Genomic Relationships, Novel Loci, and Pleiotropic Mechanisms across Eight Psychiatric Disorders

Wellcome Trust Case-Control Consortium; Cross-Disorder Group of the Psychiatric Genomics Consortium; 23andMe Research Team; Psychosis Endophenotypes International Consortium

doi:10.1016/j.cell.2019.11.020

Genomic Relationships, Novel Loci, and Pleiotropic Mechanisms across Eight Psychiatric Disorders

Wellcome Trust Case-Control Consortium, Cross-Disorder Group of the Psychiatric Genomics Consortium, 23andMe Research Team, Psychosis Endophenotypes International Consortium

Vagelos College of Physicians and Surgeons

Producción científica › revisión exhaustiva

787 Citas (Scopus)

Resumen

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 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.

Idioma original	English
Páginas (desde-hasta)	1469-1482.e11
Publicación	Cell
Volumen	179
N.º	7
DOI	https://doi.org/10.1016/j.cell.2019.11.020
Estado	Published - dic. 12 2019

Financiación

Financiadores	Número del financiador
Abide Therapeutics
Association for Cannabinoid Medicines
Camp4 Therapeutics Corporation
FP7-HEALTH-2011	316978, 278367, FP7-PEOPLE-2012-ITN
Fundacion Canna
GEI	U01 HG004422
GENEVA Coordinating Center	U01 HG004446
Gene Environment Association Studies
Genetics of Alcoholism	R01 DA013423, U10 AA008401, P01 CA089392
German Tourette Association TGD
Great Ormond Street Hospital NHS Foundation Trust
IACM
Medizinisch Wissenschaftliche Verlagsgesellschaft Berlin
National Center for Biotechnology Information
South East Norway Health Authority	2017-112
Therapix Biosiences
Therapix Biosiences and Wayland Group
Tilray
National Institutes of Health	K02NS085048, MH087748, R01 MH096767, R01NS016648, P30 NS062691, NS040024-09S1, R01MH002930-06, R01MH073250
National Institute of Mental Health	R00MH101367, R01MH071507, R01MH092513, R01MH119243, R01MH119084, R01MH092289, K01 MH109782, R01MH117599, R01MH079487, R01MH079494, R01MH092293, K01MH106675, R01MH079489, R01MH079488, 5U01MH094432-02, R01MH106547, K01MH100435
National Institute on Drug Abuse	HHSN268200782096C
National Institute on Alcohol Abuse and Alcoholism	K01 AA025113
Simons Foundation
Merck
Klarman Family Foundation
AbbVie
Aarhus Universitet
Johns Hopkins University	U01HG004438
Tourette Association of America
Janssen Pharmaceuticals
Stanley Foundation
Simons Foundation Autism Research Initiative	311789
Zynerba Pharmaceuticals
American Society of Clinical Psychopharmacology
National Institute for Health and Care Research
University College London
European Commission
Deutsche Forschungsgemeinschaft	GZ MU 1527/3-1
Bundesministerium für Bildung und Forschung	01KG1421
Else Kröner-Fresenius-Stiftung
Lundbeckfonden	R155-2014-1724, R248-2017-2003, R102-A9118, R165-2013-15320
Vetenskapsrådet	538-2013-8864
Norges Forskningsråd	223273, 248828, 283798, 248778, 262656, 273291
Novo Nordisk Fonden	1U01MH109514-01
Faculty of Science, Agriculture and Engineering, Newcastle University
NIHR Great Ormond Street Hospital Biomedical Research Centre
Tourette Gesellschaft Deutschland

ASJC Scopus Subject Areas

General Biochemistry,Genetics and Molecular Biology

Acceder al documento

10.1016/j.cell.2019.11.020

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Wellcome Trust Case-Control Consortium, Cross-Disorder Group of the Psychiatric Genomics Consortium, 23andMe Research Team, & Psychosis Endophenotypes International Consortium (2019). Genomic Relationships, Novel Loci, and Pleiotropic Mechanisms across Eight Psychiatric Disorders. Cell, 179(7), 1469-1482.e11. https://doi.org/10.1016/j.cell.2019.11.020

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title = "Genomic Relationships, Novel Loci, and Pleiotropic Mechanisms across Eight Psychiatric Disorders",

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 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.",

author = "{Wellcome Trust Case-Control Consortium} and {Cross-Disorder Group of the Psychiatric Genomics Consortium} and {23andMe Research Team} and {Psychosis Endophenotypes International Consortium} and Lee, {Phil H.} and Verneri Anttila and Hyejung Won and Feng, {Yen Chen A.} and Jacob Rosenthal and Zhaozhong Zhu and Tucker-Drob, {Elliot M.} and Nivard, {Michel G.} and Grotzinger, {Andrew D.} and Danielle Posthuma and Wang, {Meg M.J.} and Dongmei Yu and Stahl, {Eli A.} and Walters, {Raymond K.} and Anney, {Richard J.L.} and Duncan, {Laramie E.} and Tian Ge and Rolf Adolfsson and Tobias Banaschewski and Sintia Belangero and Cook, {Edwin H.} and Giovanni Coppola and Derks, {Eske M.} and Hoekstra, {Pieter J.} and Jaakko Kaprio and Anna Keski-Rahkonen and George Kirov and Kranzler, {Henry R.} and Luykx, {Jurjen J.} and Rohde, {Luis A.} and Zai, {Clement C.} and Esben Agerbo and Arranz, {M. J.} and Philip Asherson and Marie B{\ae}kvad-Hansen and G{\'i}sli Baldursson and Mark Bellgrove and Belliveau, {Richard A.} and Jan Buitelaar and Burton, {Christie L.} and Jonas Bybjerg-Grauholm and Miquel Casas and Felecia Cerrato and Kimberly Chambert and Claire Churchhouse and Bru Cormand and Jennifer Crosbie and S{\o}ren Dalsgaard and Ditte Demontis and Weissman, {Myrna M.}",

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AU - Psychosis Endophenotypes International Consortium

AU - Lee, Phil H.

AU - Anttila, Verneri

AU - Won, Hyejung

AU - Feng, Yen Chen A.

AU - Rosenthal, Jacob

AU - Zhu, Zhaozhong

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AU - Crosbie, Jennifer

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AU - Demontis, Ditte

AU - Weissman, Myrna M.

PY - 2019/12/12

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N2 - 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 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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Genomic Relationships, Novel Loci, and Pleiotropic Mechanisms across Eight Psychiatric Disorders

Resumen

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ASJC Scopus Subject Areas

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