GWASmethods2009 - Reviews and Overviews Genomewide...

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540 Am J Psychiatry 166:5, May 2009 Reviews and Overviews ajp.psychiatryonline.org Genomewide Association Studies: History, Rationale, and Prospects for Psychiatric Disorders Psychiatric GWAS Consortium Coordinating Committee Objective: The authors conducted a re- view of the history and empirical basis of genomewide association studies (GWAS), the rationale for GWAS of psychiatric dis- orders, 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 se- quence differences between any two peo- ple are common (frequency >5%) single nucleotide polymorphisms (SNPs). Be- cause of localized patterns of correlation (linkage disequilibrium), 500,000 to 1,000,000 of these SNPs can test the hy- pothesis that one or more common vari- ants explain part of the genetic risk for a disease. GWAS technologies can also de- tect some of the copy number variants (deletions and duplications) in the ge- nome. Systematic study of rare variants will require large-scale resequencing anal- yses. GWAS methods have detected a re- markable number of robust genetic asso- ciations for dozens of common diseases and traits, leading to new pathophysio- logical hypotheses, although only small proportions of genetic variance have been explained thus far and therapeutic applications will require substantial fur- ther effort. Study design issues, power, and limitations are discussed. For psychi- atric 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 de- tect larger numbers of common suscepti- bility variants, with smaller effects. The Psychiatric GWAS Consortium is conduct- ing GWAS meta-analyses for schizophre- nia, bipolar disorder, major depressive disorder, autism, and attention deficit hy- peractivity disorder. Based on results for other diseases, larger samples will be re- quired. The contribution of GWAS will de- pend on the true genetic architecture of each disorder. (Am J Psychiatry 2009; 166:540–556) S ince 2005 (1), genomewide association studies (GWAS [je¯´wo ¯s]) have produced strongly significant evi- dence that specific common DNA sequence differences among people influence their genetic susceptibility to more than 40 different common diseases (2). Many of these findings implicate previously unsuspected candi- date genes and new pathophysiological hypotheses. The method is feasible because millions of human DNA se- quence variations have been catalogued and new technol- ogies have been developed that can assay more than one million variants rapidly and accurately. The first GWAS re- ports have appeared for psychiatric disorders, and nearly
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GWASmethods2009 - Reviews and Overviews Genomewide...

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