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

Research output: Contribution to journal › Article › peer-review

821 Scopus citations

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.

Original language	English
Pages (from-to)	1469-1482.e11
Journal	Cell
Volume	179
Issue number	7
DOIs	https://doi.org/10.1016/j.cell.2019.11.020
State	Published - 12 Dec 2019

Funding

Funders	Funder number
Therapix Biosiences
Tourette Association of America
Great Ormond Street Hospital NHS Foundation Trust
Merck
Therapix Biosiences and Wayland Group
Zynerba Pharmaceuticals
Else Kröner-Fresenius-Stiftung
National Center for Biotechnology Information
Aarhus Universitet
Tourette Gesellschaft Deutschland
Medizinisch Wissenschaftliche Verlagsgesellschaft Berlin
IACM
AbbVie
German Tourette Association TGD
National Institute for Health and Care Research
Camp4 Therapeutics Corporation
Stanley Foundation
European Commission
Faculty of Science, Agriculture and Engineering, Newcastle University
Janssen Pharmaceuticals
University College London
Fundacion Canna
Tilray
Klarman Family Foundation
Association for Cannabinoid Medicines
Abide Therapeutics
NIHR Great Ormond Street Hospital Biomedical Research Centre
Simons Foundation
Gene Environment Association Studies
American Society of Clinical Psychopharmacology
National Institute of Neurological Disorders and Stroke	K02NS085048, R01NS016648, U01NS040024, P30NS062691
National Institute of Mental Health	R00MH101367, R01MH071507, R01MH092289, U01MH085520, U01MH109501, R01MH117599, R00MH113823, R01MH079494, K01MH106675, U01MH094421, K01MH109765, U01MH109528, R21MH087748, K01MH100435, U01MH085518, R01MH092513, R01MH119243, U01MH085513, R01MH119084, R13MH073250, DP2MH122403, R01MH113362, K01MH109782, U01MH109514, U01MH109536, R01MH079487, U01MH109499, U01MH109532, R01MH092293, K01MH113848, R01MH079489, U01MH094432, R01MH079488, U01MH109539, U01MH094411, R01MH096767, R01MH106547, U01MH096296, U01MH085508
National Human Genome Research Institute	U01HG008685, U01HG004446, U01HG004422, U01HG004438
Bundesministerium für Bildung und Forschung	01KG1421
GENEVA Coordinating Center	U01 HG004446
National Institute on Drug Abuse	HHSN268200782096C, R01DA013423
Novo Nordisk Fonden	1U01MH109514-01
National Cancer Institute	P01CA089392
Simons Foundation Autism Research Initiative	311789, 5U01MH094432-02
Seventh Framework Programme	316978, 278367
GEI	U01 HG004422
Johns Hopkins University	U01HG004438
Lundbeckfonden	R155-2014-1724, R248-2017-2003, R165-2013-15320, R102-A9118
FP7-HEALTH-2011	FP7-PEOPLE-2012-ITN
Genetics of Alcoholism	R01 DA013423, U10 AA008401, P01 CA089392
National Institute on Alcohol Abuse and Alcoholism	U10AA008401, K01AA025113
South East Norway Health Authority	2017-112
Deutsche Forschungsgemeinschaft	GZ MU 1527/3-1
Vetenskapsrådet	538-2013-8864
National Institutes of Health	R01MH002930-06
Norges Forskningsråd	248828, 223273, 283798, 248778, 262656, 273291

Keywords

GWAS
Psychiatric genetics
cross-disorder genetics
functional genomics
gene expression
genetic architecture
genetic correlation
neurodevelopment
pleiotropy
psychiatric disorders

Access to Document

10.1016/j.cell.2019.11.020

Cite this

@article{7e7c52a2d10943988d19070b42f16202,

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.",

keywords = "GWAS, Psychiatric genetics, cross-disorder genetics, functional genomics, gene expression, genetic architecture, genetic correlation, neurodevelopment, pleiotropy, psychiatric disorders",

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 Mark Weiser and Stein, {Dan J.}",

note = "Publisher Copyright: {\textcopyright} 2019 Elsevier Inc.",

year = "2019",

month = dec,

day = "12",

doi = "10.1016/j.cell.2019.11.020",

language = "אנגלית",

volume = "179",

pages = "1469--1482.e11",

journal = "Cell",

issn = "0092-8674",

publisher = "Elsevier B.V.",

number = "7",

}

TY - JOUR

T1 - Genomic Relationships, Novel Loci, and Pleiotropic Mechanisms across Eight Psychiatric Disorders

AU - Wellcome Trust Case-Control Consortium

AU - Cross-Disorder Group of the Psychiatric Genomics Consortium

AU - 23andMe Research Team

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

AU - Tucker-Drob, Elliot M.

AU - Nivard, Michel G.

AU - Grotzinger, Andrew D.

AU - Posthuma, Danielle

AU - Wang, Meg M.J.

AU - Yu, Dongmei

AU - Stahl, Eli A.

AU - Walters, Raymond K.

AU - Anney, Richard J.L.

AU - Duncan, Laramie E.

AU - Ge, Tian

AU - Adolfsson, Rolf

AU - Banaschewski, Tobias

AU - Belangero, Sintia

AU - Cook, Edwin H.

AU - Coppola, Giovanni

AU - Derks, Eske M.

AU - Hoekstra, Pieter J.

AU - Kaprio, Jaakko

AU - Keski-Rahkonen, Anna

AU - Kirov, George

AU - Kranzler, Henry R.

AU - Luykx, Jurjen J.

AU - Rohde, Luis A.

AU - Zai, Clement C.

AU - Agerbo, Esben

AU - Arranz, M. J.

AU - Asherson, Philip

AU - Bækvad-Hansen, Marie

AU - Baldursson, Gísli

AU - Bellgrove, Mark

AU - Belliveau, Richard A.

AU - Buitelaar, Jan

AU - Burton, Christie L.

AU - Bybjerg-Grauholm, Jonas

AU - Casas, Miquel

AU - Cerrato, Felecia

AU - Chambert, Kimberly

AU - Churchhouse, Claire

AU - Cormand, Bru

AU - Crosbie, Jennifer

AU - Dalsgaard, Søren

AU - Weiser, Mark

AU - Stein, Dan J.

PY - 2019/12/12

Y1 - 2019/12/12

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.

AB - 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.

KW - GWAS

KW - Psychiatric genetics

KW - cross-disorder genetics

KW - functional genomics

KW - gene expression

KW - genetic architecture

KW - genetic correlation

KW - neurodevelopment

KW - pleiotropy

KW - psychiatric disorders

UR - http://www.scopus.com/inward/record.url?scp=85076270049&partnerID=8YFLogxK

U2 - 10.1016/j.cell.2019.11.020

DO - 10.1016/j.cell.2019.11.020

M3 - ???researchoutput.researchoutputtypes.contributiontojournal.article???

C2 - 31835028

AN - SCOPUS:85076270049

SN - 0092-8674

VL - 179

SP - 1469-1482.e11

JO - Cell

JF - Cell

IS - 7

ER -

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

Abstract

Funding

Keywords

Access to Document

Other files and links

Fingerprint

Cite this