Thus, GWAS has been remarkably successful for many common diseases. Large multicenter samples have usually been required, and larger samples have detected more associations. Only a small part of the genetic risk for any one disease has been explained, but these discoveries have suggested new disease mechanisms and targets for therapy and prevention, although direct therapeutic applications will require substantial additional effort to characterize the biological mechanisms and develop new treatments. Some of the unexplained variance is likely to be due to other common SNPs (those that have smaller effects than can be detected with current sample sizes, or that are not tagged by the arrays, or were missed because of technical or sampling problems). The remaining variance may be due to rare SNPs, CNVs, other unsuspected genomic mechanisms, gene-gene or gene-environment interactions that have not been adequately modeled, and epigenetic effects. The results suggest that the largest possible samples should be studied by GWAS for each of the major psychiatric disorders, to test the hypothesis that common SNPs or detectable CNVs are involved in etiology. Positive findings could lead to important etiologic discoveries.
