Genomewide Association Studies: History, Rationale, and Prospects for Psychiatric Disorders

Psychiatric GWAS Consortium Coordinating Committee

doi:10.1176/appi.ajp.2008.08091354

Cited by 450Genetic Associations and EpidemiologySchizophrenia research and treatmentGenetic Mapping and Diversity in Plants and Animals

Genomewide Association Studies: History, Rationale, and Prospects for Psychiatric Disorders

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Psychiatric GWAS Consortium Coordinating Committee·2009·American Journal of Psychiatry

DOI 10.1176/appi.ajp.2008.08091354PMC PMC3894622

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Abstract

OBJECTIVE: The authors conducted a review of the history and empirical basis of genomewide association studies (GWAS), the rationale for GWAS of psychiatric disorders, results to date, limitations, and plans for GWAS meta-analyses. METHOD: A literature review was carried out, power and other issues discussed, and planned studies assessed. RESULTS: Most of the genomic DNA sequence differences between any two people are common (frequency >5%) single nucleotide polymorphisms (SNPs). Because of localized patterns of correlation (linkage disequilibrium), 500,000 to 1,000,000 of these SNPs can test the hypothesis that one or more common variants explain part of the genetic risk for a disease. GWAS technologies can also detect some of the copy number variants (deletions and duplications) in the genome. Systematic study of rare variants will require large-scale resequencing analyses. GWAS methods have detected a remarkable number of robust genetic associations for dozens of common diseases and traits, leading to new pathophysiological hypotheses, although only small proportions of genetic variance have been explained thus far and therapeutic applications will require substantial further effort. Study design issues, power, and limitations are discussed. For psychiatric disorders, there are initial significant findings for common SNPs and for rare copy number variants, and many other studies are in progress. CONCLUSIONS: GWAS of large samples have detected associations of common SNPs and of rare copy number variants with psychiatric disorders. More findings are likely, since larger GWAS samples detect larger numbers of common susceptibility variants, with smaller effects. The Psychiatric GWAS Consortium is conducting GWAS meta-analyses for schizophrenia, bipolar disorder, major depressive disorder, autism, and attention deficit hyperactivity disorder. Based on results for other diseases, larger samples will be required. The contribution of GWAS will depend on the true genetic architecture of each disorder.

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For most GWAS variants associated with neuropsychiatric disease, the molecular mechanisms affecting the brain are poorly understood.
“for most of these variants, we have little understanding of the molecular mechanisms affecting the brain (7).”
From Comprehensive functional genomic resource and integrative model for the human brain (2018) · cites this paper as [7]
There have been multiple meta-analysis consortia in psychiatric genetics, of which the Psychiatric Genomics Consortium is the largest and most encompassing.
“there have been multiple meta-analysis 146,147 consortia in psychiatric genetics, of which the Psychiatric Genomics Consortium (http://pgc.unc.edu) is the largest and most encompassing. 123,148,149”
From Genetic architectures of psychiatric disorders: the emerging picture and its implications (2012) · cites this paper as [149]

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Authors: Psychiatric GWAS Consortium Coordinating Committee
Corresponding author: Psychiatric GWAS Consortium Coordinating Committee
Venue: American Journal of Psychiatry
Publisher: American Psychiatric Association Publishing
Published: 2009-05
Volume: 166
Issue: 5
Pages: 540-556
ISSN: 0002-953X (ISSN-L)
1535-7228
DOI: 10.1176/appi.ajp.2008.08091354
PMC: PMC3894622
OpenAlex: W2154246724
Cited by: 450
References: 95
Citations by year: 2026: 8 · 2025: 7 · 2024: 15 · 2023: 5 · 2022: 6 · 2021: 11 · 2020: 10 · 2019: 22 · 2018: 10 · 2017: 19 · 2016: 17 · 2015: 20 · 2014: 38 · 2013: 35 · 2012: 58
FWCI: 7.15
Type: journal article
Language: en
Open access: green
pure.amsterdamumc.nl
Licence: other-oa
Locations: American Journal of Psychiatry (publishedVersion)
PubMed (publishedVersion)
Pure Amsterdam UMC (publishedVersion, other-oa)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
VU Research Portal (submittedVersion)
Digital Academic REpository of VU University Amsterdam (Vrije Universiteit Amsterdam) (submittedVersion)
UCL Discovery (University College London) (submittedVersion)
Radboud Repository (Radboud University) (submittedVersion)
STM:n Hallinnonalan avoin julkaisuarkisto (Julkari) (submittedVersion)
Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
Funders: Eli Lilly and Company
Pfizer
Massachusetts General Hospital
Children's Hospital of Philadelphia
Vanderbilt University
Northwestern University
Harvard University
State University of New York
North Carolina State University
Helsingin Yliopisto
University of Washington
Johns Hopkins University
University of Pittsburgh
Virginia Commonwealth University
National Alliance for Research on Schizophrenia and Depression
McMaster University
Children’s Hospital of Wisconsin Research Institute
NorthShore University HealthSystem
Broad Institute
University College London
Cardiff University
Trinity College Dublin
Radboud Universiteit
Nederlandse Organisatie voor Wetenschappelijk Onderzoek (NWO 480‐05‐003, 480- 05-003)
University of Toronto
Universitetet i Oslo
Rheinische Friedrich-Wilhelms-Universität Bonn
National Institutes of Health
University of Illinois at Urbana-Champaign
University of North Carolina at Chapel Hill
University of California, San Diego
Feinberg School of Medicine
State University of New York Upstate Medical University
National Institute of Mental Health (R01MH062276, U01MH094411, U01MH085520, MH085520, R01MH083094, U01MH079470, R01MH061686)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Mapping and Diversity in Plants and Animals
Keywords: genome-wide association study, mental illness, single nucleotide polymorphisms, copy number variation, genetic risk, linkage disequilibrium, rare variants, genetic architecture, schizophrenia, bipolar disorder, major depressive disorder, autism spectrum disorder, attention deficit hyperactivity disorder, statistical power
MeSH terms: Alleles, Mental Disorders, Humans, Genetic Linkage, Phenotype, Linkage Disequilibrium, Genome, Polymorphism, Single Nucleotide, History, 20th Century, History, 21st Century

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Genomewide Association Studies: History, Rationale, and Prospects for Psychiatric Disorders

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