3,772 GR-response meCpGs corresponding to 104,828 local GR-response meQTLs that did not strongly overlap with baseline meQTLs. eQTM and eQTL analyses revealed distinct genetic influences on gene expression and DNAm. Multi-level network analysis uncovered GR-response network trio QTLs, characterized by SNP-CpG-transcript combinations where meQTLs act as both eQTLs and eQTMs. GR-response trio variants were enriched in GWAS for psychiatric, respiratory, autoimmune and cardiovascular diseases and conferred a higher relative heritability per SNP than GR-response meQTL and baseline QTL SNP. CONCLUSIONS: Genetic variants modulating the molecular effects of glucocorticoids are associated with psychiatric as well as medical diseases and not uncovered in baseline QTL analyses.
AU  - Knauer-Arloth, J.
AU  - Hryhorzhevska, A.*
AU  - Binder, E.B.*
C1  - 71986
C2  - 56538
CY  - Ste 800, 230 Park Ave, New York, Ny 10169 Usa
SP  - 794-805
TI  - Multi-omics analysis of the molecular response to glucocorticoids - insights into shared genetic risk from psychiatric to medical disorders.
JO  - Biol. Psychiatry
VL  - 97
IS  - 8
PB  - Elsevier Science Inc
PY  - 2024
SN  - 0006-3223
ER  - 

TY  - JOUR
AB  - Background: Early stress increases the risk for psychiatric disorders. Glucocorticoids are stress mediators that regulate transcriptional activity and morphology in the hippocampus, which is implicated in the pathophysiology of multiple psychiatric conditions. We aimed to establish the relevance of hippocampal, glucocorticoid-induced transcriptional activity as a mediator of the effects of early life on later psychopathology in humans. Methods: RNA sequencing was performed with anterior and posterior hippocampal dentate gyrus from adult female macaques (n = 12/group) that were chronically treated with betamethasone (glucocorticoid receptor agonist) or vehicle. Coexpression network analysis identified a preserved gene network in the posterior hippocampal dentate gyrus that was strongly associated with glucocorticoid exposure. The single nucleotide polymorphisms in the genes in this network were used to create an expression-based polygenic score in humans. Results: The expression-based polygenic score significantly moderated the association between early adversity and psychotic disorders in adulthood (UK Biobank, women, n = 44,519) and on child peer relations (ALSPAC [Avon Longitudinal Study of Parents and Children], girls, n = 1666 for 9-year-olds and n = 1594 for 11-year-olds), an endophenotype for later psychosis. Analyses revealed that this network was enriched for glucocorticoid-induced epigenetic remodeling in human hippocampal cells. We also found a significant association between single nucleotide polymorphisms from the expression-based polygenic score and adult brain gray matter density. Conclusions: We provide an approach for the use of transcriptomic data from animal models together with human data to study the impact of environmental influences on mental health. The results are consistent with the hypothesis that hippocampal glucocorticoid-related transcriptional activity mediates the effects of early adversity on neural mechanisms implicated in psychiatric disorders.
AU  - Arcego, D.M.*
AU  - Buschdorf, J.P.*
AU  - O'Toole, N.*
AU  - Wang, Z.*
AU  - Barth, B.*
AU  - Pokhvisneva, I.*
AU  - Rayan, N.A.*
AU  - Patel, S.*
AU  - de Mendonça Filho, E.J.*
AU  - Lee, P.*
AU  - Tan, J.*
AU  - Koh, M.X.*
AU  - Sim, C.M.*
AU  - Parent, C.*
AU  - de Lima, R.M.S.*
AU  - Clappison, A.*
AU  - O'Donnell, K.J.*
AU  - Dalmaz, C.*
AU  - Arloth, J.
AU  - Provençal, N.*
AU  - Binder, E.B.*
AU  - Diorio, J.*
AU  - Silveira, P.P.*
AU  - Meaney, M.J.*
C1  - 68302
C2  - 54627
CY  - Ste 800, 230 Park Ave, New York, Ny 10169 Usa
SP  - 48-61
TI  - A glucocorticoid-sensitive hippocampal gene network moderates the impact of early life adversity on mental health outcomes.
JO  - Biol. Psychiatry
VL  - 95
IS  - 1
PB  - Elsevier Science Inc
PY  - 2023
SN  - 0006-3223
ER  - 

TY  - JOUR
AB  - BACKGROUND: Symptoms of Major Depressive Disorder (MDD) are commonly assessed using self-rating instruments like the Patient Health Questionnaire 9 (PHQ9, current symptoms), and the Composite International Diagnostic Interview Short-Form (CIDI-SF, worst-episode symptoms). We perform a systematic comparison between them for their genetics and utility in investigating MDD heterogeneity. METHODS: Using data from the UKBiobank (N = 41948 - 109417), we assess the SNP heritability (h2) and genetic correlation (rG) of both sets of MDD symptoms. We further compare their rG with non-MDD traits, and use Mendelian Randomization (MR) to assess if either set of symptoms have more genetic sharing with non-MDD traits. We further assess how specific each set of symptoms is to MDD, using the metric PRS Pleiotropy. Finally, we use Genomic SEM to identify factors explaining the genetic covariance between each set of symptoms. RESULTS: Corresponding symptoms endorsed through PHQ9 and CIDI-SF have low to moderate genetic correlations (rG=0.43-0.87), and this cannot be fully attributed to different severity thresholds or the use of a skip-structure in CIDI-SF. Both MR and PRS Pleiotropy analyses show that PHQ9 symptoms are more associated with traits which reflect general dysphoria, while the skip-structure in CIDI-SF allows for the identification of heterogeneity among likely MDD cases. Finally, the two sets of symptoms show different factor structures in Genomic SEM, reflective of their genetic differences. CONCLUSIONS: MDD symptoms assessed via the PHQ9 and CIDI-SF are not interchangeable: the former better indexes general dysphoria, while the latter is more informative of within-MDD heterogeneity.
AU  - Huang, L.
AU  - Tang, S.*
AU  - Rietkerk, J.
AU  - Appadurai, V.*
AU  - Krebs, M.D.*
AU  - Schork, A.J.*
AU  - Werge, T.*
AU  - Zuber, V.*
AU  - Kendler, K.*
AU  - Cai, N.
C1  - 68944
C2  - 53783
CY  - Ste 800, 230 Park Ave, New York, Ny 10169 Usa
SP  - 1110-1121
TI  - Polygenic analyses show important differences between MDD symptoms collected using PHQ9 and CIDI-SF.
JO  - Biol. Psychiatry
VL  - 95
IS  - 12
PB  - Elsevier Science Inc
PY  - 2023
SN  - 0006-3223
ER  - 

TY  - JOUR
AB  - BACKGROUND: A large body of evidence highlights the importance of genetic variants in the development of psychiatric and metabolic conditions. Among these, the TaqIA polymorphism is one of the most commonly studied in psychiatry. TaqIA is located in the gene that codes for the Ankyrin repeat and kinase domain containing 1 kinase (Ankk1) near the dopamine D2 dopamine receptor (D2R) gene. Homozygous expression of the A1 allele correlates with a 30 to 40% reduction of striatal D2R, a typical feature of addiction, over-eating and other psychiatric pathologies. The mechanisms by which the variant influences dopamine signaling and behavior are unknown. METHODS: Here we used transgenic and viral-mediated strategies to reveal the role of Ankk1 in the regulation of activity and functions of the striatum. RESULTS: We found that Ankk1 is preferentially enriched in striatal D2R-expressing neurons and that Ankk1 loss-of-function in dorsal and ventral striatum leads to alteration in learning, impulsivity and flexibibility resembling endophenotypes described in A1 carriers. We also observed an unsuspected role of Ankk1 in striatal D2R-expressing neurons of the ventral striatum in the regulation of energy homeostasis and documented differential nutrient partitioning in humans with or without the A1 allele. CONCLUSIONS: Overall, our data demonstrate that the Ankk1 gene is necessary for the integrity of striatal functions and reveal a new role for Ankk1 in the regulation of body metabolism.
AU  - Montalban, E.*
AU  - Walle, R.*
AU  - Castel, J.*
AU  - Ansoult, A.*
AU  - Hassouna, R.*
AU  - Foppen, E.*
AU  - Fang, X.*
AU  - Hutelin, Z.*
AU  - Mickus, S.*
AU  - Perszyk, E.*
AU  - Petitbon, A.*
AU  - Berthelet, J.*
AU  - Rodrigues-Lima, F.*
AU  - Cebrian Serrano, A.
AU  - Gangarossa, G.*
AU  - Martin, C.*
AU  - Trifilieff, P.*
AU  - Bosch-Bouju, C.*
AU  - Small, D.*
AU  - Luquet, S.*
C1  - 67456
C2  - 54113
CY  - Ste 800, 230 Park Ave, New York, Ny 10169 Usa
SP  - 424-436
TI  - The addiction-susceptibility TaqIA/Ankyrin repeat and kinase domain containing 1 kinase (ANKK1) controls reward and metabolism through dopamine receptor type 2 (D2R)-expressing neurons.
JO  - Biol. Psychiatry
VL  - 94
IS  - 5
PB  - Elsevier Science Inc
PY  - 2023
SN  - 0006-3223
ER  - 

TY  - JOUR
AB  - Background: Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders. Methods: We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors. Results: Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged. Conclusions: Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders.
AU  - Mullins, N.*
AU  - Kang, J.E.*
AU  - Campos, A.I.*
AU  - Coleman, J.R.I.*
AU  - Edwards, A.C.*
AU  - Galfalvy, H.*
AU  - Levey, D.F.*
AU  - Lori, A.*
AU  - Shabalin, A.A.*
AU  - Starnawska, A.*
AU  - Su, M.H.*
AU  - Watson, H.J.*
AU  - Adams, M.*
AU  - Awasthi, S.*
AU  - Gandal, M.*
AU  - Hafferty, J.D.*
AU  - Hishimoto, A.*
AU  - Kim, M.*
AU  - Okazaki, S.*
AU  - Otsuka, I.*
AU  - Ripke, S.*
AU  - Ware, E.B.*
AU  - Bergen, A.W.*
AU  - Berrettini, W.H.*
AU  - Bohus, M.*
AU  - Brandt, H.*
AU  - Chang, X.*
AU  - Chen, W.J.*
AU  - Chen, H.C.*
AU  - Crawford, S.*
AU  - Crow, S.*
AU  - DiBlasi, E.*
AU  - Duriez, P.*
AU  - Fernández-Aranda, F.*
AU  - Fichter, M.M.*
AU  - Gallinger, S.*
AU  - Glatt, S.J.*
AU  - Gorwood, P.*
AU  - Guo, Y.*
AU  - Hakonarson, H.*
AU  - Halmi, K.A.*
AU  - Hwu, H.G.*
AU  - Jain, S.*
AU  - Jamain, S.*
AU  - Jiménez-Murcia, S.*
AU  - Johnson, C.*
AU  - Kaplan, A.S.*
AU  - Kaye, W.H.*
AU  - Keel, P.K.*
AU  - Kennedy, J.L.*
AU  - Klump, K.L.*
AU  - Li, D.*
AU  - Liao, S.C.*
AU  - Lieb, K.*
AU  - Lilenfeld, L.*
AU  - Liu, C.M.*
AU  - Magistretti, P.J.*
AU  - Marshall, C.R.*
AU  - Mitchell, J.E.*
AU  - Monson, E.T.*
AU  - Myers, R.M.*
AU  - Pinto, D.*
AU  - Powers, A.C.*
AU  - Ramoz, N.*
AU  - Roepke, S.*
AU  - Rozanov, V.*
AU  - Scherer, S.W.*
AU  - Schmahl, C.*
AU  - Sokolowski, M.*
AU  - Strober, M.*
AU  - Thornton, L.M.*
AU  - Treasure, J.*
AU  - Tsuang, M.T.*
AU  - Witt, S.H.*
AU  - Woodside, D.B.*
AU  - Yilmaz, Z.*
AU  - Zillich, L.*
AU  - Adolfsson, R.*
AU  - Agartz, I.*
AU  - Air, T.M.*
AU  - Alda, M.*
AU  - Alfredsson, L.*
AU  - Andreassen, O.A.*
AU  - Anjorin, A.*
AU  - Appadurai, V.*
AU  - Soler Artigas, M.*
AU  - Van der Auwera, S.*
AU  - Azevedo, M.H.*
AU  - Bass, N.J.*
AU  - Bau, C.H.D.*
AU  - Baune, B.T.*
AU  - Bellivier, F.*
AU  - Berger, K.*
AU  - Biernacka, J.M.*
AU  - Bigdeli, T.B.*
AU  - Binder, E.B.*
AU  - Boehnke, M.*
AU  - Boks, M.P.*
AU  - Bosch, R.*
AU  - Braff, D.L.*
AU  - Streit, F.*
AU  - Willour, V.*
AU  - Ruderfer, D.*
AU  - Eating Disorders Working Group of the Psychiatric Genomics Consortium (Hatzikotoulas, K.
AU  - Zeggini, E.
AU  - Wichmann, H.-E.
AU  - Jablensky, A.V.)
C1  - 66507
C2  - 52857
SP  - 313-327
TI  - Dissecting the shared genetic architecture of suicide attempt, psychiatric disorders, and known risk factors.
JO  - Biol. Psychiatry
VL  - 91
IS  - 3
PY  - 2022
SN  - 0006-3223
ER  - 

TY  - JOUR
AB  - Background: Recent genome-wide association studies (GWASs) identified the first genetic loci associated with attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD). The next step is to use these results to increase our understanding of the biological mechanisms involved. Most of the identified variants likely influence gene regulation. The aim of the current study is to shed light on the mechanisms underlying the genetic signals and prioritize genes by integrating GWAS results with gene expression and DNA methylation (DNAm) levels. Methods: We applied summary-data–based Mendelian randomization to integrate ADHD and ASD GWAS data with fetal brain expression and methylation quantitative trait loci, given the early onset of these disorders. We also analyzed expression and methylation quantitative trait loci datasets of adult brain and blood, as these provide increased statistical power. We subsequently used summary-data–based Mendelian randomization to investigate if the same variant influences both DNAm and gene expression levels. Results: We identified multiple gene expression and DNAm levels in fetal brain at chromosomes 1 and 17 that were associated with ADHD and ASD, respectively, through pleiotropy at shared genetic variants. The analyses in brain and blood showed additional associated gene expression and DNAm levels at the same and additional loci, likely because of increased statistical power. Several of the associated genes have not been identified in ADHD and ASD GWASs before. Conclusions: Our findings identified the genetic variants associated with ADHD and ASD that likely act through gene regulation. This facilitates prioritization of candidate genes for functional follow-up studies.
AU  - Hammerschlag, A.R.*
AU  - Byrne, E.M.*
AU  - Bartels, M.*
AU  - Wray, N.R.*
AU  - Middeldorp, C.M.*
AU  - eQTLGen Consortium (Müller-Nurasyid, M.
AU  - Prokisch, H.
AU  - Schramm, K.)
C1  - 60714
C2  - 49484
SP  - 470-479
TI  - Refining attention-deficit/hyperactivity disorder and autism spectrum disorder genetic loci by integrating summary data from genome-wide association, gene expression, and DNA methylation studies.
JO  - Biol. Psychiatry
VL  - 88
IS  - 6
PY  - 2020
SN  - 0006-3223
ER  - 

TY  - JOUR
AU  - Ahmed, A.T.*
AU  - Dehkordi, S.M.*
AU  - Bhattacharyya, S.*
AU  - Arnold, M.
AU  - Louie, G.*
AU  - Dunlop, B.*
AU  - Wang, L.*
AU  - Weinshilboum, R.*
AU  - Krishnan, R.*
AU  - Bobo, W.V.*
AU  - Posse, P.R.*
AU  - Craighead, W.E.*
AU  - McDonald, W.*
AU  - Skime, M.K.*
AU  - Rush, A.J.*
AU  - Frye, M.A.*
AU  - Kaddurah-Daouk, R.*
C1  - 56532
C2  - 47087
CY  - Ste 800, 230 Park Ave, New York, Ny 10169 Usa
SP  - S177-S178
TI  - Short-vs medium plus long-chain plasma acylcarnitine in phenotypes of major depression at baseline and after citalopram/escitalopram treatment.
JO  - Biol. Psychiatry
VL  - 85
IS  - 10
PB  - Elsevier Science Inc
PY  - 2019
SN  - 0006-3223
ER  - 

TY  - JOUR
AB  - BACKGROUND: Smoking and alcohol use have been associated with common genetic variants in multiple loci. Rare variants within these loci hold promise in the identification of biological mechanisms in substance use. Exome arrays and genotype imputation can now efficiently genotype rare nonsynonymous and loss of function variants. Such variants are expected to have deleterious functional consequences and to contribute to disease risk. METHODS: We analyzed ∼250,000 rare variants from 16 independent studies genotyped with exome arrays and augmented this dataset with imputed data from the UK Biobank. Associations were tested for five phenotypes: cigarettes per day, pack-years, smoking initiation, age of smoking initiation, and alcoholic drinks per week. We conducted stratified heritability analyses, single-variant tests, and gene-based burden tests of nonsynonymous/loss-of-function coding variants. We performed a novel fine-mapping analysis to winnow the number of putative causal variants within associated loci. RESULTS: Meta-analytic sample sizes ranged from 152,348 to 433,216, depending on the phenotype. Rare coding variation explained 1.1% to 2.2% of phenotypic variance, reflecting 11% to 18% of the total single nucleotide polymorphism heritability of these phenotypes. We identified 171 genome-wide associated loci across all phenotypes. Fine mapping identified putative causal variants with double base-pair resolution at 24 of these loci, and between three and 10 variants for 65 loci. Twenty loci contained rare coding variants in the 95% credible intervals. CONCLUSIONS: Rare coding variation significantly contributes to the heritability of smoking and alcohol use. Fine-mapping genome-wide association study loci identifies specific variants contributing to the biological etiology of substance use behavior.
AU  - Brazel, D.M.*
AU  - Jiang, Y.*
AU  - Hughey, J.M.*
AU  - Turcot, V.*
AU  - Zhan, X.*
AU  - Gong, J.*
AU  - Batini, C.*
AU  - Weissenkampen, J.D.*
AU  - Liu, M.*
AU  - Barnes, D.R.*
AU  - Bertelsen, S.*
AU  - Chou, Y.L.*
AU  - Erzurumluoglu, A.M.*
AU  - Faul, J.D.*
AU  - Haessler, J.*
AU  - Hammerschlag, A.R.*
AU  - Hsu, C.*
AU  - Kapoor, M.*
AU  - Lai, D.*
AU  - Le, N.*
AU  - de Leeuw, C.A.*
AU  - Loukola, A.*
AU  - Mangino, M.*
AU  - Melbourne, C.A.*
AU  - Pistis, G.*
AU  - Qaiser, B.*
AU  - Rohde, R.*
AU  - Shao, Y.*
AU  - Stringham, H.*
AU  - Wetherill, L.*
AU  - Zhao, W.*
AU  - Agrawal, A.*
AU  - Bierut, L.*
AU  - Chen, C.*
AU  - Eaton, C.B.*
AU  - Goate, A.*
AU  - Haiman, C.*
AU  - Heath, A.*
AU  - Iacono, W.G.*
AU  - Martin, N.G.*
AU  - Polderman, T.J.*
AU  - Reiner, A.*
AU  - Rice, J.*
AU  - Schlessinger, D.*
AU  - Scholte, H.S.*
AU  - Smith, J.A.*
AU  - Tardif, J.C.*
AU  - Tindle, H.A.*
AU  - van der Leij, A.R.*
AU  - Boehnke, M.*
AU  - Chang-Claude, J.*
AU  - Cucca, F.*
AU  - David, S.P.*
AU  - Foroud, T.*
AU  - Howson, J.M.M.*
AU  - Kardia, S.L.R.*
AU  - Kooperberg, C.*
AU  - Laakso, M.*
AU  - Lettre, G.*
AU  - Madden, P.*
AU  - McGue, M.*
AU  - North, K.*
AU  - Posthuma, D.*
AU  - Spector, T.*
AU  - Stram, D.*
AU  - Tobin, M.D.*
AU  - Weir, D.R.*
AU  - Kaprio, J.*
AU  - Abecasis, G.R.*
AU  - CHD Exome Consortium (Müller-Nurasyid, M.
AU  - Zeggini, E.)
AU  - Vrieze, S.*
C1  - 55848
C2  - 46603
SP  - 946-955
TI  - Exome chip meta-analysis fine maps causal variants and elucidates the genetic architecture of rare coding variants in smoking and alcohol use.
JO  - Biol. Psychiatry
VL  - 85
IS  - 11
PY  - 2019
SN  - 0006-3223
ER  - 

TY  - JOUR
AB  - Background: The genetics of depression has been explored in genome-wide association studies that focused on either major depressive disorder or depressive symptoms with mostly negative findings. A broad depression phenotype including both phenotypes has not been tested previously using a genome-wide association approach. We aimed to identify genetic polymorphisms significantly associated with a broad phenotype from depressive symptoms to major depressive disorder. Methods: We analyzed two prior studies of 70,017 participants of European ancestry from general and clinical populations in the discovery stage. We performed a replication meta-analysis of 28,328 participants. Single nucleotide polymorphism (SNP)-based heritability and genetic correlations were calculated using linkage disequilibrium score regression. Discovery and replication analyses were performed using a . p-value-based meta-analysis. Lifetime major depressive disorder and depressive symptom scores were used as the outcome measures. Results: The SNP-based heritability of major depressive disorder was 0.21 (SE = 0.02), the SNP-based heritability of depressive symptoms was 0.04 (SE = 0.01), and their genetic correlation was 1.001 (SE = 0.2). We found one genome-wide significant locus related to the broad depression phenotype (rs9825823, chromosome 3: 61,082,153, p = 8.2 × 10-9) located in an intron of the FHIT gene. We replicated this SNP in independent samples (p = .02) and the overall meta-analysis of the discovery and replication cohorts (1.0 × 10-9). Conclusions: This large study identified a new locus for depression. Our results support a continuum between depressive symptoms and major depressive disorder. A phenotypically more inclusive approach may help to achieve the large sample sizes needed to detect susceptibility loci for depression.
AU  - Direk, N.*
AU  - Williams, S.*
AU  - Smith, J.A.*
AU  - Ripke, S.*
AU  - Air, T.*
AU  - Amare, A.T.*
AU  - Amin, N.*
AU  - Baune, B.T.*
AU  - Bennett, D.A.*
AU  - Blackwood, D.H.R.*
AU  - Boomsma, D.*
AU  - Breen, G.*
AU  - Buttenschøn, H.N.*
AU  - Byrne, E.M.*
AU  - Børglum, A.D.*
AU  - Castelao, E.*
AU  - Cichon, S.*
AU  - Clarke, T.K.*
AU  - Cornelis, M.C.*
AU  - Dannlowski, U.*
AU  - de Jager, P.L.*
AU  - Demirkan, A.*
AU  - Domenici, E.*
AU  - van Duijn, C.M.*
AU  - Dunn, E.C.*
AU  - Eriksson, J.G.*
AU  - Esko, T.*
AU  - Faul, J.D.*
AU  - Ferrucci, L.*
AU  - Fornage, M.*
AU  - de Geus, E.*
AU  - Gill, M.*
AU  - Gordon, S.D.*
AU  - Grabe, H.J.*
AU  - van Grootheest, G.*
AU  - Hamilton, S.P.*
AU  - Hartman, C.A.*
AU  - Heath, A.C.*
AU  - Hek, K.*
AU  - Hofman, A.*
AU  - Homuth, G.*
AU  - Horn, C.*
AU  - Jan Hottenga, J.*
AU  - Kardia, S.L.R.*
AU  - Kloiber, S.*
AU  - Koenen, K.*
AU  - Kutalik, Z.*
AU  - Ladwig, K.-H.
AU  - Lahti, J.*
AU  - Levinson, D.F.*
AU  - Lewis, C.M.*
AU  - Lewis, G.*
AU  - Li, Q.S.*
AU  - Llewellyn, D.J.*
AU  - Lucae, S.*
AU  - Lunetta, K.L.*
AU  - MacIntyre, D.J.*
AU  - Madden, P.*
AU  - Martin, N.G.*
AU  - McIntosh, A.M.*
AU  - Metspalu, A.*
AU  - Milaneschi, Y.*
AU  - Montgomery, G.W.*
AU  - Mors, O.*
AU  - Mosley, T.H.*
AU  - Murabito, J.M.*
AU  - Müller-Myhsok, B.*
AU  - Nöthen, M.M.*
C1  - 50349
C2  - 42267
CY  - New York
SP  - 322-329
TI  - An analysis of two genome-wide association meta-analyses identifies a new locus for broad depression phenotype.
JO  - Biol. Psychiatry
VL  - 82
IS  - 5
PB  - Elsevier Science Inc
PY  - 2017
SN  - 0006-3223
ER  - 

TY  - JOUR
AB  - BACKGROUND: Major depressive disorder (MDD) is a disabling mood disorder, and despite a known heritable component, a large meta-analysis of genome-wide association studies revealed no replicable genetic risk variants. Given prior evidence of heterogeneity by age at onset in MDD, we tested whether genome-wide significant risk variants for MDD could be identified in cases subdivided by age at onset. METHODS: Discovery case-control genome-wide association studies were performed where cases were stratified using increasing/decreasing age-at-onset cutoffs; significant single nucleotide polymorphisms were tested in nine independent replication samples, giving a total sample of 22,158 cases and 133,749 control subjects for subsetting. Polygenic score analysis was used to examine whether differences in shared genetic risk exists between earlier and adult-onset MDD with commonly comorbid disorders of schizophrenia, bipolar disorder, Alzheimer's disease, and coronary artery disease. RESULTS: We identified one replicated genome-wide significant locus associated with adult-onset (>27 years) MDD (rs7647854, odds ratio: 1.16, 95% confidence interval: 1.11-1.21, p = 5.2 x 10(-11)). Using polygenic score analyses, we show that earlier-onset MDD is genetically more similar to schizophrenia and bipolar disorder than adult-onset MDD. CONCLUSIONS: We demonstrate that using additional phenotype data previously collected by genetic studies to tackle phenotypic heterogeneity in MDD can successfully lead to the discovery of genetic risk factor despite reduced sample size. Furthermore, our results suggest that the genetic susceptibility to MDD differs between adult-and earlier-onset MDD, with earlier-onset cases having a greater genetic overlap with schizophrenia and bipolar disorder.
AU  - Power, R.A.*
AU  - Tansey, K.E.*
AU  - Buttenschon, H.N.*
AU  - Cohen-Woods, S.*
AU  - Bigdeli, T.*
AU  - Hall, L.S.*
AU  - Kutalik, Z.*
AU  - Lee, S.H.*
AU  - Ripke, S.*
AU  - Steinberg, S.*
AU  - Teumer, A.*
AU  - Viktorin, A.*
AU  - Wray, N.R.*
AU  - Arolt, V.*
AU  - Baune, B.T.*
AU  - Boomsma, D.I.*
AU  - Borglum, A.D.*
AU  - Byrne, E.M.*
AU  - Castelao, E.*
AU  - Craddock, N.*
AU  - Craig, I.W.*
AU  - Dannlowski, U.*
AU  - Deary, I.J.*
AU  - Degenhardt, F.*
AU  - Forstner, A.J.*
AU  - Gordon, S.D.*
AU  - Grabe, H.J.*
AU  - Grove, J.R.*
AU  - Hamilton, S.P.*
AU  - Hayward, C.*
AU  - Heath, A.C.*
AU  - Hocking, L.J.*
AU  - Homuth, G.*
AU  - Hottenga, J.J.*
AU  - Kloiber, S.*
AU  - Krogh, J.*
AU  - Landen, M.*
AU  - Lang, M.*
AU  - Levinson, D.F.*
AU  - Lichtenstein, P.*
AU  - Lucae, S.*
AU  - MacIntyre, D.J.*
AU  - Madden, P.*
AU  - Magnusson, P.K.E.*
AU  - Martin, N.G.*
AU  - McIntosh, A.M.*
AU  - Middeldorp, C.M.*
AU  - Milaneschi, Y.*
AU  - Montgomery, G.W.*
AU  - Mors, O.*
AU  - Müller-Myhsok, B.*
AU  - Nyholt, D.R.*
AU  - Oskarsson, H.*
AU  - Owen, M.J.*
AU  - Padmanabhan, S.*
AU  - Penninx, B.W.J.H.*
AU  - Pergadia, M.L.*
AU  - Porteous, D.J.*
AU  - Potash, J.B.*
AU  - Preisig, M.*
AU  - Rivera, M.*
AU  - Shi, J.*
AU  - Shyn, S.I.*
AU  - Sigurdsson, E.*
AU  - Smit, J.H.*
AU  - Smith, B.H.*
AU  - Stefansson, H.*
AU  - Stefansson, K.*
AU  - Strohmaier, J.*
AU  - Sullivan, P.F.*
AU  - Thomson, P.*
AU  - Thorgeirsson, T.E.*
AU  - Van der Auwera, S.*
AU  - Weissman, M.M.*
AU  - Breen, G.*
AU  - Lewis, C.M.*
AU  - CARDIoGRAM Consortium (Gieger, C.
AU  - Döring, A.
AU  - Illig, T.
AU  - Meisinger, C.
AU  - Peters, A.
AU  - Wichmann, H.-E.
AU  - Meitinger, T.)
C1  - 50868
C2  - 42920
CY  - New York
SP  - 325-335
TI  - Genome-wide association for major depression through age at onset stratification: Major depressive disorder working group of the Psychiatric Genomics Consortium.
JO  - Biol. Psychiatry
VL  - 81
IS  - 4
PB  - Elsevier Science Inc
PY  - 2017
SN  - 0006-3223
ER  - 

TY  - JOUR
AB  - Background: Depression is a heritable trait that exists on a continuum of varying severity and duration. Yet, the search for genetic variants associated with depression has had few successes. We exploit the entire continuum of depression to find common variants for depressive symptoms. Methods: In this genome-wide association study, we combined the results of 17 population-based studies assessing depressive symptoms with the Center for Epidemiological Studies Depression Scale. Replication of the independent top hits (p < 1 x 10(-5)) was performed in five studies assessing depressive symptoms with other instruments. In addition, we performed a combined meta-analysis of all 22 discovery and replication studies. Results: The discovery sample comprised 34,549 individuals (mean age of 66.5) and no loci reached genome-wide significance (lowest p = 1.05 x 10(-7)). Seven independent single nucleotide polymorphisms were considered for replication. In the replication set (n = 16,709), we found suggestive association of one single nucleotide polymorphism with depressive symptoms (rs161645, 5q21, p = 9.19 x 10(-3)). This 5q21 region reached genome-wide significance (p = 4.78 x 10(-8)) in the overall meta-analysis combining discovery and replication studies (n = 51,258). Conclusions: The results suggest that only a large sample comprising more than 50,000 subjects may be sufficiently powered to detect genes for depressive symptoms.
AU  - Hek, K.*
AU  - Demirkan, A.*
AU  - Lahti, J.*
AU  - Terracciano, A.*
AU  - Teumer, A.*
AU  - Cornelis, M.C.*
AU  - Amin, N.*
AU  - Bakshis, E.*
AU  - Baumert, J.J.
AU  - Ding, J.Z.*
AU  - Liu, Y.M.*
AU  - Marciante, K.*
AU  - Meirelles, O.*
AU  - Nalls, M.A.*
AU  - Sun, Y.V.*
AU  - Vogelzangs, N.*
AU  - Yu, L.*
AU  - Bandinelli, S.*
AU  - Benjamin, E.J.*
AU  - Bennett, D.A.*
AU  - Boomsma, D.*
AU  - Cannas, A.*
AU  - Coker, L.H.*
AU  - de Geus, E.*
AU  - de Jager, P.L.*
AU  - Diez-Roux, A.V.*
AU  - Purcell, S.*
AU  - Hu, F.B.*
AU  - Rimm, E.B.*
AU  - Hunter, D.J.*
AU  - Jensen, M.K.*
AU  - Curhan, G.*
AU  - Rice, K.*
AU  - Penman, A.D.*
AU  - Rotter, J.I.*
AU  - Sotoodehnia, N.*
AU  - Emeny, R.T.
AU  - Eriksson, J.G.*
AU  - Evans, D.A.*
AU  - Ferrucci, L.*
AU  - Fornage, M.*
AU  - Gudnason, V.*
AU  - Hofman, A.*
AU  - Illig, T.
AU  - Kardia, S.*
AU  - Kelly-Hayes, M.*
AU  - Koenen, K.*
AU  - Kraft, P.*
AU  - Kuningas, M.*
AU  - Massaro, J.M.*
AU  - Melzer, D.*
AU  - Mulas, A.*
AU  - Mulder, C.L.*
AU  - Murray, A.*
AU  - Oostra, B.A.*
AU  - Palotie, A.*
AU  - Penninx, B.*
AU  - Petersmann, A.*
AU  - Pilling, L.C.*
AU  - Psaty, B.*
AU  - Rawal, R.
AU  - Reiman, E.M.*
AU  - Schulz, A.*
AU  - Shulman, J.M.*
AU  - Singleton, A.B.*
AU  - Smith, A.V.*
AU  - Sutin, A.R.*
AU  - Uitterlinden, A.G.*
AU  - Völzke, H.*
AU  - Widen, E.*
AU  - Yaffe, K.*
AU  - Zonderman, A.B.*
AU  - Cucca, F.*
AU  - Harris, T.*
AU  - Ladwig, K.-H.
AU  - Llewellyn, D.J.*
AU  - Räikkönen, K.*
AU  - Tanaka, T.*
AU  - van Duijn, C.M.*
AU  - Grabe, H.J.*
AU  - Launer, L.J.*
AU  - Lunetta, K.L.*
AU  - Mosley, T.H.*
AU  - Newman, A.B.*
AU  - Tiemeier, H.*
AU  - Murabito, J.*
C1  - 24104
C2  - 31329
SP  - 667-678
TI  - A genome-wide association study of depressive symptoms.
JO  - Biol. Psychiatry
VL  - 73
IS  - 7
PB  - Elsevier Science
PY  - 2013
SN  - 0006-3223
ER  - 

TY  - JOUR
AB  - BACKGROUND: Sleep is an active and complex behavior, yet it has two straightforward properties-timing and duration. Clock genes are associated with dysfunctional timing of sleep, mood, and obesity disorders, which are commonly associated with sleep duration. METHODS: Sleep duration was assessed in Central Europe, Estonia, and South Tyrol (n approximately 77,000) with the Munich ChronoType Questionnaire. It showed a Gaussian distribution in all investigated populations after averaging over a standard workweek and normalization according to age and gender. A follow-up, two-stage design, linkage disequilibrium-based association study was conducted with subjects from South Tyrol (discovery sample; n = 283) and with short (< 7 hours) and long (> 8.5 hours) sleepers from Estonia (confirmation sample; n = 1011). One hundred ninety-four single nucleotide polymorphism markers covering 19 candidate clock genes were genotyped in the discovery sample, and two of the best association signals (analyzed by a linear regression model) were investigated in the confirmation sample. RESULTS: Single and multi-marker associations were found within a CLOCK gene intronic region (rs12649507 and rs11932595). In a meta-analysis between South Tyrol and Estonia association signals, rs12649507 (p = .0087) remained significant. Significance persisted only for the multiple-marker association signal of the rs12649507/rs11932595 haplotype GGAA with long sleep (p = .0015). CONCLUSIONS: We report an association between variants of the human CLOCK gene and sleep duration in two independent populations. This adds another putative function for CLOCK besides its possible involvement in circadian timing, depression, obesity, and personality.
AU  - Allebrandt, K.V.
AU  - Teder-Laving, M.*
AU  - Akyol, M.
AU  - Pichler, I.*
AU  - Müller-Myhsok, B.*
AU  - Pramstaller, P.*
AU  - Merrow, M.*
AU  - Meitinger, T.
AU  - Metspalu, A.*
AU  - Roenneberg, T.*
C1  - 879
C2  - 27161
SP  - 1040-1047
TI  - CLOCK gene variants associate with sleep duration in two independent populations.
JO  - Biol. Psychiatry
VL  - 67
IS  - 11
PB  - Elsevier
PY  - 2010
SN  - 0006-3223
ER  - 

TY  - JOUR
AB  - BACKGROUND: Genome-wide association studies are a powerful tool for unravelling the genetic background of complex disorders such as major depression. METHODS: We conducted a genome-wide association study of 604 patients with major depression and 1364 population based control subjects. The top hundred findings were followed up in a replication sample of 409 patients and 541 control subjects. RESULTS: Two SNPs showed nominally significant association in both the genome-wide association study and the replication samples: 1) rs9943849 (p(combined) = 3.24E-6) located upstream of the carboxypeptidase M (CPM) gene and 2) rs7713917 (p(combined) = 1.48E-6), located in a putative regulatory region of HOMER1. Further evidence for HOMER1 was obtained through gene-wide analysis while conditioning on the genotypes of rs7713917 (p(combined) = 4.12E-3). Homer1 knockout mice display behavioral traits that are paradigmatic of depression, and transcriptional variants of Homer1 result in the dysregulation of cortical-limbic circuitry. This is consistent with the findings of our subsequent human imaging genetics study, which revealed that variation in single nucleotide polymorphism rs7713917 had a significant influence on prefrontal activity during executive cognition and anticipation of reward. CONCLUSION: Our findings, combined with evidence from preclinical and animal studies, suggest that HOMER1 plays a role in the etiology of major depression and that the genetic variation affects depression via the dysregulation of cognitive and motivational processes.
AU  - Rietschel, M.*
AU  - Mattheisen, M.*
AU  - Frank, J.*
AU  - Treutlein, J.*
AU  - Degenhardt, F.*
AU  - Breuer, R.*
AU  - Steffens, M.*
AU  - Mier, D.*
AU  - Esslinger, C.*
AU  - Walter, H.*
AU  - Kirsch, P.*
AU  - Erk, S.*
AU  - Schnell, K.*
AU  - Herms, S.*
AU  - Wichmann, H.-E.
AU  - Schreiber, S.*
AU  - Jöckel, K.-H.*
AU  - Strohmaier, J.*
AU  - Roeske, D.*
AU  - Haenisch, B.*
AU  - Gross, M.*
AU  - Hoefels, S.*
AU  - Lucae, S.*
AU  - Binder, E.B.*
AU  - Wienker, T.F.*
AU  - Schulze, T.G.*
AU  - Schmäl, C.*
AU  - Zimmer, A.*
AU  - Juraeva, D.*
AU  - Brors, B.*
AU  - Bettecken, T.*
AU  - Meyer-Lindenberg, A.*
AU  - Müller-Myhsok, B.*
AU  - Maier, W.*
AU  - Nöthen, M.M.*
AU  - Cichon, S.*
C1  - 4737
C2  - 28167
CY  - New York, NY
SP  - 589-601
TI  - Genome-wide association-, replication-, and neuroimaging study implicates HOMER1 in the etiology of major depression.
JO  - Biol. Psychiatry
VL  - 68
IS  - 6
PB  - Elsevier Science Inc.
PY  - 2010
SN  - 0006-3223
ER  - 

TY  - JOUR
AB  - Evidence has recently accumulated that single nucleotide polymorphisms in the genetic region encoding the nicotinic acetylcholine receptor subunits alpha-5, alpha-3, and beta-4 are associated with smoking and nicotine dependence. We aimed to determine whether these genetic variations are also predictive of smoking cessation. Methods: Lifetime history of smoking was assessed by questionnaire at enrolment into a large epidemiological study of the German elderly population (ESTHER study). Cox proportional hazards modeling was applied in a retrospective cohort approach to determine the associations of individual polymorphisms and haplotypes with smoking cessation probability in 1446 subjects who reported regularly smoking more than 20 cigarettes at some point in their lives. Results: Given the genotype distributions and number of cessation events observed, the power to detect associations ranged from 54% to 97% for hazard ratios of 1.2 to 1.4 in case of the variant with strongest prior evidence (alpha = .05). Nonetheless, neither individual polymorphisms nor inferred multilocus haplotypes were significantly associated with smoking cessation. Conclusions: Although the robust association of the nicotinic acetylcholine receptor subunit genes investigated with smoking-related phenotypes is an apparent success story of genetic epidemiology, the respective variations seem to exert no relevant influence on smoking cessation probability in heavy smokers in the general population.
AU  - Breitling, L.P.*
AU  - Dahmen, N.*
AU  - Mittelstraß, K.
AU  - Illig, T.
AU  - Rujescu, D.*
AU  - Raum, E.*
AU  - Winterer, G.*
AU  - Brenner, H.*
C1  - 1420
C2  - 26439
SP  - 691-695
TI  - Smoking cessation and variations in nicotinic acetylcholine receptor subunits α-5, α-3, and β-4 genes.
JO  - Biol. Psychiatry
VL  - 65
IS  - 8
PB  - Elsevier Science Inc
PY  - 2009
SN  - 0006-3223
ER  - 

TY  - JOUR
AU  - Glaser, B.*
AU  - Klopp, N.
AU  - Illig, T.
C1  - 4053
C2  - 23269
SP  - 78-80
TI  - No association between the putative functional ZDHHC8 single nucleotide polymorphism rs175174 and schizophrenia in large European samples.
JO  - Biol. Psychiatry
VL  - 58
PY  - 2005
SN  - 0006-3223
ER  - 

TY  - JOUR
AU  - Schumacher, J.*
AU  - Klopp, N.
AU  - Illig, T.
C1  - 4820
C2  - 23268
SP  - 307-314
TI  - Evidence for a relationship between genetic variants at the brain-derived neurotrophic factor(BDNF) locus and major depression.
JO  - Biol. Psychiatry
VL  - 58
PY  - 2005
SN  - 0006-3223
ER  -