TY - JOUR AB - Correction to: Molecular Psychiatryhttps://doi.org/10.1038/s41380-024-02878-x, published online 27 December 2024 In this article the author’s name Wouter J. Peyrot was incorrectly written as Wouter Peyrout. The original article has been corrected. AU - Cai, N. AU - Verhulst, B.* AU - Andreassen, O.A.* AU - Buitelaar, J.K.* AU - Edenberg, H.J.* AU - Hettema, J.M.* AU - Gandal, M.* AU - Grotzinger, A.* AU - Jonas, K.* AU - Lee, P.* AU - Mallard, T.T.* AU - Mattheisen, M.* AU - Neale, M.C.* AU - Nurnberger, J.I.* AU - Peyrot, W.J.* AU - Tucker-Drob, E.M.* AU - Smoller, J.W.* AU - Kendler, K.S.* C1 - 73217 C2 - 56958 TI - Correction: Assessment and ascertainment in psychiatric molecular genetics: challenges and opportunities for cross-disorder research. JO - Mol. Psychiatry VL - 30 PY - 2025 SN - 1359-4184 ER - TY - JOUR AB - Anorexia Nervosa (AN) is a severe eating disorder characterized by endocrine and metabolic abnormalities. In this study, we evaluated how the concentrations of proteins recently linked with energy homeostasis might be altered in acute AN (acAN), whether their levels are associated with reproductive hormones and whether they are restored after weight recovery. Our results show that activin A, follistatin, LH and estradiol concentrations are decreased while growth/differentiation factor-15 (GDF-15) concentrations are increased in 79 females with acAN before weight restoration (acAN_T1) compared to 79 healthy control females not receiving oral contraception (HC_OCP-). The concentrations of all hormones were partially or completely restored after weight restoration by short-term refeeding (acAN_T2) and in 35 females after long-term ( >6 months) recovery from AN not receiving OCPs (recAN_OCP-). Low activin A and high GDF-15 concentrations, as in acAN_T1, were also observed in 45 healthy control females under OCP (HC_OCP+) compared to HC_OCP-. Follistatin levels were ~3-fold higher in HC_OCP+ and recAN_OCP+ (45 female recAN under OCP) compared to HC_OCP- or recAN_OCP- respectively. LH, FSH and estradiol concentrations were positively associated with activin A and negatively with GDF-15 and follistatin. In conclusion, we report profound alterations in GDF-15, activin A and follistatin concentrations in acAN, which are associated with the concentrations of reproductive hormones and they are regulated by OCP and weight recovery by refeeding. Our findings support the evaluation of strategies targeting these hormones (e.g. GDF-15 inhibition) in AN to potentially increase body weight and thereby facilitate the resumption of reproductive function. AU - Ehrlich, S.* AU - Licht, L.* AU - Kolb, T.* AU - Hoffmann, C.* AU - Stender, E.* AU - Tam, F.I.* AU - Poitz, D.M.* AU - Roessner, V.* AU - Bornstein, S.R. AU - Perakakis, N. C1 - 75595 C2 - 58048 CY - Campus, 4 Crinan St, London, N1 9xw, England TI - Impact of acute anorexia nervosa and of short-/long-term recovery after refeeding on the hormonal profiles of activin A, GDF-15 and follistatins. JO - Mol. Psychiatry PB - Springernature PY - 2025 SN - 1359-4184 ER - TY - JOUR AB - Developmental stuttering is a common childhood condition characterized by disfluencies in speech, such as blocks, prolongations, and repetitions. While most children who stutter do so only transiently, there are some for whom stuttering persists into adulthood. Rare-variant screens in families including multiple relatives with persistent stuttering have so far identified six genes carrying putative pathogenic variants hypothesized to act in a monogenic fashion. Here, we applied a complementary study design, searching instead for de novo variants in exomes of 85 independent parent-child trios, each with a child with transient or persistent stuttering. Exome sequencing analysis yielded a pathogenic variant in SPTBN1 as well as likely pathogenic variants in PRPF8, TRIO, and ZBTB7A - four genes previously implicated in neurodevelopmental disorders with or without speech problems. Our results also highlighted two further genes of interest for stuttering: FLT3 and IREB2. We used extensive bioinformatic approaches to investigate overlaps in brain-related processes among the twelve genes associated with monogenic forms of stuttering. Analyses of gene-expression datasets of the developing and adult human brain, and data from a genome-wide association study of human brain structural connectivity, did not find links of monogenic stuttering to specific brain processes. Overall, our results provide the first direct genetic link between stuttering and other neurodevelopmental disorders, including speech delay and aphasia. In addition, we systematically demonstrate a dissimilarity in biological pathways associated with the genes thus far implicated in monogenic forms of stuttering, indicating heterogeneity in the etiological basis of this condition. AU - Eising, E.* AU - Dzinovic, I. AU - Vino, A.* AU - Stipdonk, L.* AU - Pavlov, M. AU - Winkelmann, J. AU - Sommer, M.* AU - Franken, M.J.P.* AU - Oexle, K. AU - Fisher, S.E.* C1 - 75383 C2 - 57954 CY - Campus, 4 Crinan St, London, N1 9xw, England TI - De novo protein-coding gene variants in developmental stuttering. JO - Mol. Psychiatry PB - Springernature PY - 2025 SN - 1359-4184 ER - TY - JOUR AB - Anorexia nervosa (AN) has extensive genetic correlations with other psychiatric disorders, and genetic risk for different psychiatric disorders was associated with distinct clinical courses in AN. Uncovering associations between transdiagnostic psychiatric genetic liability and AN outcomes can facilitate its personalized treatment. In this study, we investigated the associations between transdiagnostic psychiatric genetic liability and outcomes of AN. Genomic structural equation models were fitted to genome-wide association data for AN and psychiatric disorders with high genetic correlations with AN (obsessive-compulsive symptoms [OCS], major depressive disorder [MDD], schizophrenia, and anxiety disorders) to extract one shared and five trait-specific genetic components. Next, we calculated the polygenic risk scores (PRS) for these components, including PRSshared, PRSAN-specific, PRSOCS-specific, PRSMDD-specific, PRSSCZ-specific and PRSANX-specific, which index the shared genetic liability to all five psychiatric traits, and genetic liability specific to AN, OCS, MDD, SCZ and ANX, respectively. We then tested associations between these PRSs and clinical outcomes reported between 1997 and 2018 among AN cases from the Anorexia Nervosa Genetics Initiative (ANGI), linked to Swedish National Registers. The clinical outcomes included cumulative disease burden (i.e., number of diagnoses, medication prescriptions, and inpatient days), risks of psychiatric comorbidities, and AN symptomatology. Among 4028 included AN cases, the mean (SD) birth year was 1985 (9), and 3947 (98.0%) were female. Within AN, +1 SD increase of PRSshared was associated with 9–39% excess risk of disease burden and psychiatric comorbidity, whereas the associations between PRSAN-specific and most clinical outcomes were statistically non-significant. +1 SD increase of PRSMDD-specific was associated with 3–29% increased risk of AN disease burden. Our findings show that shared psychiatric liability is associated with more adverse AN outcomes, whereas AN-specific liability is not a good indicator for its clinical course. This study provides a novel perspective on factors influencing heterogeneity in AN clinical course. AU - Lu, Z.A.* AU - Ploner, A.* AU - Birgegård, A.* AU - Eating Disorders Working Group of the Psychiatric Genomics Consortium (Zeggini, E. AU - Wichmann, H.-E. AU - Southam, L. AU - Hatzikotoulas, K.) AU - Landén, M.* AU - Bulik, C.M.* AU - Bergen, S.E.* C1 - 75789 C2 - 57996 TI - Leveraging transdiagnostic genetic liability to psychiatric disorders to dissect clinical outcomes of anorexia nervosa. JO - Mol. Psychiatry PY - 2025 SN - 1359-4184 ER - TY - JOUR AB - Maternal perceived prenatal stress (PPS) is a known risk factor for diverse developmental impairments in newborns, but the underlying molecular processes are incompletely understood. Here, we report that maternal PPS altered the birth profiles of blood transfer RNA fragments (tRFs), 16-50 nt long non-random cleavage products of tRNAs, in a sex-dependent manner. Importantly, comparing stressed versus control maternal and umbilical cord blood serum presented alterations that were not limited to individual tRFs, but rather reflected selective changes in particular tRF families grouped by their mitochondrial or nuclear genome origin, parental tRNA coded amino acid, and cleavage type. Specifically, tRF families that show stress- and sex-specific effects, revealed shared length and expression patterns which were strongest in the female newborns. Several of these tRFs carry complementary motifs to particular cholinergic mRNAs, suggesting possible translational regulation similar to microRNAs. Compatible with the cholinergic regulation of stress reactions, those "CholinotRFs" achieved an AUC of 95% when classifying female newborns according to maternal PPS. Moreover, we found altered catalytic activity of serum acetylcholinesterase, which was particularly elevated in male newborns, marking a second sex-specific effect. Our findings demonstrate an association of tRF families' patterns with newborns' sex-specific stress response to PPS and may lead to better diagnosis and therapeutic tools for these and other stressors. AU - Vaknine Treidel, S.* AU - Lobmaier, S.M.* AU - Sharma, R. AU - Madrer, N.* AU - Dubnov, S.* AU - Shulman, D.* AU - Greenberg, P.* AU - Bennett, E.R.* AU - Greenberg, D.S.* AU - Turjeman, A.* AU - Zelgert, C.* AU - Zimmermann, P.* AU - Frasch, M.G.* AU - Carmel, L.* AU - Antonelli, M.C.* AU - Soreq, H.* C1 - 73992 C2 - 57293 CY - Campus, 4 Crinan St, London, N1 9xw, England TI - Maternal prenatal stress induces sex-dependent changes in tRNA fragment families and cholinergic pathways in newborns. JO - Mol. Psychiatry PB - Springernature PY - 2025 SN - 1359-4184 ER - TY - JOUR AB - Allelic variation to the APOE gene confers the greatest genetic risk for sporadic Alzheimer’s disease (AD). Independent of genotype, low abundance of apolipoprotein E (apoE), is characteristic of AD CSF, and predicts cognitive decline. The mechanisms underlying the genotype and apoE level risks are uncertain. Recent fluid and imaging biomarker studies have revealed an unexpected link between apoE and brain iron, which also forecasts disease progression, possibly through ferroptosis, an iron-dependent regulated cell death pathway. Here, we report that apoE is a potent inhibitor of ferroptosis (EC50 ≈ 10 nM; N27 neurons). We demonstrate that apoE signals to activate the PI3K/AKT pathway that then inhibits the autophagic degradation of ferritin (ferritinophagy), thus averting iron-dependent lipid peroxidation. Using postmortem inferior temporal brain cortex tissue from deceased subjects from the Rush Memory and Aging Project (MAP) (N = 608), we found that the association of iron with pathologically confirmed clinical Alzheimer’s disease was stronger among those with the adverse APOE-ε4 allele. While protection against ferroptosis did not differ between apoE isoforms in vitro, other features of ε4 carriers, such as low abundance of apoE protein and higher levels of polyunsaturated fatty acids (which fuel ferroptosis) could mediate the ε4 allele’s heighted risk of AD. These data support ferroptosis as a putative pathway to explain the major genetic risk associated with late onset AD. AU - Belaidi, A.A.* AU - Masaldan, S.* AU - Southon, A.* AU - Kalinowski, P.* AU - Acevedo, K.* AU - Appukuttan, A.T.* AU - Portbury, S.* AU - Lei, P.* AU - Agarwal, P.* AU - Leurgans, S.E.* AU - Schneider, J.* AU - Conrad, M. AU - Bush, A.I.* AU - Ayton, S.* C1 - 64943 C2 - 51986 TI - Apolipoprotein E potently inhibits ferroptosis by blocking ferritinophagy. JO - Mol. Psychiatry PY - 2024 SN - 1359-4184 ER - TY - JOUR AB - Psychiatric disorders are highly comorbid, heritable, and genetically correlated [1-4]. The primary objective of cross-disorder psychiatric genetics research is to identify and characterize both the shared genetic factors that contribute to convergent disease etiologies and the unique genetic factors that distinguish between disorders [4, 5]. This information can illuminate the biological mechanisms underlying comorbid presentations of psychopathology, improve nosology and prediction of illness risk and trajectories, and aid the development of more effective and targeted interventions. In this review we discuss how estimates of comorbidity and identification of shared genetic loci between disorders can be influenced by how disorders are measured (phenotypic assessment) and the inclusion or exclusion criteria in individual genetic studies (sample ascertainment). Specifically, the depth of measurement, source of diagnosis, and time frame of disease trajectory have major implications for the clinical validity of the assessed phenotypes. Further, biases introduced in the ascertainment of both cases and controls can inflate or reduce estimates of genetic correlations. The impact of these design choices may have important implications for large meta-analyses of cohorts from diverse populations that use different forms of assessment and inclusion criteria, and subsequent cross-disorder analyses thereof. We review how assessment and ascertainment affect genetic findings in both univariate and multivariate analyses and conclude with recommendations for addressing them in future research. AU - Cai, N. AU - Verhulst, B.* AU - Andreassen, O.A.* AU - Buitelaar, J.K.* AU - Edenberg, H.J.* AU - Hettema, J.M.* AU - Gandal, M.* AU - Grotzinger, A.* AU - Jonas, K.* AU - Lee, P.* AU - Mallard, T.T.* AU - Mattheisen, M.* AU - Neale, M.C.* AU - Nurnberger, J.I.* AU - Peyrout, W.* AU - Tucker-Drob, E.M.* AU - Smoller, J.W.* AU - Kendler, K.S.* C1 - 72909 C2 - 56796 CY - Campus, 4 Crinan St, London, N1 9xw, England TI - Assessment and ascertainment in psychiatric molecular genetics: challenges and opportunities for cross-disorder research. JO - Mol. Psychiatry PB - Springernature PY - 2024 SN - 1359-4184 ER - TY - JOUR AB - The C-terminal binding protein 2 (CTBP2) gene (translational isoforms: CTBP2-L/S, RIBEYE) had been identified by a cross-trait analysis of genome-wide association studies for anorexia nervosa (AN) and body mass index (BMI). Here, we did a mutation analysis in CTBP2 by performing polymerase chain reactions with subsequent Sanger-sequencing to identify variants relevant for AN and body weight regulation and ensued functional studies. Analysis of the coding regions of CTBP2 in 462 female patients with AN (acute or recovered), 490 children and adolescents with severe obesity, 445 healthy-lean adult individuals and 168 healthy adult individuals with normal body weight detected 24 variants located in the specific exon of RIBEYE. In the initial analysis, three of these were rare non-synonymous variants (NSVs) detected heterozygously in patients with AN (p.Arg72Trp - rs146900874; p.Val289Met -rs375685611 and p.Gly362Arg - rs202010294). Four NSVs and one heterozygous frameshift variant were exclusively detected in children and adolescents with severe obesity (p.Pro53Ser - rs150867595; p.Gln175ArgfsTer45 - rs141864737; p.Leu310Val - rs769811964; p.Pro397Ala - rs76134089 and p.Pro402Ser - rs113477585). Ribeye mRNA was detected in mouse hypothalamus. No effect of fasting or overfeeding on murine hypothalamic Ribeye expression was determined. Yet, increased Ribeye expression was detected in hypothalami of leptin-treated Lepob/ob mice. This increase was not related to reduced food intake and leptin-induced weight loss. We detected rare and frequent variants in the RIBEYE specific exon in both patients with AN and in children and adolescents with severe obesity. Our data suggest RIBEYE as a relevant gene for weight regulation. AU - Giuranna, J.* AU - Zheng, Y.* AU - Brandt, M.* AU - Jall, S. AU - Mukherjee, A.* AU - Shankhwar, S.* AU - Renner, S.* AU - Kurapati, N.K.* AU - May, C.* AU - Peters, T.* AU - Herpertz-Dahlmann, B.* AU - Seitz, J.* AU - de Zwaan, M.* AU - Herzog, W.* AU - Ehrlich, S.* AU - Zipfel, S.* AU - Giel, K.* AU - Egberts, K.* AU - Burghardt, R.* AU - Foecker, M.* AU - Marcus, K.* AU - Keyvani, K.* AU - Müller, T.D. AU - Schmitz, F.* AU - Rajcsanyi, L.S.* AU - Hinney, A.* C1 - 72649 C2 - 56672 CY - Campus, 4 Crinan St, London, N1 9xw, England TI - Genetic and functional analyses of CTBP2 in anorexia nervosa and body weight regulation. JO - Mol. Psychiatry PB - Springernature PY - 2024 SN - 1359-4184 ER - TY - JOUR AB - Resilience is the capacity to adapt to stressful life events. As such, this trait is associated with physical and mental functions and conditions. Here, we aimed to identify the genetic factors contributing to shape resilience. We performed variant- and gene-based meta-analyses of genome-wide association studies from six German cohorts (N = 15822) using the 11-item version of the Resilience Scale (RS-11) as outcome measure. Variant- and gene-level results were combined to explore the biological context using network analysis. In addition, we conducted tests of correlation between RS-11 and the polygenic scores (PGSs) for 12 personality and mental health traits in one of these cohorts (PROCAM-2, N = 3879). The variant-based analysis found no signals associated with resilience at the genome-wide level (p < 5 × 10-8), but suggested five genomic loci (p < 1 × 10-5). The gene-based analysis identified three genes (ROBO1, CIB3 and LYPD4) associated with resilience at genome-wide level (p < 2.48 × 10-6) and 32 potential candidates (p < 1 × 10-4). Network analysis revealed enrichment of biological pathways related to neuronal proliferation and differentiation, synaptic organization, immune responses and vascular homeostasis. We also found significant correlations (FDR < 0.05) between RS-11 and the PGSs for neuroticism and general happiness. Overall, our observations suggest low heritability of resilience. Large, international efforts will be required to uncover the genetic factors that contribute to shape trait resilience. Nevertheless, as the largest investigation of the genetics of resilience in general population to date, our study already offers valuable insights into the biology potentially underlying resilience and resilience's relationship with other personality traits and mental health. AU - Herrera-Rivero, M.* AU - Garvert, L.* AU - Horn, K.* AU - Löbner, M.* AU - Weitzel, E.C.* AU - Stoll, M.* AU - Lichtner, P. AU - Teismann, H.* AU - Teumer, A.* AU - Van der Auwera, S.* AU - Völzke, H.* AU - Völker, U.* AU - Andlauer, T.F.M.* AU - Meinert, S.* AU - Heilmann-Heimbach, S.* AU - Forstner, A.J.* AU - Streit, F.* AU - Witt, S.H.* AU - Kircher, T.* AU - Dannlowski, U.* AU - Scholz, M.* AU - Riedel-Heller, S.G.* AU - Grabe, H.J.* AU - Baune, B.T.* AU - Berger, K.* C1 - 71438 C2 - 56173 CY - Campus, 4 Crinan St, London, N1 9xw, England TI - A meta-analysis of genome-wide studies of resilience in the German population. JO - Mol. Psychiatry PB - Springernature PY - 2024 SN - 1359-4184 ER - TY - JOUR AB - Major Depressive Disorder (MDD) is a common, frequently chronic condition characterized by substantial molecular alterations and pathway dysregulations. Single metabolite and targeted metabolomics platforms have revealed several metabolic alterations in depression, including energy metabolism, neurotransmission, and lipid metabolism. More comprehensive coverage of the metabolome is needed to further specify metabolic dysregulations in depression and reveal previously untargeted mechanisms. Here, we measured 820 metabolites using the metabolome-wide Metabolon platform in 2770 subjects from a large Dutch clinical cohort with extensive clinical phenotyping (1101 current MDD, 868 remitted MDD, 801 healthy controls) at baseline, which were repeated in 1805 subjects at 6-year follow up (327 current MDD, 1045 remitted MDD, 433 healthy controls). MDD diagnosis was based on DSM-IV psychiatric interviews. Depression severity was measured with the Inventory of Depressive Symptomatology Self-report. Associations between metabolites and MDD status and depression severity were assessed at baseline and at 6-year follow-up. At baseline, 139 and 126 metabolites were associated with current MDD status and depression severity, respectively, with 79 overlapping metabolites. Adding body mass index and lipid-lowering medication to the models changed results only marginally. Among the overlapping metabolites, 34 were confirmed in internal replication analyses using 6-year follow-up data. Downregulated metabolites were enriched with long-chain monounsaturated (P = 6.7e-07) and saturated (P = 3.2e-05) fatty acids; upregulated metabolites were enriched with lysophospholipids (P = 3.4e-4). Mendelian randomization analyses using genetic instruments for metabolites (N = 14,000) and MDD (N = 800,000) showed that genetically predicted higher levels of the lysophospholipid 1-linoleoyl-GPE (18:2) were associated with greater risk of depression. The identified metabolome-wide profile of depression indicated altered lipid metabolism with downregulation of long-chain fatty acids and upregulation of lysophospholipids, for which causal involvement was suggested using genetic tools. This metabolomics signature offers a window on depression pathophysiology and a potential access point for the development of novel therapeutic approaches. AU - Jansen, R.* AU - Milaneschi, Y.* AU - Schranner, D. AU - Kastenmüller, G. AU - Arnold, M. AU - Han, X.* AU - Dunlop, B.W.* AU - Rush, A.J.* AU - Kaddurah-Daouk, R.* AU - Penninx, B.W.J.H.* C1 - 70816 C2 - 55754 CY - Campus, 4 Crinan St, London, N1 9xw, England TI - The metabolome-wide signature of major depressive disorder. JO - Mol. Psychiatry PB - Springernature PY - 2024 SN - 1359-4184 ER - TY - JOUR AB - The single nucleotide polymorphism rs13166360, causing a substitution of valine (Val) 147 to leucine (Leu) in the adenylyl cyclase 2 (ADCY2), has previously been associated with bipolar disorder (BD). Here we show that the disease-associated ADCY2 missense mutation diminishes the enzyme´s capacity to generate the second messenger 3',5'-cylic adenosine monophosphate (cAMP) by altering its subcellular localization. We established mice specifically carrying the Val to Leu substitution using CRISPR/Cas9-based gene editing. Mice homozygous for the Leu variant display symptoms of a mania-like state accompanied by cognitive impairments. Mutant animals show additional characteristic signs of rodent mania models, i.e., they are hypersensitive to amphetamine, the observed mania-like behaviors are responsive to lithium treatment and the Val to Leu substitution results in a shifted excitatory/inhibitory synaptic balance towards more excitation. Exposure to chronic social defeat stress switches homozygous Leu variant carriers from a mania- to a depressive-like state, a transition which is reminiscent of the alternations characterizing the symptomatology in BD patients. Single-cell RNA-seq (scRNA-seq) revealed widespread Adcy2 mRNA expression in numerous hippocampal cell types. Differentially expressed genes particularly identified from glutamatergic CA1 neurons point towards ADCY2 variant-dependent alterations in multiple biological processes including cAMP-related signaling pathways. These results validate ADCY2 as a BD risk gene, provide insights into underlying disease mechanisms, and potentially open novel avenues for therapeutic intervention strategies. AU - Sen, P.* AU - Ortiz, O. AU - Brivio, E.* AU - Menegaz, D.* AU - Sotillos Elliott, L.* AU - Du, Y.* AU - Ries, C.* AU - Chen, A.* AU - Wurst, W. AU - Lopez, J.P.* AU - Eder, M.* AU - Deussing, J.M.* C1 - 71137 C2 - 55876 CY - Campus, 4 Crinan St, London, N1 9xw, England TI - A bipolar disorder-associated missense variant alters adenylyl cyclase 2 activity and promotes mania-like behavior. JO - Mol. Psychiatry PB - Springernature PY - 2024 SN - 1359-4184 ER - TY - JOUR AB - Maternal educational attainment (MEA) shapes offspring health through multiple potential pathways. Differential DNA methylation may provide a mechanistic understanding of these long-term associations. We aimed to quantify the associations of MEA with offspring DNA methylation levels at birth, in childhood and in adolescence. Using 37 studies from high-income countries, we performed meta-analysis of epigenome-wide association studies (EWAS) to quantify the associations of completed years of MEA at the time of pregnancy with offspring DNA methylation levels at birth (n = 9 881), in childhood (n = 2 017), and adolescence (n = 2 740), adjusting for relevant covariates. MEA was found to be associated with DNA methylation at 473 cytosine-phosphate-guanine sites at birth, one in childhood, and four in adolescence. We observed enrichment for findings from previous EWAS on maternal folate, vitamin-B12 concentrations, maternal smoking, and pre-pregnancy BMI. The associations were directionally consistent with MEA being inversely associated with behaviours including smoking and BMI. Our findings form a bridge between socio-economic factors and biology and highlight potential pathways underlying effects of maternal education. The results broaden our understanding of bio-social associations linked to differential DNA methylation in multiple early stages of life. The data generated also offers an important resource to help a more precise understanding of the social determinants of health. AU - Choudhary, P.* AU - Monasso, G.S.* AU - Karhunen, V.* AU - Ronkainen, J.* AU - Mancano, G.* AU - Howe, C.G.* AU - Niu, Z.* AU - Zeng, X.* AU - Guan, W.* AU - Dou, J.* AU - Feinberg, J.I.* AU - Mordaunt, C.* AU - Pesce, G.* AU - Baïz, N.* AU - Alfano, R.* AU - Martens, D.S.* AU - Wang, C.* AU - Isaevska, E.* AU - Keikkala, E.* AU - Mustaniemi, S.* AU - Thio, C.H.L.* AU - Fraszczyk, E.* AU - Tobi, E.W.* AU - Starling, A.P.* AU - Cosin-Tomas, M.* AU - Urquiza, J.* AU - Roeder, S.* AU - Hoang, T.T.* AU - Page, C.M.* AU - Jima, D.D.* AU - House, J.S.* AU - Maguire, R.L.* AU - Ott, R. AU - Pawlow, X. AU - Sirignano, L.* AU - Zillich, L.* AU - Malmberg, A.* AU - Rauschert, S.* AU - Melton, P.* AU - Gong, T.* AU - Karlsson, R.* AU - Fore, R.* AU - Perng, W.* AU - Laubach, Z.M.* AU - Czamara, D.* AU - Sharp, G.C.* AU - Breton, C.V.* AU - Schisterman, E.* AU - Yeung, E.* AU - Mumford, S.L.* AU - Fallin, M.D.* AU - LaSalle, J.M.* AU - Schmidt, R.J.* AU - Bakulski, K.M.* AU - Annesi-Maesano, I.* AU - Heude, B.* AU - Nawrot, T.S.* AU - Plusquin, M.* AU - Ghantous, A.* AU - Herceg, Z.* AU - Nisticò, L.* AU - Vafeiadi, M.* AU - Kogevinas, M.* AU - Vaeaeraesmaeki, M.* AU - Kajantie, E.* AU - Snieder, H.* AU - Corpeleijn, E.* AU - Steegers-Theunissen, R.P.M.* AU - Yang, I.V.* AU - Dabelea, D.* AU - Fossati, S.* AU - Zenclussen, A.C.* AU - Herberth, G.* AU - Magnus, M.C.* AU - Haberg, S.E.* AU - London, S.J.* AU - Munthe-Kaas, M.C.* AU - Murphy, S.K.* AU - Hoyo, C.* AU - Ziegler, A.-G. AU - Hummel, S. AU - Witt, S.H.* AU - Streit, F.* AU - Frank, J.* AU - Raeikkoenen, K.* AU - Lahti, J.* AU - Huang, R.* AU - Almqvist, C.* AU - Hivert, M.-F.* AU - Jaddoe, V.W.V.* AU - Jaervelin, M.* AU - Kantomaa, M.* AU - Felix, J.F.* AU - Sebert, S.* C1 - 69796 C2 - 54995 CY - Campus, 4 Crinan St, London, N1 9xw, England TI - Maternal educational attainment in pregnancy and epigenome-wide DNA methylation changes in the offspring from birth until adolescence. JO - Mol. Psychiatry PB - Springernature PY - 2023 SN - 1359-4184 ER - TY - JOUR AB - Metabolome reflects the interplay of genome and exposome at molecular level and thus can provide deep insights into the pathogenesis of a complex disease like major depression. To identify metabolites associated with depression we performed a metabolome-wide association analysis in 13,596 participants from five European population-based cohorts characterized for depression, and circulating metabolites using ultra high-performance liquid chromatography/tandem accurate mass spectrometry (UHPLC/MS/MS) based Metabolon platform. We tested 806 metabolites covering a wide range of biochemical processes including those involved in lipid, amino-acid, energy, carbohydrate, xenobiotic and vitamin metabolism for their association with depression. In a conservative model adjusting for life style factors and cardiovascular and antidepressant medication use we identified 8 metabolites, including 6 novel, significantly associated with depression. In individuals with depression, increased levels of retinol (vitamin A), 1-palmitoyl-2-palmitoleoyl-GPC (16:0/16:1) (lecithin) and mannitol/sorbitol and lower levels of hippurate, 4-hydroxycoumarin, 2-aminooctanoate (alpha-aminocaprylic acid), 10-undecenoate (11:1n1) (undecylenic acid), 1-linoleoyl-GPA (18:2) (lysophosphatidic acid; LPA 18:2) are observed. These metabolites are either directly food derived or are products of host and gut microbial metabolism of food-derived products. Our Mendelian randomization analysis suggests that low hippurate levels may be in the causal pathway leading towards depression. Our findings highlight putative actionable targets for depression prevention that are easily modifiable through diet interventions. AU - van der Spek, A.* AU - Stewart, I.D.* AU - Kühnel, B. AU - Pietzner, M.* AU - Alshehri, T.* AU - Gauß, F.* AU - Hysi, P.G.* AU - MahmoudianDehkordi, S.* AU - Heinken, A.* AU - Luik, A.I.* AU - Ladwig, K.-H. AU - Kastenmüller, G. AU - Menni, C.* AU - Hertel, J.* AU - Ikram, M.A.* AU - de Mutsert, R.* AU - Suhre, K.* AU - Gieger, C. AU - Strauch, K. AU - Völzke, H.* AU - Meitinger, T. AU - Mangino, M.* AU - Flaquer, A. AU - Waldenberger, M. AU - Peters, A. AU - Thiele, I.* AU - Kaddurah-Daouk, R.* AU - Dunlop, B.W.* AU - Rosendaal, F.R.* AU - Wareham, N.J.* AU - Spector, T.D.* AU - Kunze, S. AU - Grabe, H.J.* AU - Mook-Kanamori, D.O.* AU - Langenberg, C.* AU - van Duijn, C.M.* AU - Amin, N.* C1 - 68065 C2 - 54543 CY - Campus, 4 Crinan St, London, N1 9xw, England SP - 3874-3887 TI - Circulating metabolites modulated by diet are associated with depression. JO - Mol. Psychiatry VL - 28 IS - 9 PB - Springernature PY - 2023 SN - 1359-4184 ER - TY - JOUR AB - MYT1L is an autism spectrum disorder (ASD)-associated transcription factor that is expressed in virtually all neurons throughout life. How MYT1L mutations cause neurological phenotypes and whether they can be targeted remains enigmatic. Here, we examine the effects of MYT1L deficiency in human neurons and mice. Mutant mice exhibit neurodevelopmental delays with thinner cortices, behavioural phenotypes, and gene expression changes that resemble those of ASD patients. MYT1L target genes, including WNT and NOTCH, are activated upon MYT1L depletion and their chemical inhibition can rescue delayed neurogenesis in vitro. MYT1L deficiency also causes upregulation of the main cardiac sodium channel, SCN5A, and neuronal hyperactivity, which could be restored by shRNA-mediated knockdown of SCN5A or MYT1L overexpression in postmitotic neurons. Acute application of the sodium channel blocker, lamotrigine, also rescued electrophysiological defects in vitro and behaviour phenotypes in vivo. Hence, MYT1L mutation causes both developmental and postmitotic neurological defects. However, acute intervention can normalise resulting electrophysiological and behavioural phenotypes in adulthood. AU - Weigel, B.* AU - Tegethoff, J.F.* AU - Grieder, S.D.* AU - Lim, B.* AU - Nagarajan, B.* AU - Liu, Y.C.* AU - Truberg, J.* AU - Papageorgiou, D.* AU - Adrian-Segarra, J.M.* AU - Schmidt, L.K.* AU - Kaspar, J.* AU - Poisel, E.* AU - Heinzelmann, E.* AU - Saraswat, M.* AU - Christ, M.* AU - Arnold, C.* AU - Ibarra Del Rio, I.A. AU - Campos, J.* AU - Krijgsveld, J.* AU - Monyer, H.* AU - Zaugg, J.B.* AU - Acuna, C.* AU - Mall, M.* C1 - 67756 C2 - 55153 SP - 2122-2135 TI - MYT1L haploinsufficiency in human neurons and mice causes autism-associated phenotypes that can be reversed by genetic and pharmacologic intervention. JO - Mol. Psychiatry VL - 28 IS - 5 PY - 2023 SN - 1359-4184 ER - TY - JOUR AB - As millions of patients have been infected by SARS-CoV-2 virus a vast number of individuals complain about continuing breathlessness and fatigue even months after the onset of the disease. This overwhelming phenomenon has not been well defined and has been called "post-COVID syndrome" or "long-COVID" [1]. There are striking similarities to myalgic encephalomyelitis also called chronic fatigue syndrome linked to a viral and autoimmune pathogenesis. In both disorders neurotransmitter receptor antibodies against ß-adrenergic and muscarinic receptors may play a key role. We found similar elevation of these autoantibodies in both patient groups. Extracorporeal apheresis using a special filter seems to be effective in reducing these antibodies in a significant way clearly improving the debilitating symptoms of patients with chronic fatigue syndrome. Therefore, such a form of neuropheresis may provide a promising therapeutic option for patients with post-COVID-19 syndrome. This method will also be effective when other hitherto unknown antibodies and inflammatory mediators are involved. AU - Bornstein, S.R. AU - Voit-Bak, K.* AU - Donate, T.* AU - Rodionov, R.N.* AU - Gainetdinov, R.R.* AU - Tselmin, S.* AU - Kanczkowski, W.* AU - Müller, G.M.* AU - Achleitner, M.* AU - Wang, J.* AU - Licinio, J.* AU - Bauer, M.* AU - Young, A.H.* AU - Thuret, S.* AU - Bechmann, N.* AU - Straube, R.* C1 - 62327 C2 - 50710 CY - Campus, 4 Crinan St, London, N1 9xw, England SP - 34-37 TI - Chronic post-COVID-19 syndrome and chronic fatigue syndrome: Is there a role for extracorporeal apheresis? JO - Mol. Psychiatry VL - 27 IS - 1 PB - Springernature PY - 2022 SN - 1359-4184 ER - TY - JOUR AB - Major depression (MD) is a heterogeneous disorder; however, the extent to which genetic factors distinguish MD patient subgroups (genetic heterogeneity) remains uncertain. This study sought evidence for genetic heterogeneity in MD. Using UK Biobank cohort, the authors defined 16 MD subtypes within eight comparison groups (vegetative symptoms, symptom severity, comorbid anxiety disorder, age at onset, recurrence, suicidality, impairment, and postpartum depression; N ~ 3000-47000). To compare genetic component of these subtypes, subtype-specific genome-wide association studies were performed to estimate SNP-heritability, and genetic correlations within subtype comparison and with other related disorders/traits. The findings indicated that MD subtypes were divergent in their SNP-heritability, and genetic correlations both within subtype comparisons and with other related disorders/traits. Three subtype comparisons (vegetative symptoms, age at onset, and impairment) showed significant differences in SNP-heritability; while genetic correlations within subtype comparisons ranged from 0.55 to 0.86, suggesting genetic profiles are only partially shared among MD subtypes. Furthermore, subtypes that are more clinically challenging, e.g., early-onset, recurrent, suicidal, more severely impaired, had stronger genetic correlations with other psychiatric disorders. MD with atypical-like features showed a positive genetic correlation (+0.40) with BMI while a negative correlation (-0.09) was found in those without atypical-like features. Novel genomic loci with subtype-specific effects were identified. These results provide the most comprehensive evidence to date for genetic heterogeneity within MD, and suggest that the phenotypic complexity of MD can be effectively reduced by studying the subtypes which share partially distinct etiologies. AU - Nguyen, T.D.* AU - Harder, A.* AU - Xiong, Y.* AU - Kowalec, K.* AU - Hägg, S.* AU - Cai, N. AU - Kuja-Halkola, R.* AU - Dalman, C.* AU - Sullivan, P.F.* AU - Lu, Y.* C1 - 64002 C2 - 51795 CY - Campus, 4 Crinan St, London, N1 9xw, England SP - 1667–1675 TI - Genetic heterogeneity and subtypes of major depression. JO - Mol. Psychiatry VL - 27 PB - Springernature PY - 2022 SN - 1359-4184 ER - TY - JOUR AB - Educational attainment is widely used as a surrogate for socioeconomic status (SES). Low SES is a risk factor for hypertension and high blood pressure (BP). To identify novel BP loci, we performed multi-ancestry meta-analyses accounting for gene-educational attainment interactions using two variables, “Some College” (yes/no) and “Graduated College” (yes/no). Interactions were evaluated using both a 1 degree of freedom (DF) interaction term and a 2DF joint test of genetic and interaction effects. Analyses were performed for systolic BP, diastolic BP, mean arterial pressure, and pulse pressure. We pursued genome-wide interrogation in Stage 1 studies (N = 117 438) and follow-up on promising variants in Stage 2 studies (N = 293 787) in five ancestry groups. Through combined meta-analyses of Stages 1 and 2, we identified 84 known and 18 novel BP loci at genome-wide significance level (P < 5 × 10-8). Two novel loci were identified based on the 1DF test of interaction with educational attainment, while the remaining 16 loci were identified through the 2DF joint test of genetic and interaction effects. Ten novel loci were identified in individuals of African ancestry. Several novel loci show strong biological plausibility since they involve physiologic systems implicated in BP regulation. They include genes involved in the central nervous system-adrenal signaling axis (ZDHHC17, CADPS, PIK3C2G), vascular structure and function (GNB3, CDON), and renal function (HAS2 and HAS2-AS1, SLIT3). Collectively, these findings suggest a role of educational attainment or SES in further dissection of the genetic architecture of BP. AU - de Las Fuentes, L.* AU - Sung, Y.J.* AU - Noordam, R.* AU - Winkler, T.* AU - Feitosa, M.F.* AU - Schwander, K.* AU - Bentley, A.R.* AU - Brown, M.R.* AU - Guo, X.* AU - Manning, A.* AU - Chasman, D.I.* AU - Aschard, H.* AU - Bartz, T.M.* AU - Bielak, L.F.* AU - Campbell, A.* AU - Cheng, C.Y.* AU - Dorajoo, R.* AU - Hartwig, F.P.* AU - Horimoto, A.R.V.R.* AU - Li, C.* AU - Li-Gao, R.* AU - Liu, Y.* AU - Marten, J.* AU - Musani, S.K.* AU - Ntalla, I.* AU - Rankinen, T.* AU - Richard, M.* AU - Sim, X.* AU - Smith, A.V.* AU - Tajuddin, S.M.* AU - Tayo, B.O.* AU - Vojinovic, D.* AU - Warren, H.R.* AU - Xuan, D.* AU - Alver, M.* AU - Boissel, M.* AU - Chai, J.F.* AU - Chen, X.* AU - Christensen, K.* AU - Divers, J.* AU - Evangelou, E.* AU - Gao, C.* AU - Girotto, G.* AU - Harris, S.E.* AU - He, M.* AU - Hsu, F.C.* AU - Kühnel, B. AU - Laguzzi, F.* AU - Li, X.* AU - Lyytikäinen, L.P.* AU - Nolte, I.M.* AU - Poveda, A.* AU - Rauramaa, R.* AU - Riaz, M.* AU - Rueedi, R.* AU - Shu, X.O.* AU - Snieder, H.* AU - Sofer, T.* AU - Takeuchi, F.* AU - Verweij, N.* AU - Ware, E.B.* AU - Weiss, S.* AU - Yanek, L.R.* AU - Amin, N.* AU - Arking, D.E.* AU - Arnett, D.K.* AU - Bergmann, S.* AU - Boerwinkle, E.* AU - Brody, J.A.* AU - Broeckel, U.* AU - Brumat, M.* AU - Burke, G.* AU - Cabrera, C.P.* AU - Canouil, M.* AU - Chee, M.L.* AU - Chen, Y.I.* AU - Cocca, M.* AU - Connell, J.* AU - de Silva, H.J.* AU - de Vries, P.S.* AU - Eiriksdottir, G.* AU - Faul, J.D.* AU - Fisher, V.* AU - Forrester, T.* AU - Fox, E.F.* AU - Friedlander, Y.* AU - Gao, H.* AU - Gigante, B.* AU - Giulianini, F.* AU - Gu, C.C.* AU - Gu, D.* AU - Harris, T.B.* AU - He, J.* AU - Heikkinen, S.* AU - Heng, C.K.* AU - Hunt, S.* AU - Ikram, M.A.* AU - Irvin, M.R.* AU - Kähönen, M.* AU - Kavousi, M.* AU - Khor, C.C.* AU - Kilpeläinen, T.O.* AU - Koh, W.P.* AU - Komulainen, P.* AU - Kraja, A.T.* AU - Krieger, J.E.* AU - Langefeld, C.D.* AU - Li, Y.* AU - Liang, J.* AU - Liewald, D.C.M.* AU - Liu, C.T.* AU - Liu, J.* AU - Lohman, K.K.* AU - Mägi, R.* AU - McKenzie, C.A.* AU - Meitinger, T. AU - Metspalu, A.* AU - Milaneschi, Y.* AU - Milani, L.* AU - Mook-Kanamori, D.O.* AU - Nalls, M.A.* AU - Nelson, C.P.* AU - Norris, J.M.* AU - O'Connell, J.* AU - Ogunniyi, A.* AU - Padmanabhan, S.* AU - Palmer, N.D.* AU - Pedersen, N.L.* AU - Perls, T.* AU - Peters, A. AU - Petersmann, A.* AU - Peyser, P.A.* AU - Polasek, O.* AU - Porteous, D.J.* AU - Raffel, L.J.* AU - Rice, T.K.* AU - Rotter, J.I.* AU - Rudan, I.* AU - Rueda-Ochoa, O.L.* AU - Sabanayagam, C.* AU - Salako, B.L.* AU - Schreiner, P.J.* AU - Shikany, J.M.* AU - Sidney, S.S.* AU - Sims, M.* AU - Sitlani, C.M.* AU - Smith, J.A.* AU - Starr, J.M.* AU - Strauch, K. AU - Swertz, M.A.* AU - Teumer, A.* AU - Tham, Y.C.* AU - Uitterlinden, A.G.* AU - Vaidya, D.* AU - van der Ende, M.Y.* AU - Waldenberger, M. AU - Wang, L.* AU - Wang, Y.X.* AU - Wei, W.B.* AU - Weir, D.R.* AU - Wen, W.* AU - Yao, J.* AU - Yu, B.* AU - Yu, C.* AU - Yuan, J.M.* AU - Zhao, W.* AU - Zonderman, A.B.* AU - Becker, D.M.* AU - Bowden, D.W.* AU - Deary, I.J.* AU - Dörr, M.* AU - Esko, T.* AU - Freedman, B.I.* AU - Froguel, P.* AU - Gasparini, P.* AU - Gieger, C. AU - Jonas, J.B.* AU - Kammerer, C.M.* AU - Kato, N.* AU - Lakka, T.A.* AU - Leander, K.* AU - Lehtimäki, T.* AU - Magnusson, P.K.E.* AU - Marques-Vidal, P.* AU - Penninx, B.W.J.H.* AU - Samani, N.J.* AU - van der Harst, P.* AU - Wagenknecht, L.E.* AU - Wu, T.* AU - Zheng, W.* AU - Zhu, X.* AU - Bouchard, C.* AU - Cooper, R.S.* AU - Correa, A.* AU - Evans, M.K.* AU - Gudnason, V.* AU - Hayward, C.* AU - Horta, B.L.* AU - Kelly, T.N.* AU - Kritchevsky, S.B.* AU - Levy, D.* AU - Palmas, W.R.* AU - Pereira, A.C.* AU - Province, M.M.* AU - Psaty, B.M.* AU - Ridker, P.M.* AU - Rotimi, C.N.* AU - Tai, E.S.* AU - van Dam, R.M.* AU - van Duijn, C.M.* AU - Wong, T.Y.* AU - Rice, K.* AU - Gauderman, W.J.* AU - Morrison, A.C.* AU - North, K.E.* AU - Kardia, S.L.R.* AU - Caulfield, M.J.* AU - Elliott, P.* AU - Munroe, P.B.* AU - Franks, P.W.* AU - Rao, D.C.* AU - Fornage, M.* C1 - 59037 C2 - 48547 CY - Macmillan Building, 4 Crinan St, London N1 9xw, England SP - 2111–2125 TI - Gene-educational attainment interactions in a multi-ancestry genome-wide meta-analysis identify novel blood pressure loci. JO - Mol. Psychiatry VL - 26 PB - Nature Publishing Group PY - 2021 SN - 1359-4184 ER - TY - JOUR AB - Developmental dyslexia (DD) is a learning disorder affecting the ability to read, with a heritability of 40-60%. A notable part of this heritability remains unexplained, and large genetic studies are warranted to identify new susceptibility genes and clarify the genetic bases of dyslexia. We carried out a genome-wide association study (GWAS) on 2274 dyslexia cases and 6272 controls, testing associations at the single variant, gene, and pathway level, and estimating heritability using single-nucleotide polymorphism (SNP) data. We also calculated polygenic scores (PGSs) based on large-scale GWAS data for different neuropsychiatric disorders and cortical brain measures, educational attainment, and fluid intelligence, testing them for association with dyslexia status in our sample. We observed statistically significant (p < 2.8 x 10(-6)) enrichment of associations at the gene level, forLOC388780(20p13; uncharacterized gene), and forVEPH1(3q25), a gene implicated in brain development. We estimated an SNP-based heritability of 20-25% for DD, and observed significant associations of dyslexia risk with PGSs for attention deficit hyperactivity disorder (atp(T) = 0.05 in the training GWAS: OR = 1.23[1.16; 1.30] per standard deviation increase;p = 8 x 10(-13)), bipolar disorder (1.53[1.44; 1.63];p = 1 x 10(-43)), schizophrenia (1.36[1.28; 1.45];p = 4 x 10(-22)), psychiatric cross-disorder susceptibility (1.23[1.16; 1.30];p = 3 x 10(-12)), cortical thickness of the transverse temporal gyrus (0.90[0.86; 0.96];p = 5 x 10(-4)), educational attainment (0.86[0.82; 0.91];p = 2 x 10(-7)), and intelligence (0.72[0.68; 0.76];p = 9 x 10(-29)). This study suggests an important contribution of common genetic variants to dyslexia risk, and novel genomic overlaps with psychiatric conditions like bipolar disorder, schizophrenia, and cross-disorder susceptibility. Moreover, it revealed the presence of shared genetic foundations with a neural correlate previously implicated in dyslexia by neuroimaging evidence. AU - Gialluisi, A.* AU - Andlauer, T.F.M.* AU - Mirza-Schreiber, N. AU - Moll, K.* AU - Becker, J.* AU - Hoffmann, P.* AU - Ludwig, K.U.* AU - Czamara, D.* AU - Pourcain, B.S.* AU - Honbolygó, F.* AU - Tóth, D.* AU - Csépe, V.* AU - Huguet, G.* AU - Chaix, Y.* AU - Iannuzzi, S.* AU - Demonet, J.F.* AU - Morris, A.P.* AU - Hulslander, J.* AU - Willcutt, E.G.* AU - DeFries, J.C.* AU - Olson, R.K.* AU - Smith, S.D.* AU - Pennington, B.F.* AU - Vaessen, A.* AU - Maurer, U.* AU - Lyytinen, H.* AU - Peyrard-Janvid, M.* AU - Leppänen, P.H.T.* AU - Brandeis, D.* AU - Bonte, M.* AU - Stein, J.F.* AU - Talcott, J.B.* AU - Fauchereau, F.* AU - Wilcke, A.* AU - Kirsten, H.* AU - Müller, B.* AU - Francks, C.* AU - Bourgeron, T.* AU - Monaco, A.P.* AU - Ramus, F.* AU - Landerl, K.* AU - Kere, J.* AU - Scerri, T.S.* AU - Paracchini, S.* AU - Fisher, S.E.* AU - Schumacher, J.* AU - Nöthen, M.M.* AU - Müller-Myhsok, B.* AU - Schulte-Körne, G.* C1 - 60321 C2 - 49258 CY - Campus, 4 Crinan St, London, N1 9xw, England SP - 3004–3017 TI - Genome-wide association study reveals new insights into the heritability and genetic correlates of developmental dyslexia. JO - Mol. Psychiatry VL - 26 PB - Springernature PY - 2021 SN - 1359-4184 ER - TY - JOUR AB - Frontotemporal dementia (FTD) is a clinically and genetically heterogeneous disorder. To which extent genetic aberrations dictate clinical presentation remains elusive. We investigated the spectrum of genetic causes and assessed the genotype-driven differences in biomarker profiles, disease severity and clinical manifestation by recruiting 509 FTD patients from different centers of the German FTLD consortium where individuals were clinically assessed including biomarker analysis. Exome sequencing as well as C9orf72 repeat analysis were performed in all patients. These genetic analyses resulted in a diagnostic yield of 18.1%. Pathogenic variants in C9orf72 (n = 47), GRN (n = 26), MAPT (n = 11), TBK1 (n = 5), FUS (n = 1), TARDBP (n = 1), and CTSF (n = 1) were identified across all clinical subtypes of FTD. TBK1-associated FTD was frequent accounting for 5.4% of solved cases. Detection of a homozygous missense variant verified CTSF as an FTD gene. ABCA7 was identified as a candidate gene for monogenic FTD. The distribution of APOE alleles did not differ significantly between FTD patients and the average population. Male sex was weakly associated with clinical manifestation of the behavioral variant of FTD. Age of onset was lowest in MAPT patients. Further, high CSF neurofilament light chain levels were found to be related to GRN-associated FTD. Our study provides large-scale retrospective clinico-genetic data such as on disease manifestation and progression of FTD. These data will be relevant for counseling patients and their families. AU - Wagner, M. AU - Lorenz, G.* AU - Volk, A.E.* AU - Brunet, T. AU - Edbauer, D.* AU - Berutti, R. AU - Zhao, C. AU - Anderl-Straub, S.* AU - Bertram, L.* AU - Danek, A.* AU - Deschauer, M.* AU - Dill, V.* AU - Fassbender, K.* AU - Fliessbach, K.* AU - Götze, K.S.* AU - Jahn, H.* AU - Kornhuber, J.* AU - Landwehrmeyer, B.* AU - Lauer, M.* AU - Obrig, H.* AU - Prudlo, J.* AU - Schneider, A.* AU - Schroeter, M.L.* AU - Uttner, I.* AU - Vukovich, R.* AU - Wiltfang, J.* AU - Winkler, A.S.* AU - Zhou, Q.* AU - Ludolph, A.C.* AU - Oexle, K. AU - Otto, M.* AU - Diehl-Schmid, J.* AU - Winkelmann, J. C1 - 63112 C2 - 51323 CY - Campus, 4 Crinan St, London, N1 9xw, England TI - Clinico-genetic findings in 509 frontotemporal dementia patients. JO - Mol. Psychiatry PB - Springernature PY - 2021 SN - 1359-4184 ER - TY - JOUR AB - Long and short sleep duration are associated with elevated blood pressure (BP), possibly through effects on molecular pathways that influence neuroendocrine and vascular systems. To gain new insights into the genetic basis of sleep-related BP variation, we performed genome-wide gene by short or long sleep duration interaction analyses on four BP traits (systolic BP, diastolic BP, mean arterial pressure, and pulse pressure) across five ancestry groups in two stages using 2 degree of freedom (df) joint test followed by 1df test of interaction effects. Primary multi-ancestry analysis in 62,969 individuals in stage 1 identified three novel gene by sleep interactions that were replicated in an additional 59,296 individuals in stage 2 (stage 1 + 2 Pjoint < 5 × 10-8), including rs7955964 (FIGNL2/ANKRD33) that increases BP among long sleepers, and rs73493041 (SNORA26/C9orf170) and rs10406644 (KCTD15/LSM14A) that increase BP among short sleepers (Pint < 5 × 10-8). Secondary ancestry-specific analysis identified another novel gene by long sleep interaction at rs111887471 (TRPC3/KIAA1109) in individuals of African ancestry (Pint = 2 × 10-6). Combined stage 1 and 2 analyses additionally identified significant gene by long sleep interactions at 10 loci including MKLN1 and RGL3/ELAVL3 previously associated with BP, and significant gene by short sleep interactions at 10 loci including C2orf43 previously associated with BP (Pint < 10-3). 2df test also identified novel loci for BP after modeling sleep that has known functions in sleep-wake regulation, nervous and cardiometabolic systems. This study indicates that sleep and primary mechanisms regulating BP may interact to elevate BP level, suggesting novel insights into sleep-related BP regulation. AU - Wang, H.* AU - Noordam, R.* AU - Cade, B.E.* AU - Schwander, K.* AU - Winkler, T.W.* AU - Lee, J.* AU - Sung, Y.J.* AU - Bentley, A.R.* AU - Manning, A.K.* AU - Aschard, H.* AU - Kilpeläinen, T.O.* AU - Ilkov, M.* AU - Brown, M.R.* AU - Horimoto, A.R.* AU - Richard, M.* AU - Bartz, T.M.* AU - Vojinovic, D.* AU - Lim, E.* AU - Nierenberg, J.L.* AU - Liu, Y.* AU - Chitrala, K.* AU - Rankinen, T.* AU - Musani, S.K.* AU - Franceschini, N.* AU - Rauramaa, R.* AU - Alver, M.* AU - Zee, P.C.* AU - Harris, S.E.* AU - van der Most, P.J.* AU - Nolte, I.M.* AU - Munroe, P.B.* AU - Palmer, N.D.* AU - Kühnel, B. AU - Weiss, S.* AU - Wen, W.* AU - Hall, K.A.* AU - Lyytikäinen, L.P.* AU - O'Connell, J.* AU - Eiriksdottir, G.* AU - Launer, L.J.* AU - de Vries, P.S.* AU - Arking, D.E.* AU - Chen, H.* AU - Boerwinkle, E.* AU - Krieger, J.E.* AU - Schreiner, P.J.* AU - Sidney, S.* AU - Shikany, J.M.* AU - Rice, K.* AU - Chen, Y.I.* AU - Gharib, S.A.* AU - Bis, J.C.* AU - Luik, A.I.* AU - Ikram, M.A.* AU - Uitterlinden, A.G.* AU - Amin, N.* AU - Xu, H.* AU - Levy, D.* AU - He, J.* AU - Lohman, K.K.* AU - Zonderman, A.B.* AU - Rice, T.K.* AU - Sims, M.* AU - Wilson, G.* AU - Sofer, T.* AU - Rich, S.S.* AU - Palmas, W.* AU - Yao, J.* AU - Guo, X.* AU - Rotter, J.I.* AU - Biermasz, N.R.* AU - Mook-Kanamori, D.O.* AU - Martin, L.W.* AU - Barac, A.* AU - Wallace, R.B.* AU - Gottlieb, D.J.* AU - Komulainen, P.* AU - Heikkinen, S.* AU - Mägi, R.* AU - Milani, L.* AU - Metspalu, A.* AU - Starr, J.M.* AU - Milaneschi, Y.* AU - Waken, R.J.* AU - Gao, C.* AU - Waldenberger, M. AU - Peters, A. AU - Strauch, K. AU - Meitinger, T. AU - Roenneberg, T.* AU - Völker, U.* AU - Dörr, M.* AU - Shu, X.O.* AU - Mukherjee, S.* AU - Hillman, D.R.* AU - Kähönen, M.* AU - Wagenknecht, L.E.* AU - Gieger, C. AU - Grabe, H.J.* AU - Zheng, W.* AU - Palmer, L.J.* AU - Lehtimäki, T.* AU - Gudnason, V.* AU - Morrison, A.C.* AU - Pereira, A.C.* AU - Fornage, M.* AU - Psaty, B.M.* AU - van Duijn, C.M.* AU - Liu, C.T.* AU - Kelly, T.N.* AU - Evans, M.K.* AU - Bouchard, C.* AU - Fox, E.R.* AU - Kooperberg, C.* AU - Zhu, X.* AU - Lakka, T.A.* AU - Esko, T.* AU - North, K.E.* AU - Deary, I.J.* AU - Snieder, H.* AU - Penninx, B.W.J.H.* AU - Gauderman, W.J.* AU - Rao, D.C.* AU - Redline, S.* AU - van Heemst, D.* C1 - 61845 C2 - 50492 CY - Campus, 4 Crinan St, London, N1 9xw, England SP - 6293-6304 TI - Multi-ancestry genome-wide gene-sleep interactions identify novel loci for blood pressure. JO - Mol. Psychiatry VL - 26 IS - 11 PB - Springernature PY - 2021 SN - 1359-4184 ER - TY - JOUR AB - Depression constitutes a leading cause of disability worldwide. Despite extensive research on its interaction with psychobiological factors, associated pathways are far from being elucidated. Metabolomics, assessing the final products of complex biochemical reactions, has emerged as a valuable tool for exploring molecular pathways. We conducted a metabolome-wide association analysis to investigate the link between the serum metabolome and depressed mood (DM) in 1411 participants of the KORA (Cooperative Health Research in the Augsburg Region) F4 study (discovery cohort). Serum metabolomics data comprised 353 unique metabolites measured by Metabolon. We identified 72 (5.1%) KORA participants with DM. Linear regression tests were conducted modeling each metabolite value by DM status, adjusted for age, sex, body-mass index, antihypertensive, cardiovascular, antidiabetic, and thyroid gland hormone drugs, corticoids and antidepressants. Sensitivity analyses were performed in subcohorts stratified for sex, suicidal ideation, and use of antidepressants. We replicated our results in an independent sample of 968 participants of the SHIP-Trend (Study of Health in Pomerania) study including 52 (5.4%) individuals with DM (replication cohort). We found significantly lower laurylcarnitine levels in KORA F4 participants with DM after multiple testing correction according to Benjamini/Hochberg. This finding was replicated in the independent SHIP-Trend study. Laurylcarnitine remained significantly associated (p value < 0.05) with depression in samples stratified for sex, suicidal ideation, and antidepressant medication. Decreased blood laurylcarnitine levels in depressed individuals may point to impaired fatty acid oxidation and/or mitochondrial function in depressive disorders, possibly representing a novel therapeutic target. AU - Zacharias, H.U.* AU - Hertel, J.* AU - Johar, H. AU - Pietzner, M.* AU - Lukaschek, K.* AU - Atasoy, S.* AU - Kunze, S. AU - Völzke, H.* AU - Nauck, M.* AU - Friedrich, N.* AU - Kastenmüller, G. AU - Grabe, H.J.* AU - Gieger, C. AU - Krumsiek, J. AU - Ladwig, K.-H. C1 - 62189 C2 - 50691 CY - Campus, 4 Crinan St, London, N1 9xw, England SP - 7372–7383 TI - A metabolome-wide association study in the general population reveals decreased levels of serum laurylcarnitine in people with depression. JO - Mol. Psychiatry VL - 26 PB - Springernature PY - 2021 SN - 1359-4184 ER - TY - JOUR AB - Smoking is a major heritable and modifiable risk factor for many diseases, including cancer, common respiratory disorders and cardiovascular diseases. Fourteen genetic loci have previously been associated with smoking behaviour-related traits. We tested up to 235,116 single nucleotide variants (SNVs) on the exome-array for association with smoking initiation, cigarettes per day, pack-years, and smoking cessation in a fixed effects meta-analysis of up to 61 studies (up to 346,813 participants). In a subset of 112,811 participants, a further one million SNVs were also genotyped and tested for association with the four smoking behaviour traits. SNV-trait associations withP < 5 x 10(-8)in either analysis were taken forward for replication in up to 275,596 independent participants from UK Biobank. Lastly, a meta-analysis of the discovery and replication studies was performed. Sixteen SNVs were associated with at least one of the smoking behaviour traits (P < 5 x 10(-8)) in the discovery samples. Ten novel SNVs, including rs12616219 nearTMEM182, were followed-up and five of them (rs462779 inREV3L, rs12780116 inCNNM2, rs1190736 inGPR101, rs11539157 inPJA1, and rs12616219 nearTMEM182) replicated at a Bonferroni significance threshold (P < 4.5 x 10(-3)) with consistent direction of effect. A further 35 SNVs were associated with smoking behaviour traits in the discovery plus replication meta-analysis (up to 622,409 participants) including a rare SNV, rs150493199, inCCDC141and two low-frequency SNVs inCEP350andHDGFRP2. Functional follow-up implied that decreased expression ofREV3Lmay lower the probability of smoking initiation. The novel loci will facilitate understanding the genetic aetiology of smoking behaviour and may lead to the identification of potential drug targets for smoking prevention and/or cessation. AU - Erzurumluoglu, A.M.* AU - Liu, M.* AU - Jackson, V.E.* AU - Barnes, D.R.* AU - Datta, G.* AU - Melbourne, C.A.* AU - Young, R.* AU - Batini, C.* AU - Surendran, P.* AU - Jiang, T.* AU - Adnan, S.D.* AU - Afaq, S.* AU - Agrawal, A.* AU - Altmaier, E. AU - Antoniou, A.C.* AU - Asselbergs, F.W.* AU - Baumbach, C. AU - Bierut, L.* AU - Bertelsen, S.* AU - Boehnke, M.* AU - Bots, M.L.* AU - Brazel, D.M.* AU - Chambers, J.C.* AU - Chang-Claude, J.* AU - Chen, C.* AU - Corley, J.* AU - Chou, Y.L.* AU - David, S.P.* AU - de Boer, R.A.* AU - de Leeuw, C.A.* AU - Dennis, J.G.* AU - Dominiczak, A.F.* AU - Dunning, A.M.* AU - Easton, D.F.* AU - Eaton, C.* AU - Elliott, P.* AU - Evangelou, E.* AU - Faul, J.D.* AU - Foroud, T.* AU - Goate, A.* AU - Gong, J.* AU - Grabe, H.J.* AU - Haessler, J.* AU - Haiman, C.* AU - Hallmans, G.* AU - Hammerschlag, A.R.* AU - Harris, S.E.* AU - Hattersley, A.* AU - Heath, A.* AU - Hsu, C.* AU - Iacono, W.G.* AU - Kanoni, S.* AU - Kapoor, M.* AU - Kaprio, J.* AU - Kardia, S.L.* AU - Karpe, F.* AU - Kontto, J.* AU - Kooner, J.S.* AU - Kooperberg, C.* AU - Kuulasmaa, K.* AU - Laakso, M.* AU - Lai, D.* AU - Langenberg, C.* AU - Le, N.* AU - Lettre, G.* AU - Loukola, A.* AU - Luan, J.* AU - Madden, P.A.F.* AU - Mangino, M.* AU - Marioni, R.E.* AU - Marouli, E.* AU - Marten, J.* AU - Martin, N.G.* AU - McGue, M.* AU - Michailidou, K.* AU - Mihailov, E.* AU - Moayyeri, A.* AU - Moitry, M.* AU - Müller-Nurasyid, M. AU - Naheed, A.I.* AU - Nauck, M.* AU - Neville, M.J.* AU - Nielsen, S.F.* AU - North, K.* AU - Perola, M.* AU - Pharoah, P.D.P.* AU - Pistis, G.* AU - Polderman, T.J.* AU - Posthuma, D.* AU - Poulter, N.* AU - Qaiser, B.* AU - Rasheed, A.* AU - Reiner, A.* AU - Renström, F.* AU - Rice, J.* AU - Rohde, R.* AU - Rolandsson, O.* AU - Samani, N.J.* AU - Samuel, M.* AU - Schlessinger, D.* AU - Scholte, S.H.* AU - Scott, R.A.* AU - Sever, P.* AU - Shao, Y.* AU - Shrine, N.* AU - Smith, J.A.* AU - Starr, J.M.* AU - Stirrups, K.* AU - Stram, D.* AU - Stringham, H.M.* AU - Tachmazidou, I.* AU - Tardif, J.C.* AU - Thompson, D.J.* AU - Tindle, H.A.* AU - Tragante, V.* AU - Trompet, S.* AU - Turcot, V.* AU - Tyrrell, J.* AU - Vaartjes, I.* AU - van der Leij, A.R.* AU - van der Meer, P.* AU - Varga, T.V.* AU - Verweij, N.* AU - Völzke, H.* AU - Wareham, N.J.* AU - Warren, H.R.* AU - Weir, D.R.* AU - Weiss, S.* AU - Wetherill, L.* AU - Yaghootkar, H.* AU - Yavas, E.* AU - Jiang, Y.* AU - Chen, F.* AU - Zhan, X.* AU - Zhang, W.* AU - Zhao, W.* AU - Zhou, K.* AU - Amouyel, P.* AU - Blankenberg, S.* AU - Caulfield, M.J.* AU - Chowdhury, R.* AU - Cucca, F.* AU - Deary, I.J.* AU - Deloukas, P.* AU - di Angelantonio, E.* AU - Ferrario, M.* AU - Ferrières, J.* AU - Franks, P.W.* AU - Frayling, T.M.* AU - Frossard, P.* AU - Hall, I.P.* AU - Hayward, C.* AU - Jansson, J.H.* AU - Jukema, J.W.* AU - Kee, F.* AU - Männistö, S.* AU - Metspalu, A.* AU - Munroe, P.B.* AU - Nørdestgaard, B.G.* AU - Palmer, C.N.A.* AU - Salomaa, V.* AU - Sattar, N.* AU - Spector, T.* AU - Strachan, D.P.* AU - van der Harst, P.* AU - Zeggini, E.* AU - Saleheen, D.* AU - Butterworth, A.S.* AU - Wain, L.V.* AU - Abecasis, G.R.* AU - Danesh, J.* AU - Tobin, M.D.* AU - Vrieze, S.* AU - Liu, D.J.* AU - Howson, J.M.M.* C1 - 55095 C2 - 46285 CY - Campus, 4 Crinan St, London, N1 9xw, England SP - 2392-2409 TI - Meta-analysis of up to 622,409 individuals identifies 40 novel smoking behaviour associated genetic loci. JO - Mol. Psychiatry VL - 25 IS - 10 PB - Springernature PY - 2020 SN - 1359-4184 ER - TY - JOUR AU - Bornstein, S.R. AU - Steenblock, C.* AU - Chrousos, G.P.* AU - Schally, A.V.* AU - Beuschlein, F.* AU - Kline, G.* AU - Krone, N.P.* AU - Licinio, J.* AU - Wong, M.L.* AU - Ullmann, E.* AU - Ruiz-Babot, G.* AU - Boehm, B.O.* AU - Behrens, A.* AU - Brennand, A.* AU - Santambrogio, A.* AU - Berger, I.* AU - Werdermann, M.* AU - Sancho, R.* AU - Linkermann, A.* AU - Lenders, J.W.* AU - Eisenhofer, G.* AU - Andoniadou, C.L.* C1 - 55001 C2 - 45980 CY - Macmillan Building, 4 Crinan St, London N1 9xw, England SP - 2-9 TI - Stress-inducible-stem cells: A new view on endocrine, metabolic and mental disease? JO - Mol. Psychiatry VL - 24 IS - 1 PB - Nature Publishing Group PY - 2019 SN - 1359-4184 ER - TY - JOUR AB - Single-nucleotide polymorphisms (SNPs) in CACNA1C, the a1C subunit of the voltage-gated L-type calcium channel Ca(v)1.2, rank among the most consistent and replicable genetics findings in psychiatry and have been associated with schizophrenia, bipolar disorder and major depression. However, genetic variants of complex diseases often only confer a marginal increase in disease risk, which is additionally influenced by the environment. Here we show that embryonic deletion of Cacna1c in forebrain glutamatergic neurons promotes the manifestation of endophenotypes related to psychiatric disorders including cognitive decline, impaired synaptic plasticity, reduced sociability, hyperactivity and increased anxiety. Additional analyses revealed that depletion of Cacna1c during embryonic development also increases the susceptibility to chronic stress, which suggest that Ca(v)1.2 interacts with the environment to shape disease vulnerability. Remarkably, this was not observed when Cacna1c was deleted in glutamatergic neurons during adulthood, where the later deletion even improved cognitive flexibility, strengthened synaptic plasticity and induced stress resilience. In a parallel gene x environment design in humans, we additionally demonstrate that SNPs in CACNA1C significantly interact with adverse life events to alter the risk to develop symptoms of psychiatric disorders. Overall, our results further validate Cacna1c as a cross-disorder risk gene in mice and humans, and additionally suggest a differential role for Ca(v)1.2 during development and adulthood in shaping cognition, sociability, emotional behavior and stress susceptibility. This may prompt the consideration for pharmacological manipulation of Ca(v)1.2 in neuropsychiatric disorders with developmental and/or stressrelated origins. AU - Dedic, N.* AU - Pöhlmann, M.L.* AU - Richter, J.S.* AU - Mehta, D.* AU - Czamara, D.* AU - Metzger, M.W.* AU - Dine, J.* AU - Bedenk, B.T.* AU - Hartmann, J.* AU - Wagner, K.V.* AU - Jurik, A.* AU - Almli, L.M.* AU - Lori, A.* AU - Moosmang, S.* AU - Hofmann, F.* AU - Wotjak, C.T.* AU - Rammes, G.* AU - Eder, M.* AU - Chen, A.* AU - Ressler, K.J.* AU - Wurst, W. AU - Schmidt, M.V.* AU - Binder, E.B.* AU - Deussing, J.M.* C1 - 51505 C2 - 43289 CY - London SP - 533-543 TI - Cross-disorder risk gene CACNA1C differentially modulates susceptibility to psychiatric disorders during development and adulthood. JO - Mol. Psychiatry VL - 23 IS - 3 PB - Nature Publishing Group PY - 2018 SN - 1359-4184 ER - TY - JOUR AB - Anorexia nervosa (AN) is a complex neuropsychiatric disorder presenting with dangerously low body weight, and a deep and persistent fear of gaining weight. To date, only one genome-wide significant locus associated with AN has been identified. We performed an exome-chip based genome-wide association studies (GWAS) in 2158 cases from nine populations of European origin and 15 485 ancestrally matched controls. Unlike previous studies, this GWAS also probed association in low-frequency and rare variants. Sixteen independent variants were taken forward for in silico and de novo replication (11 common and 5 rare). No findings reached genome-wide significance. Two notable common variants were identified: rs10791286, an intronic variant in OPCML (P=9.89 × 10(-6)), and rs7700147, an intergenic variant (P=2.93 × 10(-5)). No low-frequency variant associations were identified at genome-wide significance, although the study was well-powered to detect low-frequency variants with large effect sizes, suggesting that there may be no AN loci in this genomic search space with large effect sizes. AU - Huckins, L.M.* AU - Hatzikotoulas, K.* AU - Southam, L.* AU - Thornton, L.M.* AU - Steinberg, J.* AU - Aguilera-McKay, F.* AU - Treasure, J.* AU - Schmidt, U.* AU - Gunasinghe, C.* AU - Romero, A.M.* AU - Curtis, C.* AU - Rhodes, D.* AU - Moens, J.* AU - Kalsi, G.* AU - Dempster, D.* AU - Leung, R.* AU - Keohane, A.* AU - Burghardt, R.* AU - Ehrlich, S.* AU - Hebebrand, J.* AU - Hinney, A.* AU - Ludolph-Donislawski, A. AU - Walton, E.* AU - Deloukas, P.* AU - Hofman, A.* AU - Palotie, A.* AU - Palta, P.* AU - van Rooij, F.J.A.* AU - Stirrups, K.* AU - Adan, R.A.* AU - Boni, C.* AU - Cone, R.D.* AU - Dedoussis, G.* AU - van Furth, E.F.* AU - Gonidakis, F.* AU - Gorwood, P.* AU - Hudson, J.I.* AU - Kaprio, J.* AU - Kas, M.J.* AU - Keski-Rahonen, A.* AU - Kiezebrink, K.* AU - Knudsen, G.P.* AU - Slof-Op 't Landt, M.C.T.* AU - Maj, M.* AU - Monteleone, A.M.* AU - Monteleone, P.* AU - Raevuori, A.H.* AU - Reichborn-Kjennerud, T.* AU - Tozzi, F.* AU - Tsitsika, A.* AU - van Elburg, A.A.* AU - Collier, D.A.* AU - Sullivan, P.F.* AU - Breen, G.* AU - Bulik, C.M.* AU - Zeggini, E.* C1 - 52369 C2 - 43937 SP - 1169-1180 TI - Investigation of common, low-frequency and rare genome-wide variation in anorexia nervosa. JO - Mol. Psychiatry VL - 23 IS - 5 PY - 2018 SN - 1359-4184 ER - TY - JOUR AB - The fortieth author's name was listed incorrectly. The correct presentation is A Keski-Rahkonen. AU - Huckins, L.M.* AU - Hatzikotoulas, K.* AU - Southam, L.* AU - Thornton, L.M.* AU - Steinberg, J.* AU - Aguilera-McKay, F.* AU - Treasure, J.* AU - Schmidt, U.* AU - Gunasinghe, C.* AU - Romero, A.* AU - Curtis, C.* AU - Rhodes, D.* AU - Moens, J.* AU - Kalsi, G.* AU - Dempster, D.* AU - Leung, R.* AU - Keohane, A.* AU - Burghardt, R.* AU - Ehrlich, S.* AU - Hebebrand, J.* AU - Hinney, A.* AU - Ludolph-Donislawski, A. AU - Walton, E.* AU - Deloukas, P.* AU - Hofman, A.* AU - Palotie, A.* AU - Palta, P.* AU - van Rooij, F.J.A.* AU - Stirrups, K.* AU - Adan, R.A.* AU - Boni, C.* AU - Cone, R.* AU - Dedoussis, G.* AU - van Furth, E.* AU - Gonidakis, F.* AU - Gorwood, P.* AU - Hudson, J.* AU - Kaprio, J.* AU - Kas, M.* AU - Keski-Rahonen, A.* AU - Kiezebrink, K.* AU - Knudsen, G.P.* AU - Maj, M.* AU - Monteleone, A.M.* AU - Monteleone, P.* AU - Raevuori, A.H.* AU - Reichborn-Kjennerud, T.* AU - Tozzi, F.* AU - Tsitsika, A.* AU - van Elburg, A.A.* AU - Collier, D.A.* AU - Sullivan, P.F.* AU - Breen, G.* AU - Bulik, C.M.* AU - Zeggini, E.* C1 - 54720 C2 - 45810 TI - Correction: Investigation of common, low-frequency and rare genome-wide variation in anorexia nervosa. JO - Mol. Psychiatry VL - 23 IS - 9 PY - 2018 SN - 1359-4184 ER - TY - JOUR AB - The lack of reliable measures of alcohol intake is a major obstacle to the diagnosis and treatment of alcohol-related diseases. Epigenetic modifications such as DNA methylation may provide novel biomarkers of alcohol use. To examine this possibility, we performed an epigenome-wide association study of methylation of cytosine-phosphate-guanine dinucleotide (CpG) sites in relation to alcohol intake in 13 population-based cohorts (n(total) = 13 317; 54% women; mean age across cohorts 42-76 years) using whole blood (9643 European and 2423 African ancestries) or monocyte-derived DNA (588 European, 263 African and 400 Hispanic ancestry) samples. We performed meta-analysis and variable selection in whole-blood samples of people of European ancestry (n = 6926) and identified 144 CpGs that provided substantial discrimination (area under the curve = 0.90-0.99) for current heavy alcohol intake (>= 42 g per day in men and >= 28 g per day in women) in four replication cohorts. The ancestry-stratified meta-analysis in whole blood identified 328 (9643 European ancestry samples) and 165 (2423 African ancestry samples) alcohol-related CpGs at Bonferroni-adjusted P < 1 x 10(-7). Analysis of the monocyte-derived DNA (n = 1251) identified 62 alcohol-related CpGs at P < 1 x 10(-7). In whole-blood samples of people of European ancestry, we detected differential methylation in two neurotransmitter receptor genes, the gamma-Aminobutyric acid-A receptor delta and gamma-aminobutyric acid B receptor subunit 1; their differential methylation was associated with expression levels of a number of genes involved in immune function. In conclusion, we have identified a robust alcohol-related DNA methylation signature and shown the potential utility of DNA methylation as a clinically useful diagnostic test to detect current heavy alcohol consumption. AU - Liu, C.* AU - Marioni, R.E.* AU - Hedman, A.K.* AU - Pfeiffer, L. AU - Tsai, P.C.* AU - Reynolds, L.M.* AU - Just, A.C.* AU - Duan, Q.* AU - Boer, C.G.* AU - Tanaka, T.* AU - Elks, C.E.* AU - Aslibekyan, S.* AU - Brody, J.A.* AU - Kühnel, B. AU - Herder, C.* AU - Almli, L.M.* AU - Zhi, D.* AU - Wang, Y.* AU - Huan, T.* AU - Yao, C.* AU - Mendelson, M.* AU - Joehanes, R.* AU - Liang, L.* AU - Love, S.A.* AU - Guan, W.* AU - Shah, S.* AU - McRae, A.F.* AU - Kretschmer, A. AU - Prokisch, H. AU - Strauch, K. AU - Peters, A. AU - Visscher, P.M.* AU - Wray, N.R.* AU - Guo, X.* AU - Wiggins, K.L.* AU - Smith, A.K.* AU - Binder, E.B.* AU - Ressler, K.J.* AU - Irvin, M.R.* AU - Absher, D.M.* AU - Hernandez, D.* AU - Ferrucci, L.* AU - Bandinelli, S.* AU - Lohman, K.* AU - Ding, J.* AU - Trevisi, L.* AU - Gustafsson, S.* AU - Sandling, J.H.* AU - Stolk, L.* AU - Uitterlinden, A.G.* AU - Yet, I.* AU - Castillo-Fernandez, J.E.* AU - Spector, T.D.* AU - Schwartz, J.D.* AU - Vokonas, P.* AU - Lind, L.* AU - Li, Y.* AU - Fornage, M.* AU - Arnett, D.K.* AU - Wareham, N.J.* AU - Sotoodehnia, N.* AU - Ong, K.K.* AU - van Meurs, J.B.J.* AU - Conneely, K.N.* AU - Baccarelli, A.A.* AU - Deary, I.J.* AU - Bell, J.T.* AU - North, K.E.* AU - Liu, Y.* AU - Waldenberger, M. AU - London, S.J.* AU - Ingelsson, E.* AU - Levy, D.* C1 - 50008 C2 - 41964 CY - London SP - 422-433 TI - A DNA methylation biomarker of alcohol consumption. JO - Mol. Psychiatry VL - 23 IS - 2 PB - Nature Publishing Group PY - 2018 SN - 1359-4184 ER - TY - JOUR AB - The maintenance of normal body weight is disrupted in patients with anorexia nervosa (AN) for prolonged periods of time. Prior to the onset of AN, premorbid body mass index (BMI) spans the entire range from underweight to obese. After recovery, patients have reduced rates of overweight and obesity. As such, loci involved in body weight regulation may also be relevant for AN and vice versa. Our primary analysis comprised a cross-trait analysis of the 1000 single-nucleotide polymorphisms (SNPs) with the lowest P-values in a genome-wide association meta-analysis (GWAMA) of AN (GCAN) for evidence of association in the largest published GWAMA for BMI (GIANT). Subsequently we performed sex-stratified analyses for these 1000 SNPs. Functional ex vivo studies on four genes ensued. Lastly, a look-up of GWAMA-derived BMI-related loci was performed in the AN GWAMA. We detected significant associations (P-values <5 × 10(-5), Bonferroni-corrected P<0.05) for nine SNP alleles at three independent loci. Interestingly, all AN susceptibility alleles were consistently associated with increased BMI. None of the genes (chr. 10: CTBP2, chr. 19: CCNE1, chr. 2: CARF and NBEAL1; the latter is a region with high linkage disequilibrium) nearest to these SNPs has previously been associated with AN or obesity. Sex-stratified analyses revealed that the strongest BMI signal originated predominantly from females (chr. 10 rs1561589; Poverall: 2.47 × 10(-06)/Pfemales: 3.45 × 10(-07)/Pmales: 0.043). Functional ex vivo studies in mice revealed reduced hypothalamic expression of Ctbp2 and Nbeal1 after fasting. Hypothalamic expression of Ctbp2 was increased in diet-induced obese (DIO) mice as compared with age-matched lean controls. We observed no evidence for associations for the look-up of BMI-related loci in the AN GWAMA. A cross-trait analysis of AN and BMI loci revealed variants at three chromosomal loci with potential joint impact. The chromosome 10 locus is particularly promising given that the association with obesity was primarily driven by females. In addition, the detected altered hypothalamic expression patterns of Ctbp2 and Nbeal1 as a result of fasting and DIO implicate these genes in weight regulation. AU - Hinney, A.* AU - Kesselmeier, M.* AU - Jall, S. AU - Volckmar, A.L.* AU - Föcker, M.* AU - Antel, J.* AU - Genetic Consortium for Anorexia Nervosa (GCAN) (*) AU - Wellcome Trust Case Control Consortium 3 (WTCCC3) (*) AU - Heid, I.M.* AU - Winkler, T.W.* AU - GIANT Consortium (Collier, D.A. AU - Gieger, C. AU - Müller, T.D. AU - Illig, T. AU - Scherag, A. AU - Hebebrand, J. AU - Thorand, B. AU - Wichmann, H.-E.) AU - Grant, S.F.* AU - Early Growth Genetics Consortium (*) AU - Guo, Y.* AU - Bergen, A.W.* AU - Kaye, W.* AU - Berrettini, W.* AU - Hakonarson, H.* AU - Price Foundation Collaborative Group (*) AU - Children's Hospital of Philadelphia/Price Foundation (*) AU - Herpertz-Dahlmann, B.* AU - de Zwaan, M.* AU - Herzog, W.* AU - Ehrlich, S.* AU - Zipfel, S.* AU - Egberts, K.M.* AU - Adan, R.A.* AU - Brandys, M.K.* AU - van Elburg, A.A.* AU - Boraska Perica, V.* AU - Franklin, C.S.* AU - Tschöp, M.H. C1 - 48759 C2 - 41326 CY - London SP - 192-201 TI - Evidence for three genetic loci involved in both anorexia nervosa risk and variation of body mass index. JO - Mol. Psychiatry VL - 22 IS - 2 PB - Nature Publishing Group PY - 2017 SN - 1359-4184 ER - TY - JOUR AU - Hinney, A.* AU - Kesselmeier, M.* AU - Jall, S. AU - Volckmar, A.L.* AU - Föcker, M.* AU - Antel, J.* AU - Heid, I.M.* AU - Winkler, T.W.* AU - Grant, S.F.A.* AU - Guo, Y.* AU - Bergen, A.W.* AU - Kaye, W.* AU - Berrettini, W.* AU - Hakonarson, H.* AU - Herpertz-Dahlmann, B.* AU - de Zwaan, M.* AU - Herzog, W.* AU - Ehrlich, S.* AU - Zipfel, S.* AU - Egberts, K.M.* AU - Adan, R.A.* AU - Brandys, M.K.* AU - van Elburg, A.A.* AU - Perica, V.B.* AU - Franklin, C.S.* AU - Tschop, M.H.* AU - Zeggini, E.* AU - Bulik, C.M.* AU - Collier, D.A.* AU - Scherag, A.* AU - Müller, T.D. AU - Hebebrand, J.* C1 - 50814 C2 - 42600 CY - London SP - 321-322 TI - Evidence for three genetic loci involved in both anorexia nervosa risk and variation of body mass index (vol 22, pg 192, 2017). JO - Mol. Psychiatry VL - 22 IS - 2 PB - Nature Publishing Group PY - 2017 SN - 1359-4184 ER - TY - JOUR AB - The epigenome is associated with biological factors, such as disease status, and environmental factors, such as smoking, alcohol consumption and body mass index. Although there is a widespread perception that environmental influences on the epigenome are pervasive and profound, there has been little evidence to date in humans with respect to environmental factors that are biologically distal. Here we provide evidence on the associations between epigenetic modifications-in our case, CpG methylation-and educational attainment (EA), a biologically distal environmental factor that is arguably among the most important life-shaping experiences for individuals. Specifically, we report the results of an epigenome-wide association study meta-analysis of EA based on data from 27 cohort studies with a total of 10 767 individuals. We find nine CpG probes significantly associated with EA. However, robustness analyses show that all nine probes have previously been found to be associated with smoking. Only two associations remain when we perform a sensitivity analysis in the subset of never-smokers, and these two probes are known to be strongly associated with maternal smoking during pregnancy, and thus their association with EA could be due to correlation between EA and maternal smoking. Moreover, the effect sizes of the associations with EA are far smaller than the known associations with the biologically proximal environmental factors alcohol consumption, body mass index, smoking and maternal smoking during pregnancy. Follow-up analyses that combine the effects of many probes also point to small methylation associations with EA that are highly correlated with the combined effects of smoking. If our findings regarding EA can be generalized to other biologically distal environmental factors, then they cast doubt on the hypothesis that such factors have large effects on the epigenome. AU - Karlsoon Linner, R.* AU - Marioni, R.E.* AU - Rietveld, C.A.* AU - Simpkin, A.J.* AU - Davies, N.M.* AU - Watanabe, K.* AU - Armstrong, N.J.* AU - Auro, K.* AU - Baumbach, C. AU - Bonder, M.J.* AU - Buchwald, J.* AU - Fiorito, G.* AU - Ismail, K.* AU - Iurato, S.* AU - Joensuu, A.* AU - Karell, P.* AU - Kasela, S.* AU - Lahti, J.* AU - McRae, A.F.* AU - Mandaviya, P.R.* AU - Seppälä, I.* AU - Wang, Y.* AU - Baglietto, L.* AU - Binder, E.B.* AU - Harris, S.E.* AU - Hodge, A.M.* AU - Horvath, S.* AU - Hurme, M.* AU - Johannesson, M.* AU - Latvala, A.* AU - Mather, K.A.* AU - Medland, S.E.* AU - Metspalu, A.* AU - Milani, L.* AU - Milne, R.L.* AU - Pattie, A.* AU - Pedersen, N.L.* AU - Peters, A. AU - Polidoro, S.* AU - Räikkönen, K.* AU - Severi, G.* AU - Starr, J.M.* AU - Stolk, L.* AU - Waldenberger, M. AU - Eriksson, J.G.* AU - Esko, T.* AU - Franke, L.* AU - Gieger, C. AU - Giles, G.G.* AU - Hägg, S.* AU - Jousilahti, P.* AU - Kaprio, J.* AU - Kähönen, M.* AU - Lehtimäki, T.* AU - Martin, N.G.* AU - van Meurs, J.B.C.* AU - Ollikainen, M.* AU - Perola, M.* AU - Posthuma, D.* AU - Raitakari, O.T.* AU - Sachdev, P.S.* AU - Taskesen, E.* AU - Uitterlinden, A.G.* AU - Vineis, P.* AU - Wijmenga, C.* AU - Wright, M.J.* AU - Relton, C.* AU - Davey Smith, G.* AU - Deary, I.J.* AU - Koellinger, P.D.* AU - Benjamin, D.J.* C1 - 52240 C2 - 43881 CY - London SP - 1680-1690 TI - An epigenome-wide association study meta-analysis of educational attainment. JO - Mol. Psychiatry VL - 22 IS - 12 PB - Nature Publishing Group PY - 2017 SN - 1359-4184 ER - TY - JOUR AB - Dietary intake of methyl donors, such as folic acid and methionine, shows considerable intra-individual variation in human populations. While it is recognized that maternal departures from the optimum of dietary methyl donor intake can increase the risk for mental health issues and neurological disorders in offspring, it has not been explored whether paternal dietary methyl donor intake influences behavioral and cognitive functions in the next generation. Here, we report that elevated paternal dietary methyl donor intake in a mouse model, transiently applied prior to mating, resulted in offspring animals (methyl donor-rich diet (MD) F1 mice) with deficits in hippocampus-dependent learning and memory, impaired hippocampal synaptic plasticity and reduced hippocampal theta oscillations. Gene expression analyses revealed altered expression of the methionine adenosyltransferase Mat2a and BK channel subunit Kcnmb2, which was associated with changes in Kcnmb2 promoter methylation in MD F1 mice. Hippocampal overexpression of Kcnmb2 in MD F1 mice ameliorated altered spatial learning and memory, supporting a role of this BK channel subunit in the MD F1 behavioral phenotype. Behavioral and gene expression changes did not extend into the F2 offspring generation. Together, our data indicate that paternal dietary factors influence cognitive and neural functions in the offspring generation.Molecular Psychiatry advance online publication, 4 April 2017; doi:10.1038/mp.2017.53. AU - Ryan, D.P.* AU - Henzel, K.S.* AU - Pearson, B.L.* AU - Siwek, M.E.* AU - Papazoglou, A.* AU - Guo, L.* AU - Paesler, K.* AU - Yu, M.* AU - Müller, R.* AU - Xie, K.* AU - Schröder, S.* AU - Becker, L. AU - Garrett, L. AU - Hölter, S.M. AU - Neff, F. AU - Rácz, I. AU - Rathkolb, B. AU - Rozman, J. AU - Ehninger, G.* AU - Klingenspor, M.* AU - Klopstock, T.* AU - Wolf, E.* AU - Wurst, W. AU - Zimmer, A.D.* AU - Fuchs, H. AU - Gailus-Durner, V. AU - Hrabě de Angelis, M. AU - Sidiropoulou, K.* AU - Weiergräber, M.* AU - Zhou, Y.* AU - Ehninger, D.* C1 - 50857 C2 - 42739 SP - 1345-1355 TI - A paternal methyl donor-rich diet altered cognitive and neural functions in offspring mice. JO - Mol. Psychiatry VL - 23 IS - 5 PY - 2017 SN - 1359-4184 ER - TY - JOUR AB - APOE ɛ4, the most significant genetic risk factor for Alzheimer disease (AD), may mask effects of other loci. We re-analyzed genome-wide association study (GWAS) data from the International Genomics of Alzheimer's Project (IGAP) Consortium in APOE ɛ4+ (10 352 cases and 9207 controls) and APOE ɛ4- (7184 cases and 26 968 controls) subgroups as well as in the total sample testing for interaction between a single-nucleotide polymorphism (SNP) and APOE ɛ4 status. Suggestive associations (P<1 × 10-4) in stage 1 were evaluated in an independent sample (stage 2) containing 4203 subjects (APOE ɛ4+: 1250 cases and 536 controls; APOE ɛ4-: 718 cases and 1699 controls). Among APOE ɛ4- subjects, novel genome-wide significant (GWS) association was observed with 17 SNPs (all between KANSL1 and LRRC37A on chromosome 17 near MAPT) in a meta-analysis of the stage 1 and stage 2 data sets (best SNP, rs2732703, P=5·8 × 10-9). Conditional analysis revealed that rs2732703 accounted for association signals in the entire 100-kilobase region that includes MAPT. Except for previously identified AD loci showing stronger association in APOE ɛ4+ subjects (CR1 and CLU) or APOE ɛ4- subjects (MS4A6A/MS4A4A/MS4A6E), no other SNPs were significantly associated with AD in a specific APOE genotype subgroup. In addition, the finding in the stage 1 sample that AD risk is significantly influenced by the interaction of APOE with rs1595014 in TMEM106B (P=1·6 × 10-7) is noteworthy, because TMEM106B variants have previously been associated with risk of frontotemporal dementia. Expression quantitative trait locus analysis revealed that rs113986870, one of the GWS SNPs near rs2732703, is significantly associated with four KANSL1 probes that target transcription of the first translated exon and an untranslated exon in hippocampus (P⩽1.3 × 10-8), frontal cortex (P⩽1.3 × 10-9) and temporal cortex (P⩽1.2 × 10-11). Rs113986870 is also strongly associated with a MAPT probe that targets transcription of alternatively spliced exon 3 in frontal cortex (P=9.2 × 10-6) and temporal cortex (P=2.6 × 10-6). Our APOE-stratified GWAS is the first to show GWS association for AD with SNPs in the chromosome 17q21.31 region. Replication of this finding in independent samples is needed to verify that SNPs in this region have significantly stronger effects on AD risk in persons lacking APOE ɛ4 compared with persons carrying this allele, and if this is found to hold, further examination of this region and studies aimed at deciphering the mechanism(s) are warranted. AU - Jun, G.* AU - Ibrahim-Verbaas, C.A.* AU - Vronskaya, M.* AU - Lambert, J.C.* AU - Chung, J.* AU - Naj, A.C.* AU - Kunkle, B.W.* AU - Wang, L.S.* AU - Bis, J.C.* AU - Bellenguez, C.* AU - Harold, D.* AU - Lunetta, K.L.* AU - DeStefano, A.L.* AU - Grenier-Boley, B.* AU - Sims, R.* AU - Beecham, G.W.* AU - Smith, A.V.* AU - Chouraki, V.* AU - Hamilton-Nelson, K.L.* AU - Ikram, M.A.* AU - Fievet, N.* AU - Denning, N.* AU - Martin, E.R.* AU - Schmidt, H.* AU - Kamatani, Y.* AU - Dunstan, M.L.* AU - Valladares, O.* AU - Laza, A.R.* AU - Zelenika, D.* AU - Ramirez, A.* AU - Foroud, T.M.* AU - Choi, S.H.* AU - Boland, A.* AU - Becker, T.* AU - Kukull, W.A.* AU - van der Lee, S.J.* AU - Pasquier, F.* AU - Cruchaga, C.* AU - Beekly, D.* AU - Fitzpatrick, A.L.* AU - Hanon, O.* AU - Gill, M.* AU - Barber, R.* AU - Gudnason, V.* AU - Campion, D.* AU - Love, S.* AU - Bennett, D.A.* AU - Amin, N.* AU - Berr, C.* AU - Tsolaki, M.* AU - Buxbaum, J.D.* AU - Lopez, O.L.* AU - Deramecourt, V.* AU - Fox, N.C.* AU - Cantwell, L.B.* AU - Tárraga, L.* AU - Dufouil, C.* AU - Hardy, J.* AU - Crane, P.K.* AU - Eiriksdottir, G.* AU - Hannequin, D.* AU - Clarke, R.* AU - Evans, D.* AU - Mosley, T.H Jr.* AU - Letenneur, L.* AU - Brayne, C.* AU - Maier, W.* AU - de Jager, P.L.* AU - Emilsson, V.* AU - Dartigues, J.F.* AU - Hampel, H.* AU - Kamboh, M.I.* AU - de Bruijn, R.F.* AU - Tzourio, C.* AU - Pastor, P.* AU - Larson, E.B.* AU - Rotter, J.I.* AU - O'Donovan, M.C.* AU - Montine, T.J.* AU - Nalls, M.A.* AU - Mead, S.* AU - Reiman, E.M.* AU - Jonsson, P.V.* AU - Holmes, C.* AU - St. George-Hyslop, P.H.* AU - Boada, M.* AU - Passmore, P.A.* AU - Wendland, J.R.* AU - Schmidt, R.* AU - Morgan, K.* AU - Winslow, A.R.* AU - Powell, J.F.* AU - Carasquillo, M.* AU - Younkin, S.G.* AU - Jakobsdottir, J.* AU - Kauwe, J.S.* AU - Wilhelmsen, K.C.* AU - Rujescu, D.* AU - Nöthen, M.M.* AU - Hofman, A.* AU - Jones, L.* AU - IGAP Consortium (Klopp, N. AU - Wichmann, H.-E.) AU - Haines, J.L.* AU - Psaty, B.M.* AU - van Broeckhoven, C.* AU - Holmans, P.* AU - Launer, L.J.* AU - Mayeux, R.* AU - Lathrop, M* AU - Goate, A.M.* AU - Escott-Price, V.* AU - Seshadri, S* AU - Pericak-Vance, M.A.* AU - Amouyel, P.* AU - Williams, J.* AU - van Duijn, C.M.* AU - Schellenberg, G.D.* AU - Farrer, L.A.* C1 - 47147 C2 - 39114 SP - 108–117 TI - A novel Alzheimer disease locus located near the gene encoding tau protein. JO - Mol. Psychiatry VL - 21 PY - 2016 SN - 1359-4184 ER - TY - JOUR AB - Hippocampal neurogenesis has been proposed to participate in a myriad of behavioral responses, both in basal states and in the context of neuropsychiatric disorders. Here, we identify activating protein 2γ (AP2γ, also known as Tcfap2c), originally described to regulate the generation of neurons in the developing cortex, as a modulator of adult hippocampal glutamatergic neurogenesis in mice. Specifically, AP2γ is present in a sub-population of hippocampal transient amplifying progenitors. There, it is found to act as a positive regulator of the cell fate determinants Tbr2 and NeuroD, promoting proliferation and differentiation of new glutamatergic granular neurons. Conditional ablation of AP2γ in the adult brain significantly reduced hippocampal neurogenesis and disrupted neural coherence between the ventral hippocampus and the medial prefrontal cortex. Furthermore, it resulted in the precipitation of multimodal cognitive deficits. This indicates that the sub-population of AP2γ-positive hippocampal progenitors may constitute an important cellular substrate for hippocampal-dependent cognitive functions. Concurrently, AP2γ deletion produced significant impairments in contextual memory and reversal learning. More so, in a water maze reference memory task a delay in the transition to cognitive strategies relying on hippocampal function integrity was observed. Interestingly, anxiety- and depressive-like behaviors were not significantly affected. Altogether, findings open new perspectives in understanding the role of specific sub-populations of newborn neurons in the (patho)physiology of neuropsychiatric disorders affecting hippocampal neuroplasticity and cognitive function in the adult brain. AU - Mateus-Pinheiro, A.* AU - Alves, N.D.* AU - Patrício, P.* AU - Machado-Santos, A.R.* AU - Loureiro-Campos, E.* AU - Silva, J.* AU - Sardinha, V.M.* AU - Reis, J.* AU - Schorle, H.* AU - Oliveira, J.F.* AU - Ninkovic, J. AU - Sousa, N.* AU - Pinto, L.* C1 - 49935 C2 - 41906 CY - London SP - 1725-1734 TI - AP2γ controls adult hippocampal neurogenesis and modulates cognitive, but not anxiety or depressive-like behavior. JO - Mol. Psychiatry VL - 22 IS - 12 PB - Nature Publishing Group PY - 2016 SN - 1359-4184 ER - TY - JOUR AB - Coffee, a major dietary source of caffeine, is among the most widely consumed beverages in the world and has received considerable attention regarding health risks and benefits. We conducted a genome-wide (GW) meta-analysis of predominately regular-type coffee consumption (cups per day) among up to 91 462 coffee consumers of European ancestry with top single-nucleotide polymorphisms (SNPs) followed-up in ~30 062 and 7964 coffee consumers of European and African-American ancestry, respectively. Studies from both stages were combined in a trans-ethnic meta-analysis. Confirmed loci were examined for putative functional and biological relevance. Eight loci, including six novel loci, met GW significance (log10Bayes factor (BF)>5.64) with per-allele effect sizes of 0.03-0.14 cups per day. Six are located in or near genes potentially involved in pharmacokinetics (ABCG2, AHR, POR and CYP1A2) and pharmacodynamics (BDNF and SLC6A4) of caffeine. Two map to GCKR and MLXIPL genes related to metabolic traits but lacking known roles in coffee consumption. Enhancer and promoter histone marks populate the regions of many confirmed loci and several potential regulatory SNPs are highly correlated with the lead SNP of each. SNP alleles near GCKR, MLXIPL, BDNF and CYP1A2 that were associated with higher coffee consumption have previously been associated with smoking initiation, higher adiposity and fasting insulin and glucose but lower blood pressure and favorable lipid, inflammatory and liver enzyme profiles (P<5 × 10(-8)).Our genetic findings among European and African-American adults reinforce the role of caffeine in mediating habitual coffee consumption and may point to molecular mechanisms underlying inter-individual variability in pharmacological and health effects of coffee. AU - Coffee and Caffeine Genetics Consortium AU - Cornelis, M.C.* AU - Byrne, E.M.* AU - Esko, T.* AU - Nalls, M.A.* AU - Ganna, A.* AU - Paynter, N.* AU - Monda, K.L.* AU - Amin, N.* AU - Fischer, K.* AU - Renström, F.* AU - Ngwa, J.S.* AU - Huikari, V.* AU - Cavadino, A.* AU - Nolte, I.M.* AU - Teumer, A.* AU - Yu, K.* AU - Marques-Vidal, P.* AU - Rawal, R. AU - Manichaikul, A.* AU - Wojczynski, M.K.* AU - Vink, J.M.* AU - Zhao, J.H.* AU - Burlutsky, G.* AU - Lahti, J.* AU - Mikkilä, V.* AU - Lemaitre, R.N.* AU - Eriksson, J.* AU - Musani, S.K.* AU - Tanaka, T.* AU - Geller, F.* AU - Luan, J.* AU - Hui, J.* AU - Mägi, R.* AU - Dimitriou, M.* AU - Garcia, M.E.* AU - Ho, W.K.* AU - Wright, M.J.* AU - Rose, L.M.* AU - Magnusson, P.K.* AU - Pedersen, N.L.* AU - Couper, D.* AU - Oostra, B.A.* AU - Hofman, A.* AU - Ikram, M.A.* AU - Tiemeier, H.W.* AU - Uitterlinden, A.G.* AU - van Rooij, F.J.* AU - Barroso, I.* AU - Johansson, I.* AU - Xue, L.* AU - Kaakinen, M.* AU - Milani, L.* AU - Power, C.* AU - Snieder, H.* AU - Stolk, R.P.* AU - Baumeister, S.E.* AU - Biffar, R.* AU - Gu, F.* AU - Bastardot, F.* AU - Kutalik, Z.* AU - Jacobs, D.R.* AU - Forouhi, N.G.* AU - Mihailov, E.* AU - Lind, L.* AU - Lindgren, C.* AU - Michaelsson, K.* AU - Morris, A.* AU - Jensen, M.* AU - Khaw, K.T.* AU - Luben, R.N.* AU - Wang, J.J.* AU - Männistö, S.* AU - Perälä, M.M.* AU - Kähönen, M.* AU - Lehtimäki, T.* AU - Viikari, J.* AU - Mozaffarian, D.* AU - Mukamal, K.J.* AU - Psaty, B.M.* AU - Döring, A. AU - Heath, A.C.* AU - Montgomery, G.W.* AU - Dahmen, N.* AU - Carithers, T.* AU - Tucker, K.L.* AU - Ferrucci, L.* AU - Boyd, H.A.* AU - Melbye, M.* AU - Treur, J.L.* AU - Mellström, D.* AU - Hottenga, J.J.* AU - Prokopenko, I.* AU - Tönjes, A.* AU - Deloukas, P.* AU - Kanoni, S.* AU - Lorentzon, M.* AU - Houston, D.K.* AU - Liu, Y.* AU - Danesh, J.* AU - Rasheed, A.* AU - Mason, M.A.* AU - Zonderman, A.B.* AU - Franke, L.* AU - Kristal, B.S.* AU - International Parkinson's Disease Genomics Consortium (IPDGC) (Illig, T. AU - Lichtner, P.) AU - North American Brain Expression Consortium (*) AU - UK Brain Expression Consortium (*) AU - Karjalainen, J.* AU - Reed, D.R.* AU - Westra, H.J.* AU - Evans, M.K.* AU - Saleheen, D.* AU - Harris, T.B.* AU - Dedoussis, G.* AU - Curhan, G.* AU - Stumvoll, M.* AU - Beilby, J.* AU - Pasquale, L.R.* AU - Feenstra, B.* AU - Bandinelli, S.* AU - Ordovas, J.M.* AU - Chan, A.T.* AU - Peters, U.* AU - Ohlsson, C.* AU - Gieger, C. AU - Martin, N.G.* AU - Waldenberger, M. AU - Siscovick, D.S.* AU - Raitakari, O.* AU - Eriksson, J.G.* AU - Mitchell, P.* AU - Hunter, D.J.* AU - Kraft, P.* AU - Rimm, E.B.* AU - Boomsma, D.I.* AU - Borecki, I.B.* AU - Loos, R.J.* AU - Wareham, N.J.* AU - Vollenweider, P.* AU - Caporaso, N.* AU - Grabe, H.J.* AU - Neuhouser, M.L.* AU - Wolffenbuttel, B.H.* AU - Hu, F.B.* AU - Hyppönen, E.* AU - Jarvelin, M.R.* AU - Cupples, L.A.* AU - Franks, P.W.* AU - Ridker, P.M.* AU - van Duijn, C.M.* AU - Heiss, G.* AU - Metspalu, A.* AU - North, K.E.* AU - Ingelsson, E.* AU - Nettleton, J.A.* AU - van Dam, R.M.* AU - Chasman, D.I.* C1 - 32489 C2 - 35111 CY - London SP - 647-656 TI - Genome-wide meta-analysis identifies six novel loci associated with habitual coffee consumption. JO - Mol. Psychiatry VL - 20 IS - 5 PB - Nature Publishing Group PY - 2015 SN - 1359-4184 ER - TY - JOUR AB - We investigated the genetic overlap between Alzheimer's disease (AD) and Parkinson's disease (PD). Using summary statistics (P-values) from large recent genome-wide association studies (GWAS) (total n = 89 904 individuals), we sought to identify single nucleotide polymorphisms (SNPs) associating with both AD and PD. We found and replicated association of both AD and PD with the A allele of rs393152 within the extended MAPT region on chromosome 17 (meta analysis P-value across five independent AD cohorts = 1.65 x 10(-7)). In independent datasets, we found a dose-dependent effect of the A allele of rs393152 on intra-cerebral MAPT transcript levels and volume loss within the entorhinal cortex and hippocampus. Our findings identify the tau-associated MAPT locus as a site of genetic overlap between AD and PD, and extending prior work, we show that the MAPT region increases risk of Alzheimer's neurodegeneration. AU - Desikan, R.S.* AU - Schork, A.J.* AU - Wang, Y.* AU - Witoelar, A.W.* AU - Sharma, M.* AU - McEvoy, L.K.* AU - Holland, D.* AU - Brewer, J.B.* AU - Chen, C.H.* AU - Thompson, W.K.* AU - Harold, D.* AU - Williams, J.* AU - Owen, M.J.* AU - O'Donovan, M.C.* AU - Pericak-Vance, M.A.* AU - Mayeux, R.* AU - Haines, J.L.* AU - Farrer, L.A.* AU - Schellenberg, G.D.* AU - Heutink, P.* AU - Singleton, A.B.* AU - Brice, A.* AU - Wood, N.W.* AU - Hardy, J.* AU - Martinez, M.* AU - Choi, S.H.* AU - DeStefano, A.L.* AU - Ikram, M.A.* AU - Bis, J.C.* AU - Smith, A.* AU - Fitzpatrick, A.L.* AU - Launer, L.* AU - van Duijn, C.M.* AU - Seshadri, S* AU - Ulstein, I.D.* AU - Aarsland, D.* AU - Fladby, T.* AU - Djurovic, S.* AU - Hyman, B.T.* AU - Snaedal, J.* AU - Stefansson, H.* AU - Stefansson, K.* AU - Gasser, T.* AU - Andreassen, O.A.* AU - Dale, A.M.* AU - ADNI Investigators (*) AU - ADGC Investigators (*) AU - GERAD Investigators (*) AU - CHARGE Investigators (*) AU - IPDGC Investigators (Illig, T. AU - Lichtner, P.) C1 - 47547 C2 - 39381 SP - 1588-1595 TI - Genetic overlap between Alzheimer's disease and Parkinson's disease at the MAPT locus. JO - Mol. Psychiatry VL - 20 IS - 12 PY - 2015 SN - 1359-4184 ER - TY - JOUR AB - An association between lower educational attainment (EA) and an increased risk for depression has been confirmed in various western countries. This study examines whether pleiotropic genetic effects contribute to this association. Therefore, data were analyzed from a total of 9662 major depressive disorder (MDD) cases and 14 949 controls (with no lifetime MDD diagnosis) from the Psychiatric Genomics Consortium with additional Dutch and Estonian data. The association of EA and MDD was assessed with logistic regression in 15 138 individuals indicating a significantly negative association in our sample with an odds ratio for MDD 0.78 (0.75-0.82) per standard deviation increase in EA. With data of 884 105 autosomal common single-nucleotide polymorphisms (SNPs), three methods were applied to test for pleiotropy between MDD and EA: (i) genetic profile risk scores (GPRS) derived from training data for EA (independent meta-analysis on ~120 000 subjects) and MDD (using a 10-fold leave-one-out procedure in the current sample), (ii) bivariate genomic-relationship-matrix restricted maximum likelihood (GREML) and (iii) SNP effect concordance analysis (SECA). With these methods, we found (i) that the EA-GPRS did not predict MDD status, and MDD-GPRS did not predict EA, (ii) a weak negative genetic correlation with bivariate GREML analyses, but this correlation was not consistently significant, (iii) no evidence for concordance of MDD and EA SNP effects with SECA analysis. To conclude, our study confirms an association of lower EA and MDD risk, but this association was not because of measurable pleiotropic genetic effects, which suggests that environmental factors could be involved, for example, socioeconomic status. AU - Peyrot, W.J.* AU - Lee, S.H.* AU - Milaneschi, Y.* AU - Abdellaoui, A.* AU - Byrne, E.M.* AU - Esko, T.* AU - de Geus, E.J.* AU - Hemani, G.* AU - Hottenga, J.J.* AU - Kloiber, S.* AU - Levinson, D.F.* AU - Lucae, S.* AU - Psychiatric GWAS Consortium Major Depressive Disorder Working Group (Wray, N.R.*) AU - Martin, N.G.* AU - Medland, S.E.* AU - Metspalu, A.* AU - Milani, L.* AU - Noethen, M.M.* AU - Potash, J.B.* AU - Rietschel, M.* AU - Rietveld, C.A.* AU - Ripke, S.* AU - Shi, J.* AU - Social Science Genetic Association Consortium (Gieger, C. AU - Holle, R. AU - Illig, T. AU - Lichtner, P. AU - Mielck, A. AU - Wichmann, H.-E.) AU - Willemsen, G.* AU - Zhu, Z.* AU - Boomsma, D.I.* AU - Penninx, B.* C1 - 45341 C2 - 37281 SP - 735-743 TI - The association between lower educational attainment and depression owing to shared genetic effects? Results in ~25 000 subjects. JO - Mol. Psychiatry VL - 20 IS - 6 PY - 2015 SN - 1359-4184 ER - TY - JOUR AB - Anorexia nervosa (AN) is a complex and heritable eating disorder characterized by dangerously low body weight. Neither candidate gene studies nor an initial genome-wide association study (GWAS) have yielded significant and replicated results. We performed a GWAS in 2907 cases with AN from 14 countries (15 sites) and 14 860 ancestrally matched controls as part of the Genetic Consortium for AN (GCAN) and the Wellcome Trust Case Control Consortium 3 (WTCCC3). Individual association analyses were conducted in each stratum and meta-analyzed across all 15 discovery data sets. Seventy-six (72 independent) single nucleotide polymorphisms were taken forward for in silico (two data sets) or de novo (13 data sets) replication genotyping in 2677 independent AN cases and 8629 European ancestry controls along with 458 AN cases and 421 controls from Japan. The final global meta-analysis across discovery and replication data sets comprised 5551 AN cases and 21 080 controls. AN subtype analyses (1606 AN restricting; 1445 AN binge-purge) were performed. No findings reached genome-wide significance. Two intronic variants were suggestively associated: rs9839776 (P=3.01 × 10(-7)) in SOX2OT and rs17030795 (P=5.84 × 10(-6)) in PPP3CA. Two additional signals were specific to Europeans: rs1523921 (P=5.76 × 10(-)(6)) between CUL3 and FAM124B and rs1886797 (P=8.05 × 10(-)(6)) near SPATA13. Comparing discovery with replication results, 76% of the effects were in the same direction, an observation highly unlikely to be due to chance (P=4 × 10(-6)), strongly suggesting that true findings exist but our sample, the largest yet reported, was underpowered for their detection. The accrual of large genotyped AN case-control samples should be an immediate priority for the field. AU - Boraska, V.* AU - Franklin, C.S.* AU - Floyd, J.A.* AU - Thornton, L.M.* AU - Huckins, L.M.* AU - Southam, L.* AU - Rayner, N.W.* AU - Tachmazidou, I.* AU - Klump, K.L.* AU - Treasure, J.* AU - Lewis, C.M.* AU - Schmidt, U.* AU - Tozzi, F.* AU - Kiezebrink, K.* AU - Hebebrand, J.* AU - Gorwood, P.* AU - Adan, R.A.* AU - Kas, M.J.* AU - Favaro, A.* AU - Santonastaso, P.* AU - Fernández-Aranda, F.* AU - Gratacos, M.* AU - Rybakowski, F.* AU - Dmitrzak-Weglarz, M.* AU - Kaprio, J.* AU - Keski-Rahkonen, A.* AU - Raevuori, A.* AU - van Furth, E.F.* AU - Slof-Op 't Landt, M.C.* AU - Hudson, J.I.* AU - Reichborn-Kjennerud, T.* AU - Knudsen, G.P.* AU - Monteleone, P.* AU - Kaplan, A.S.* AU - Karwautz, A.* AU - Hakonarson, H.* AU - Berrettini, W.H.* AU - Guo, Y.* AU - Li, D.* AU - Schork, N.J.* AU - Komaki, G.* AU - Ando, T.* AU - Inoko, H.* AU - Esko, T.* AU - Fischer, K.* AU - Männik, K.* AU - Metspalu, A.* AU - Baker, J.H.* AU - Cone, R.D.* AU - Dackor, J.* AU - DeSocio, J.E.* AU - Hilliard, C.E.* AU - O'Toole, J.K.* AU - Pantel, J.* AU - Szatkiewicz, J.P.* AU - Taico, C.* AU - Zerwas, S.* AU - Trace, S.E.* AU - Davis, O.S.* AU - Helder, S.* AU - Bühren, K.* AU - Burghardt, R.* AU - de Zwaan, M.* AU - Egberts, K.* AU - Ehrlich, S.* AU - Herpertz-Dahlmann, B.* AU - Herzog, W.* AU - Imgart, H.* AU - Scherag, A.* AU - Scherag, S.* AU - Zipfel, S.* AU - Boni, C.* AU - Ramoz, N.* AU - Versini, A.* AU - Brandys, M.K.* AU - Danner, U.N.* AU - de Kovel, C.* AU - Hendriks, J.* AU - Koeleman, B.P.* AU - Ophoff, R.A.* AU - Strengman, E.* AU - van Elburg, A.A.* AU - Bruson, A.* AU - Clementi, M.* AU - Degortes, D.* AU - Forzan, M.* AU - Tenconi, E.* AU - Docampo, E.* AU - Escaramís, G.* AU - Jiménez-Murcia, S.* AU - Lissowska, J.* AU - Rajewski, A.* AU - Szeszenia-Dabrowska, N.* AU - Slopien, A.* AU - Hauser, J.* AU - Karhunen, L.* AU - Meulenbelt, I.* AU - Slagboom, P.E.* AU - Tortorella, A.* AU - Maj, M.* AU - Dedoussis, G.* AU - Dikeos, D.* AU - Gonidakis, F.* AU - Tziouvas, K.* AU - Tsitsika, A.* AU - Papezova, H.* AU - Slachtova, L.* AU - Martaskova, D.* AU - Kennedy, J.L.* AU - Levitan, R.D.* AU - Yilmaz, Z.* AU - Huemer, J.* AU - Koubek, D.* AU - Merl, E.* AU - Wagner, G.* AU - Lichtenstein, P.* AU - Breen, G.* AU - Cohen-Woods, S.* AU - Farmer, A.* AU - McGuffin, P.* AU - Cichon, S.* AU - Giegling, I.* AU - Herms, S.* AU - Rujescu, D.* AU - Schreiber, S.* AU - Wichmann, H.-E. AU - Dina, C.* AU - Sladek, R.* AU - Gambaro, G.* AU - Soranzo, N.* AU - Julià, A.* AU - Marsal, S.* AU - Rabionet, R.* AU - Gaborieau, V.* AU - Dick, D.M.* AU - Palotie, A.* AU - Ripatti, S.* AU - Widen, E.* AU - Andreassen, O.A.* AU - Espeseth, T.* AU - Lundervold, A.* AU - Reinvang, I.* AU - Steen, V.M.* AU - le Hellard, S.* AU - Mattingsdal, M.* AU - Ntalla, I.* AU - Bencko, V.* AU - Foretova, L.* AU - Janout, V.* AU - Navratilova, M.* AU - Gallinger, S.* AU - Pinto, D.* AU - Scherer, S.W.* AU - Aschauer, H.* AU - Carlberg, L.* AU - Schosser, A.* AU - Alfredsson, L.* AU - Ding, B.* AU - Klareskog, L.* AU - Padyukov, L.* AU - Courtet, P.* AU - Guillaume, S.* AU - Jaussent, I.* AU - Finan, C.* AU - Kalsi, G.* AU - Roberts, M.* AU - Logan, D.W.* AU - Peltonen, L.* AU - Ritchie, G.R.* AU - Barrett, J.C.* AU - Estivill, X.* AU - Hinney, A.* AU - Sullivan, P.F.* AU - Collier, D.A.* AU - Zeggini, E.* AU - Bulik, C.M.* C1 - 42815 C2 - 35344 CY - London SP - 1085-1094 TI - A genome-wide association study of anorexia nervosa. JO - Mol. Psychiatry VL - 19 IS - 10 PB - Nature Publishing Group PY - 2014 SN - 1359-4184 ER - TY - JOUR AB - Circulating triglycerides (TGs) normally increase after a meal but are altered in pathophysiological conditions, such as obesity. Although TG metabolism in the brain remains poorly understood, several brain structures express enzymes that process TG-enriched particles, including mesolimbic structures. For this reason, and because consumption of high-fat diet alters dopamine signaling, we tested the hypothesis that TG might directly target mesolimbic reward circuits to control reward-seeking behaviors. We found that the delivery of small amounts of TG to the brain through the carotid artery rapidly reduced both spontaneous and amphetamine-induced locomotion, abolished preference for palatable food and reduced the motivation to engage in food-seeking behavior. Conversely, targeted disruption of the TG-hydrolyzing enzyme lipoprotein lipase specifically in the nucleus accumbens increased palatable food preference and food-seeking behavior. Finally, prolonged TG perfusion resulted in a return to normal palatable food preference despite continued locomotor suppression, suggesting that adaptive mechanisms occur. These findings reveal new mechanisms by which dietary fat may alter mesolimbic circuit function and reward seeking. AU - Cansell, C.* AU - Castel, J.* AU - Denis, R.G.* AU - Rouch, C.* AU - Delbes, A.S.* AU - Martinez, S.* AU - Mestivier, D.* AU - Finan, B. AU - Maldonado-Aviles, J.G.* AU - Rijnsburger, M.* AU - Tschöp, M.H. AU - Dileone, R.J.* AU - Eckel, R.H.* AU - la Fleur, S.E.* AU - Magnan, C.* AU - Hnasko, T.S.* AU - Luquet, S.* C1 - 31074 C2 - 34140 CY - London SP - 1095-1105 TI - Dietary triglycerides act on mesolimbic structures to regulate the rewarding and motivational aspects of feeding. JO - Mol. Psychiatry VL - 19 IS - 10 PB - Nature Publishing Group PY - 2014 SN - 1359-4184 ER - TY - JOUR AB - Attention-deficit/hyperactivity disorder (ADHD) is a common, highly heritable neurodevelopmental disorder. Genetic loci have not yet been identified by genome-wide association studies. Rare copy number variations (CNVs), such as chromosomal deletions or duplications, have been implicated in ADHD and other neurodevelopmental disorders. To identify rare (frequency 1%) CNVs that increase the risk of ADHD, we performed a whole-genome CNV analysis based on 489 young ADHD patients and 1285 adult population-based controls and identified one significantly associated CNV region. In tests for a global burden of large (>500 kb) rare CNVs, we observed a nonsignificant (P=0.271) 1.126-fold enriched rate of subjects carrying at least one such CNV in the group of ADHD cases. Locus-specific tests of association were used to assess if there were more rare CNVs in cases compared with controls. Detected CNVs, which were significantly enriched in the ADHD group, were validated by quantitative (q)PCR. Findings were replicated in an independent sample of 386 young patients with ADHD and 781 young population-based healthy controls. We identified rare CNVs within the parkinson protein 2 gene (PARK2) with a significantly higher prevalence in ADHD patients than in controls (P=2.8 × 10(-4) after empirical correction for genome-wide testing). In total, the PARK2 locus (chr 6: 162 659 756-162 767 019) harboured three deletions and nine duplications in the ADHD patients and two deletions and two duplications in the controls. By qPCR analysis, we validated 11 of the 12 CNVs in ADHD patients (P=1.2 × 10(-3) after empirical correction for genome-wide testing). In the replication sample, CNVs at the PARK2 locus were found in four additional ADHD patients and one additional control (P=4.3 × 10(-2)). Our results suggest that copy number variants at the PARK2 locus contribute to the genetic susceptibility of ADHD. Mutations and CNVs in PARK2 are known to be associated with Parkinson disease. AU - Jarick, I.* AU - Volckmar, A.L.* AU - Pütter, C.* AU - Pechlivanis, S.* AU - Nguyen, T.T.* AU - Dauvermann, M.R.* AU - Beck, S.* AU - Albayrak, Ö.* AU - Scherag, S.* AU - Gilsbach, S.* AU - Cichon, S.* AU - Hoffmann, P.* AU - Degenhardt, F.* AU - Nöthen, M.M.* AU - Schreiber, S.* AU - Wichmann, H.-E. AU - Jöckel, K.-H.* AU - Heinrich, J. AU - Tiesler, C.M. AU - Faraone, S.V.* AU - Walitza, S.* AU - Sinzig, J.* AU - Freitag, C.* AU - Meyer, J.* AU - Herpertz-Dahlmann, B.* AU - Lehmkuhl, G.* AU - Renner, T.J.* AU - Warnke, A.* AU - Romanos, M.* AU - Lesch, K.P.* AU - Reif, A.* AU - Schimmelmann, B.G.* AU - Hebebrand, J.* AU - Scherag, A.* AU - Hinney, A.* C1 - 11862 C2 - 30886 SP - 115–121 TI - Genome-wide analysis of rare copy number variations reveals PARK2 as a candidate gene for attention-deficit/hyperactivity disorder. JO - Mol. Psychiatry VL - 19 IS - 1 PB - Nature Publishing PY - 2014 SN - 1359-4184 ER - TY - JOUR AB - Humans sleep approximately a third of their lifetime. The observation that individuals with either long or short sleep duration show associations with metabolic syndrome and psychiatric disorders suggests that the length of sleep is adaptive. Although sleep duration can be influenced by photoperiod (season) and phase of entrainment (chronotype), human familial sleep disorders indicate that there is a strong genetic modulation of sleep. Therefore, we conducted high-density genome-wide association studies for sleep duration in seven European populations (N=4251). We identified an intronic variant (rs11046205; P=3.99 × 10(-8)) in the ABCC9 gene that explains ≈5% of the variation in sleep duration. An influence of season and chronotype on sleep duration was solely observed in the replication sample (N=5949). Meta-analysis of the associations found in a subgroup of the replication sample, chosen for season of entry and chronotype, together with the discovery results showed genome-wide significance. RNA interference knockdown experiments of the conserved ABCC9 homologue in Drosophila neurons renders flies sleepless during the first 3 h of the night. ABCC9 encodes an ATP-sensitive potassium channel subunit (SUR2), serving as a sensor of intracellular energy metabolism. AU - Allebrandt, K.V.* AU - Amin, N.* AU - Müller-Myhsok, B.* AU - Esko, T.* AU - Teder-Laving, M.* AU - Azevedo, R.V.* AU - Hayward, C.* AU - van Mill, J.* AU - Vogelzangs, N.* AU - Green, E.W.* AU - Melville, S.A.* AU - Lichtner, P. AU - Wichmann, H.-E. AU - Oostra, B.A.* AU - Janssens, A.C.* AU - Campbell, H.* AU - Wilson, J.F.* AU - Hicks, A.A.* AU - Pramstaller, P.P.* AU - Dogas, Z.* AU - Rudan, I.* AU - Merrow, M.* AU - Penninx, B.* AU - Kyriacou, C.P.* AU - Metspalu, A.* AU - van Duijn, C.M.* AU - Meitinger, T. AU - Roenneberg, T.* C1 - 11853 C2 - 30834 SP - 122-132 TI - A KATP channel gene effect on sleep duration: From genome-wide association studies to function in Drosophila. JO - Mol. Psychiatry VL - 18 IS - 1 PB - Nature Publishing PY - 2013 SN - 1359-4184 ER - TY - JOUR AB - Coffee consumption is a model for addictive behavior. We performed a meta-analysis of genome-wide association studies (GWASs) on coffee intake from 8 Caucasian cohorts (N = 18 176) and sought replication of our top findings in a further 7929 individuals. We also performed a gene expression analysis treating different cell lines with caffeine. Genome-wide significant association was observed for two single-nucleotide polymorphisms (SNPs) in the 15q24 region. The two SNPs rs2470893 and rs2472297 (P-values = 1.6 x 10(-11) and 2.7 x 10(-11)), which were also in strong linkage disequilibrium (r(2) = 0.7) with each other, lie in the 23-kb long commonly shared 5' flanking region between CYP1A1 and CYP1A2 genes. CYP1A1 was found to be downregulated in lymphoblastoid cell lines treated with caffeine. CYP1A1 is known to metabolize polycyclic aromatic hydrocarbons, which are important constituents of coffee, whereas CYP1A2 is involved in the primary metabolism of caffeine. Significant evidence of association was also detected at rs382140 (P-value = 3.9 x 10(-09)) near NRCAM-a gene implicated in vulnerability to addiction, and at another independent hit rs6495122 (P-value = 7.1 x 10(-09))-an SNP associated with blood pressure-in the 15q24 region near the gene ULK3, in the meta-analysis of discovery and replication cohorts. Our results from GWASs and expression analysis also strongly implicate CAB39L in coffee drinking. Pathway analysis of differentially expressed genes revealed significantly enriched ubiquitin proteasome (P-value = 2.2 x 10(-05)) and Parkinson's disease pathways (P-value = 3.6 x 10(-05)). Molecular Psychiatry (2012) 17, 1116-1129; doi: 10.1038/mp.2011.101; published online 30 August 2011 AU - Amin, N.* AU - Byrne, E.* AU - Johnson, J.* AU - Chenevix-Trench, G.* AU - Walter, S.* AU - Nolte, I.M.* AU - Vink, J.M.* AU - Rawal, R. AU - Mangino, M.* AU - Teumer, A.* AU - Keers, J.C.* AU - Verwoert, G.* AU - Baumeister, S.* AU - Biffar, R.* AU - Petersmann, A.* AU - Dahmen, N.* AU - Döring, A. AU - Isaacs, A.* AU - Broer, L.* AU - Wray, N.R.* AU - Montgomery, G.W.* AU - Levy, D.* AU - Psaty, B.M.* AU - Gudnason, V.* AU - Chakravarti, A.* AU - Sulem, P.* AU - Gudbjartsson, D.F.* AU - Kiemeney, L.A.* AU - Thorsteinsdottir, U.* AU - Stefansson, K.* AU - van Rooij, F.J.A.* AU - Aulchenko, Y.S.* AU - Hottenga, J.J.* AU - Rivadeneira, F.R.* AU - Hofman, A.* AU - Uitterlinden, A.G.* AU - Hammond, C.J.* AU - Shin, S.Y.* AU - Ikram, A.* AU - Witteman, J.C.M.* AU - Janssens, A.C.J.W.* AU - Snieder, H.* AU - Tiemeier, H.* AU - Wolfenbuttel, B.H.R.* AU - Oostra, B.A.* AU - Heath, A.C.* AU - Wichmann, H.-E. AU - Spector, T.D.* AU - Grabe, H.J.* AU - Boomsma, D.I.* AU - Martin, N.G.* AU - van Duijn, C.M.* C1 - 11107 C2 - 30558 SP - 1116-1129 TI - Genome-wide association analysis of coffee drinking suggests association with CYP1A1/CYP1A2 and NRCAM. JO - Mol. Psychiatry VL - 17 IS - 11 PB - Nature Publishing Group PY - 2012 SN - 1359-4184 ER - TY - JOUR AB - Recent molecular studies have implicated common alleles of small to moderate effect and rare alleles with larger effect sizes in the genetic architecture of schizophrenia (SCZ). It is expected that the reliable detection of risk variants with very small effect sizes can only be achieved through the recruitment of very large samples of patients and controls (that is tens of thousands), or large, potentially more homogeneous samples that have been recruited from confined geographical areas using identical diagnostic criteria. Applying the latter strategy, we performed a genome-wide association study (GWAS) of 1169 clinically well characterized and ethnically homogeneous SCZ patients from a confined area of Western Europe (464 from Germany, 705 from The Netherlands) and 3714 ethnically matched controls (1272 and 2442, respectively). In a subsequent follow-up study of our top GWAS results, we included an additional 2569 SCZ patients and 4088 controls (from Germany, The Netherlands and Denmark). Genetic variation in a region on chromosome 11 that contains the candidate genes AMBRA1, DGKZ, CHRM4 and MDK was significantly associated with SCZ in the combined sample (n = 11 540; P = 3.89 x 10(-9), odds ratio (OR) = 1.25). This finding was replicated in 23 206 independent samples of European ancestry (P = 0.0029, OR= 1.11). In a subsequent imaging genetics study, healthy carriers of the risk allele exhibited altered activation in the cingulate cortex during a cognitive control task. The area of interest is a critical interface between emotion regulation and cognition that is structurally and functionally abnormal in SCZ and bipolar disorder. Molecular Psychiatry (2012) 17, 906-917; doi: 10.1038/mp.2011.80; published online 12 July 2011 AU - Rietschel, M.* AU - Mattheisen, M.* AU - Degenhardt, F.* AU - Mühleisen, T.W.* AU - Kirsch, P.* AU - Esslinger, C.* AU - Herms, S.* AU - Demontis, D.* AU - Steffens, M.* AU - Strohmaier, J.* AU - Haenisch, B.* AU - Breuer, R.* AU - Czerski, P.M.* AU - Giegling, I.* AU - Strengman, E.* AU - Schmael, C.* AU - Mors, O.* AU - Mortensen, P.B.* AU - Hougaard, D.M.* AU - Orntoft, T.* AU - Kapelski, P.* AU - Priebe, L.* AU - Basmanav, F.B.* AU - Forstner, A.J.* AU - Hoffmann, P.* AU - Meier, S.* AU - Nikitopoulos, J.* AU - Moebus, S.* AU - Alexander, M.* AU - Mössner, R.* AU - Wichmann, H.-E. AU - Schreiber, S.* AU - Rivandeneira, F.* AU - Hofman, A.* AU - Uitterlinden, A.G.* AU - Wienker, T.F.* AU - Schumacher, J.* AU - Hauser, J.* AU - Maier, W.* AU - Cantor, R.M.* AU - Erk, S.* AU - Schulze, T.G.* AU - Craddock, N.* AU - Owen, M.J.* AU - O'Donovan, M.C.* AU - Borglum, A.D.* AU - Rujescu, D.* AU - Walter, H.* AU - Meyer-Lindenberg, A.* AU - Nöthen, M.M.* AU - Ophoff, R.A.* AU - Cichon, S.* C1 - 8625 C2 - 30267 SP - 906-917 TI - Association between genetic variation in a region on chromosome 11 and schizophrenia in large samples from Europe. JO - Mol. Psychiatry VL - 17 IS - 9 PB - Nature Publishing Group PY - 2012 SN - 1359-4184 ER - TY - JOUR AB - Impaired sleep and enhanced stress hormone secretion are the hallmarks of stress-related disorders, including major depression. The central neuropeptide, corticotropin-releasing hormone (CRH), is a key hormone that regulates humoral and behavioral adaptation to stress. Its prolonged hypersecretion is believed to play a key role in the development and course of depressive symptoms, and is associated with sleep impairment. To investigate the specific effects of central CRH overexpression on sleep, we used conditional mouse mutants that overexpress CRH in the entire central nervous system (CRH-COE-Nes) or only in the forebrain, including limbic structures (CRH-COE-Cam). Compared with wild-type or control mice during baseline, both homozygous CRH-COE-Nes and -Cam mice showed constantly increased rapid eye movement (REM) sleep, whereas slightly suppressed non-REM sleep was detected only in CRH-COE-Nes mice during the light period. In response to 6-h sleep deprivation, elevated levels of REM sleep also became evident in heterozygous CRH-COE-Nes and -Cam mice during recovery, which was reversed by treatment with a CRH receptor type 1 (CRHR1) antagonist in heterozygous and homozygous CRH-COE-Nes mice. The peripheral stress hormone levels were not elevated at baseline, and even after sleep deprivation they were indistinguishable across genotypes. As the stress axis was not altered, sleep changes, in particular enhanced REM sleep, occurring in these models are most likely induced by the forebrain CRH through the activation of CRHR1. CRH hypersecretion in the forebrain seems to drive REM sleep, supporting the notion that enhanced REM sleep may serve as biomarker for clinical conditions associated with enhanced CRH secretion. AU - Kimura, M.* AU - Müller-Preuss, P.* AU - Lu, A.* AU - Wiesner, E.* AU - Flachskamm, C.* AU - Wurst, W. AU - Holsboer, F.* AU - Deussing, J.M.* C1 - 2963 C2 - 26835 SP - 154-165 TI - Conditional corticotropin-releasing hormone overexpression in the mouse forebrain enhances rapid eye movement sleep. JO - Mol. Psychiatry VL - 15 IS - 2 PB - Nature Publ. Group PY - 2010 SN - 1359-4184 ER - TY - JOUR AB - Hypersecretion of central corticotropin-releasing hormone (CRH) has been implicated in the pathophysiology of affective disorders. Both, basic and clinical studies suggested that disrupting CRH signaling through CRH type 1 receptors (CRH-R1) can ameliorate stress-related clinical conditions. To study the effects of CRH-R1 blockade upon CRH-elicited behavioral and neurochemical changes we created different mouse lines overexpressing CRH in distinct spatially restricted patterns. CRH overexpression in the entire central nervous system, but not when overexpressed in specific forebrain regions, resulted in stress-induced hypersecretion of stress hormones and increased active stress-coping behavior reflected by reduced immobility in the forced swim test and tail suspension test. These changes were related to acute effects of overexpressed CRH as they were normalized by CRH-R1 antagonist treatment and recapitulated the effect of stress-induced activation of the endogenous CRH system. Moreover, we identified enhanced noradrenergic activity as potential molecular mechanism underlying increased active stress-coping behavior observed in these animals. Thus, these transgenic mouse lines may serve as animal models for stress-elicited pathologies and treatments that target the central CRH system. AU - Lu, A.* AU - Steiner, M.A.* AU - Whittle, N.* AU - Vogl, A.M.* AU - Walser, S.M.* AU - Ableitner, M.* AU - Refojo, D.* AU - Ekker, M.* AU - Rubenstein, J.L.* AU - Stalla, G.K.* AU - Singewald, N.* AU - Holsboer, F.* AU - Wotjak, CT.* AU - Wurst, W. AU - Deussing, J.M.* C1 - 4252 C2 - 25903 SP - 1028-1042 TI - Conditional mouse mutants highlight mechanisms of corticotropin-releasing hormone effects on stress-coping behavior. JO - Mol. Psychiatry VL - 13 IS - 11 PB - Nature Publ. Group PY - 2008 SN - 1359-4184 ER - TY - CONF AU - Lu, A.* AU - Steiner, M.A.* AU - Whittle, N.* AU - Vogl, A.M.* AU - Walser, S.M.* AU - Ableitner, M.* AU - Refojo, D.* AU - Ekker, M.* AU - Rubenstein, J.L.* AU - Stalla, G.K.* AU - Singewald, N.* AU - Holsboer, F.* AU - Wotjak, C.T.* AU - Wurst, W. AU - Deussing, J.M.* C1 - 22845 C2 - 30030 SP - 989 TI - Conditional CRH overexpressing mice: An animal model for stress-elicited pathologies and treatments that target the central CRH system. JO - Mol. Psychiatry VL - 13 IS - 11 PB - Nature Publishing PY - 2008 SN - 1359-4184 ER - TY - JOUR AB - Angiotensin-converting enzyme (ACE) is assumed to influence the activity of the hypothalamic-pituitary-adrenocortical (HPA) system, which shows hyperactivity in the majority of patients with major depression. The ACE gene, known to be associated with cardiovascular disorders, which in turn are accompanied with an increased susceptibility for depression, is therefore a promising candidate gene for affective disorders. We investigated the genetic association between 35 single-nucleotide polymorphisms (SNPs) and an insertion/deletion (I/D)-polymorphism in the ACE gene and the susceptibility for unipolar major depression together with the genetic association with ACE serum activity and functional parameters of the HPA system. Two independent case/control samples with a total of 843 unrelated unipolar depressed patients and 1479 healthy controls were investigated. A case/control sample was screened to detect genetic associations with unipolar major depression. In addition, a replication sample was used to confirm the detected associations and to further investigate functional consequences of the genetic variants associated with depression. In the screening sample, two SNPs within the ACE gene were significantly associated with unipolar major depression. The association with unipolar major depression of one SNP (rs4291) located in the promoter region of the ACE gene was confirmed in our replication sample. The T-allele of this SNP was associated with depression and depressed T-allele carriers showed higher ACE serum activity and HPA-axis hyperactivity. Variants of the ACE gene such as SNP rs4291 are suggested susceptibility factors for unipolar major depression. We could show that SNP rs4291 influences ACE activity and HPA-axis hyperactivity and might therefore represent a common pathophysiologic link for unipolar depression and cardiovascular disease. AU - Baghai, T.C.* AU - Binder, E.B.* AU - Schule, C.* AU - Salyakina, D.* AU - Eser, D.* AU - Lucae, S.* AU - Zwanzger, P.* AU - Haberger, C.* AU - Zill, P.* AU - Ising, M.* AU - Deiml, T.* AU - Uhr, M.* AU - Illig, T. AU - Wichmann, H.-E. AU - Modell, S.* AU - Nothdurfter, C.* AU - Holsboer, F.* AU - Müller-Myhsok, B.* AU - Möller, H.J.* AU - Rupprecht, R.* AU - Bondy, B.* C1 - 1122 C2 - 24058 SP - 1003-1015 TI - Polymorphisms in the angiotensin-converting enzyme gene are associated wit unipolar depression, ACE activity and hypercortisolism. JO - Mol. Psychiatry VL - 11 IS - 11 PY - 2006 SN - 1359-4184 ER - TY - JOUR AU - Schumacher, J.* AU - Klopp, N. AU - Illig, T. C1 - 991 C2 - 22548 SP - 428-429 TI - Investigation of the DAOA/G30 locus in panic disorder. JO - Mol. Psychiatry VL - 10 IS - 5 PY - 2004 SN - 1359-4184 ER - TY - JOUR AU - Schmitz, C.* AU - Rhodes, M.E.* AU - Bludau, M.* AU - Kaplan, S.* AU - Ong, P.* AU - Ueffing, M. AU - Vehoff, J.* AU - Korr, H.* AU - Frye, C.A.* C1 - 22011 C2 - 20558 SP - 810-813 TI - Depression : Reduced number of granule cells in the hippocampus of female, but not male, rats due to prenatal restraint stress. JO - Mol. Psychiatry VL - 7 PY - 2002 SN - 1359-4184 ER - TY - JOUR AB - Schizophrenia is a common and etiologically heterogeneous disorder. Although inheritance of schizophrenic syndromes is complex with genetic and environmental factors contributing to the clinical phenotype, periodic catatonia, a familial subtype of catatonic schizophrenia, appears to be transmitted in an autosomal dominant manner. We report here that a Leu309Met mutation in WKL1, a positional candidate gene on chromosome 22q13.33 encoding a putative non-selective cation channel expressed exclusively in brain, co-segregates with periodic catatonia in an extended pedigree. Structural analyses revealed that this missense mutation results in conformational changes of the mutant protein. Our results not only underscore the importance of genetic mechanisms in the etiology of schizophrenic syndromes, but also provide a better understanding of the pathogenesis and incapacitating course of catatonic schizophrenia and related disorders. AU - Meyer, J.* AU - Huberth, A.* AU - Ortega, G.* AU - Syagailo, Y.V.* AU - Jatzke, S.* AU - Mössner, R.* AU - Strom, T.M. AU - Ulzheimer-Teuber, I.* AU - Stöber, G.* AU - Schmitt, A.* AU - Lesch, K.P.* C1 - 23587 C2 - 31386 SP - 302-306 TI - A missense mutation in a novel gene encoding a putative cation channel is associated with catatonic schizophrenia in a large pedigree. JO - Mol. Psychiatry VL - 6 IS - 3 PB - Nature Publishing Group PY - 2001 SN - 1359-4184 ER -