Genomic Relationships, Novel Loci, and Pleiotropic Mechanisms across Eight Psychiatric Disorders
Cross-Disorder Working Group of the Psychiatric Genomics Consortium
(2019) Cell, volume 179, issue 7, pp. 1469 - 1482.e11
(Article)
Abstract
Genetic influences on psychiatric disorders transcend diagnostic boundaries, suggesting substantial pleiotropy of contributing loci. However, the nature and mechanisms of these pleiotropic effects remain unclear. We performed analyses of 232,964 cases and 494,162 controls from genome-wide studies of anorexia nervosa, attention-deficit/hyperactivity disorder, autism spectrum disorder, bipolar disorder, major depression, obsessive-compulsive
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disorder, schizophrenia, and Tourette syndrome. Genetic correlation analyses revealed a meaningful structure within the eight disorders, identifying three groups of inter-related disorders. Meta-analysis across these eight disorders detected 109 loci associated with at least two psychiatric disorders, including 23 loci with pleiotropic effects on four or more disorders and 11 loci with antagonistic effects on multiple disorders. The pleiotropic loci are located within genes that show heightened expression in the brain throughout the lifespan, beginning prenatally in the second trimester, and play prominent roles in neurodevelopmental processes. These findings have important implications for psychiatric nosology, drug development, and risk prediction.
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Keywords: GWAS, Psychiatric genetics, cross-disorder genetics, functional genomics, gene expression, genetic architecture, genetic correlation, neurodevelopment, pleiotropy, psychiatric disorders, General Biochemistry,Genetics and Molecular Biology
ISSN: 0092-8674
Publisher: Cell Press
Note: Funding Information: J.W.S. is an unpaid member of the Bipolar/Depression Research Community Advisory Panel of 23andMe. H.R.K. (Henry R. Kranzler) is a member of the American Society of Clinical Psychopharmacology’s Alcohol Clinical Trials Initiative, which was supported in the last three years by AbbVie, Alkermes, Ethypharm, Indivior, Lilly, Lundbeck, Otsuka, Pfizer, Arbor, and Amygdala Neurosciences. H.R.K. and J.G. (Joel Gelernter) are named as inventors on PCT patent application #15/878,640 entitled: “Genotype-guided dosing of opioid agonists,” filed January 24, 2018. B.M.N. (Benjamin M. Neale) is a member of the Deep Genomics Scientific Advisory Board, a consultant for Camp4 Therapeutics Corporation, a consultant for Merck & Co., a consultant for Avanir Pharmaceuticals, Inc, and a consultant for Takeda Pharmaceutical. K.M.V. (Kirsten Müller-Vahl) has nonfinancial competing interests as a member of the TAA medical advisory board, the scientific advisory board of the German Tourette Association TGD, the board of directors of the German (ACM) and the International (IACM) Association for Cannabinoid Medicines, and the committee of experts for narcotic drugs at the federal opium bureau of the Federal Institute for Drugs and Medical Devices (BfArM) in Germany; has received financial or material research support from the EU (FP7-HEALTH-2011 No. 278367, FP7-PEOPLE-2012-ITN No. 316978), the German Research Foundation (DFG: GZ MU 1527/3-1), the German Ministry of Education and Research (BMBF: 01KG1421), the National Institute of Mental Health (NIMH), the Tourette Gesellschaft Deutschland e.V., the Else-Kroner-Fresenius-Stiftung, and GW, Almirall, Abide Therapeutics, and Therapix Biosiences; has served as a guest editor for Frontiers in Neurology on the research topic “The neurobiology and genetics of Gilles de la Tourette syndrome: new avenues through large-scale collaborative projects,” is an associate editor for “Cannabis and Cannabinoid Research” and an Editorial Board Member of “Medical Cannabis and Cannabinoids”; has received consultant’s honoraria from Abide Therapeutics, Fundacion Canna, Therapix Biosiences and Wayland Group, speaker’s fees from Tilray, and royalties from Medizinisch Wissenschaftliche Verlagsgesellschaft Berlin, and is a consultant for Zynerba Pharmaceuticals. J.I.N. has been an investigator for Assurex and is currently an investigator for Janssen. B.F. has received educational speaking fees from Medice and Shire. The other authors declare no competing interests. Funding Information: The work of the contributing groups was supported by numerous grants from governmental and charitable bodies as well as philanthropic donation. Specifically, P.H.L. (R00MH101367; R01MH119243), and J.W.S. (R01MH106547; R01MH117599; U01HG008685). The PGC has been supported by the following grants: MH085508, MH085513, MH085518, MH085520, MH094411, MH094421, MH094432, MH096296, MH109499, MH109501, MH109514, MH109528, MH109532, MH109536, MH109539. Funding for the work in Bipolar Disorder was supported by the Research Council of Norway (#223273 , 248778 , 262656 , 273291 , 283798 , 248828 ), South East Norway Health Authority ( 2017-112 ), and KG Jebsen Stiftelsen. Funding for the work in eating disorders was supported by grants from the Klarman Family Foundation , Swedish Research Council (Vetenskapsrådet: 538-2013-8864 ), National Institute of Mental Health ( K01MH106675 , K01 MH109782 , K01MH100435, R01MH119084 ), and NIAAA ( K01 AA025113 ). The iPSYCH project is supported by grants from the Lundbeck Foundation ( R165-2013-15320 , R102-A9118 , R155-2014-1724 and R248-2017-2003 ) and the universities and university hospitals of Aarhus and Copenhagen. Genotyping of iPSYCH samples was suppozrted by grants from the Lundbeck Foundation , the Stanley Foundation , the Simons Foundation (SFARI 311789 to M.J.D.), and NIMH ( 5U01MH094432-02 to M.J.D.). The Danish National Biobank resource was supported by the Novo Nordisk Foundation . Data handling and analysis on the GenomeDK HPC facility was supported by NIMH ( 1U01MH109514-01 to A.D.B.). High-performance computer capacity for handling and statistical analysis of iPSYCH data on the GenomeDK HPC facility was provided by the Center for Genomics and Personalized Medicine and the Centre for Integrative Sequencing, iSEQ, Aarhus University, Denmark (grant to ADB). Funding for the work in Tourette Syndrome/Obsessive Compulsive Disorder was supported by NIH grants U01NS040024 , R01NS016648 , K02NS085048 , R01 MH096767 , ARRA grants NS040024-09S1 and NS040024-07S1 , P30 NS062691 , R01MH092293 , R01MH092513 , R01MH092289 , R01MH071507 , R01MH079489 , R01MH079487 , R01MH079488 , R01MH079494 , R01MH002930-06 , R01MH073250 , and MH087748 , and grants from the Tourette Association of America and the David Judah Foundation . Funding support for the Study of Addiction: Genetics and Environment (SAGE) was provided through the NIH Genes, Environment, and Health Initiative [GEI] ( U01 HG004422 ); SAGE is one of the genome-wide association studies funded as part of the Gene Environment Association Studies (GENEVA) under the NIH GEI. Assistance with phenotype harmonization and genotype cleaning, as well as with general study coordination, was provided by the GENEVA Coordinating Center ( U01 HG004446 ). Assistance with data cleaning was provided by the National Center for Biotechnology Information . Support for collection of data sets and samples was provided by the Collaborative Study on the Genetics of Alcoholism ( U10 AA008401 ), the Collaborative Genetic Study of Nicotine Dependence (P01 CA089392), and the Family Study of Cocaine Dependence ( R01 DA013423 ). Funding support for genotyping, which was performed at the Johns Hopkins University Center for Inherited Disease Research, was provided by the NIH GEI ( U01HG004438 ), the National Institute on Alcohol Abuse and Alcoholism , NIDA , and the NIH contract “High Throughput Genotyping for Studying the Genetic Contributions to Human Disease” ( HHSN268200782096C ). The data sets used for the analyses described here were obtained from dbGaP ( https://www.ncbi.nlm.nih.gov/projects/gap/cgibin/study.cgi?study_id=phs000092.v1.p1 ). All research at Great Ormond Street Hospital NHS Foundation Trust and UCL Great Ormond Street Institute of Child Health is made possible by the NIHR Great Ormond Street Hospital Biomedical Research Centre. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. We thank the research participants and employees of 23andMe, Inc. for their contribution to this study. We are grateful to Emily Madsen for assistance with manuscript preparation. Funding Information: The work of the contributing groups was supported by numerous grants from governmental and charitable bodies as well as philanthropic donation. Specifically, P.H.L. (R00MH101367; R01MH119243), and J.W.S. (R01MH106547; R01MH117599; U01HG008685). The PGC has been supported by the following grants: MH085508, MH085513, MH085518, MH085520, MH094411, MH094421, MH094432, MH096296, MH109499, MH109501, MH109514, MH109528, MH109532, MH109536, MH109539. Funding for the work in Bipolar Disorder was supported by the Research Council of Norway (#223273, 248778, 262656, 273291, 283798, 248828), South East Norway Health Authority (2017-112), and KG Jebsen Stiftelsen. Funding for the work in eating disorders was supported by grants from the Klarman Family Foundation, Swedish Research Council (Vetenskapsrådet: 538-2013-8864), National Institute of Mental Health (K01MH106675, K01 MH109782, K01MH100435, R01MH119084), and NIAAA (K01 AA025113). The iPSYCH project is supported by grants from the Lundbeck Foundation (R165-2013-15320, R102-A9118, R155-2014-1724 and R248-2017-2003) and the universities and university hospitals of Aarhus and Copenhagen. Genotyping of iPSYCH samples was suppozrted by grants from the Lundbeck Foundation, the Stanley Foundation, the Simons Foundation (SFARI 311789 to M.J.D.), and NIMH (5U01MH094432-02 to M.J.D.). The Danish National Biobank resource was supported by the Novo Nordisk Foundation. Data handling and analysis on the GenomeDK HPC facility was supported by NIMH (1U01MH109514-01 to A.D.B.). High-performance computer capacity for handling and statistical analysis of iPSYCH data on the GenomeDK HPC facility was provided by the Center for Genomics and Personalized Medicine and the Centre for Integrative Sequencing, iSEQ, Aarhus University, Denmark (grant to ADB). Funding for the work in Tourette Syndrome/Obsessive Compulsive Disorder was supported by NIH grants U01NS040024, R01NS016648, K02NS085048, R01 MH096767, ARRA grants NS040024-09S1 and NS040024-07S1, P30 NS062691, R01MH092293, R01MH092513, R01MH092289, R01MH071507, R01MH079489, R01MH079487, R01MH079488, R01MH079494, R01MH002930-06, R01MH073250, and MH087748, and grants from the Tourette Association of America and the David Judah Foundation. Funding support for the Study of Addiction: Genetics and Environment (SAGE) was provided through the NIH Genes, Environment, and Health Initiative [GEI] (U01 HG004422); SAGE is one of the genome-wide association studies funded as part of the Gene Environment Association Studies (GENEVA) under the NIH GEI. Assistance with phenotype harmonization and genotype cleaning, as well as with general study coordination, was provided by the GENEVA Coordinating Center (U01 HG004446). Assistance with data cleaning was provided by the National Center for Biotechnology Information. Support for collection of data sets and samples was provided by the Collaborative Study on the Genetics of Alcoholism (U10 AA008401), the Collaborative Genetic Study of Nicotine Dependence (P01 CA089392), and the Family Study of Cocaine Dependence (R01 DA013423). Funding support for genotyping, which was performed at the Johns Hopkins University Center for Inherited Disease Research, was provided by the NIH GEI (U01HG004438), the National Institute on Alcohol Abuse and Alcoholism, NIDA, and the NIH contract “High Throughput Genotyping for Studying the Genetic Contributions to Human Disease” (HHSN268200782096C). The data sets used for the analyses described here were obtained from dbGaP (https://www.ncbi.nlm.nih.gov/projects/gap/cgibin/study.cgi?study_id=phs000092.v1.p1). All research at Great Ormond Street Hospital NHS Foundation Trust and UCL Great Ormond Street Institute of Child Health is made possible by the NIHR Great Ormond Street Hospital Biomedical Research Centre. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. We thank the research participants and employees of 23andMe, Inc. for their contribution to this study. We are grateful to Emily Madsen for assistance with manuscript preparation. Corresponding Authors: P.H.L. and J.W.S. (Lead Contact). Writing Group: P.H.L, Y.A.F. V.A. S.V.F. B.M.N. K.S.M. L.M.T. S.R. N.W. M.N. G.B. J.T.R.W. J.S. H.J.E. J.G. O.A.A. M.B.S. C.A.M. A.Y.F. S.S. M.M. A.Z. A.D.B. K.S.K. J.W.S. (Senior Author). Analysis Group: P.H.L. (Lead), V.A. H.W. Y.A.F, J.R. Z.Z. E.M.T-D. M.G.N. A.D.G, D.P. M.M. M-J, W. R.L.C. T.G. Disorder-specific data collection, analysis, and identification of duplicate subjects were conducted by D.Y. S.R. E.A.S. R.A. R.K.W. D.M. M.M. A.D.B. 23andMe, and L.E.D. Editorial Revisions Group: S.B. E.M.D. J.J.L. H.K. A.K. E.H.C. G.K. G.C. J.K. C.C.Z. P.J.H. T.B. L.A.R. B.F. J.I.N. The remaining authors contributed to the recruitment, genotyping, or data processing for the contributing components of the study. All other authors saw, had the opportunity to comment on, and approved the final draft. J.W.S. is an unpaid member of the Bipolar/Depression Research Community Advisory Panel of 23andMe. H.R.K. (Henry R. Kranzler) is a member of the American Society of Clinical Psychopharmacology's Alcohol Clinical Trials Initiative, which was supported in the last three years by AbbVie, Alkermes, Ethypharm, Indivior, Lilly, Lundbeck, Otsuka, Pfizer, Arbor, and Amygdala Neurosciences. H.R.K. and J.G. (Joel Gelernter) are named as inventors on PCT patent application #15/878,640 entitled: “Genotype-guided dosing of opioid agonists,” filed January 24, 2018. B.M.N. (Benjamin M. Neale) is a member of the Deep Genomics Scientific Advisory Board, a consultant for Camp4 Therapeutics Corporation, a consultant for Merck & Co. a consultant for Avanir Pharmaceuticals, Inc, and a consultant for Takeda Pharmaceutical. K.M.V. (Kirsten Müller-Vahl) has nonfinancial competing interests as a member of the TAA medical advisory board, the scientific advisory board of the German Tourette Association TGD, the board of directors of the German (ACM) and the International (IACM) Association for Cannabinoid Medicines, and the committee of experts for narcotic drugs at the federal opium bureau of the Federal Institute for Drugs and Medical Devices (BfArM) in Germany; has received financial or material research support from the EU (FP7-HEALTH-2011 No. 278367, FP7-PEOPLE-2012-ITN No. 316978), the German Research Foundation (DFG: GZ MU 1527/3-1), the German Ministry of Education and Research (BMBF: 01KG1421), the National Institute of Mental Health (NIMH), the Tourette Gesellschaft Deutschland e.V. the Else-Kroner-Fresenius-Stiftung, and GW, Almirall, Abide Therapeutics, and Therapix Biosiences; has served as a guest editor for Frontiers in Neurology on the research topic “The neurobiology and genetics of Gilles de la Tourette syndrome: new avenues through large-scale collaborative projects,” is an associate editor for “Cannabis and Cannabinoid Research” and an Editorial Board Member of “Medical Cannabis and Cannabinoids”; has received consultant's honoraria from Abide Therapeutics, Fundacion Canna, Therapix Biosiences and Wayland Group, speaker's fees from Tilray, and royalties from Medizinisch Wissenschaftliche Verlagsgesellschaft Berlin, and is a consultant for Zynerba Pharmaceuticals. J.I.N. has been an investigator for Assurex and is currently an investigator for Janssen. B.F. has received educational speaking fees from Medice and Shire. The other authors declare no competing interests. Publisher Copyright: © 2019 Elsevier Inc.
(Peer reviewed)