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

Psychiatric GWAS Consortium Coordinating Committee, Martin, N., Wray, N., Mowry, B. and Holliday, E. (2009) Genomewide Association Studies: History, Rationale, and Prospects for Psychiatric Disorders. American Journal of Psychiatry, 166 5: 540-556. doi:10.1176/appi.ajp.2008.08091354


Author Psychiatric GWAS Consortium Coordinating Committee
Martin, N.
Wray, N.
Mowry, B.
Holliday, E.
Title Genomewide Association Studies: History, Rationale, and Prospects for Psychiatric Disorders
Journal name American Journal of Psychiatry   Check publisher's open access policy
ISSN 0002-953X
Publication date 2009-01-01
Year available 2009
Sub-type Critical review of research, literature review, critical commentary
DOI 10.1176/appi.ajp.2008.08091354
Open Access Status Not yet assessed
Volume 166
Issue 5
Start page 540
End page 556
Total pages 17
Place of publication Arlington, VA United States
Publisher American Psychiatric Publishing
Language eng
Subject 2738 Psychiatry and Mental health
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.
Formatted 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.
Keyword Psychiatry
Psychiatry
PSYCHIATRY, SCI
PSYCHIATRY, SSCI
Q-Index Code C1
Q-Index Status Provisional Code
Grant ID U01 MH094411
Institutional Status UQ

Document type: Journal Article
Sub-type: Critical review of research, literature review, critical commentary
Collections: Queensland Brain Institute Publications
School of Medicine Publications
 
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