Most psychiatric illnesses are relatively common, with lifetime prevalence rates in the range of 1%–40% of the population. By the mid-1990s, the common disease–common variant hypothesis was developed, suggesting that the genetic component of common diseases would be explained by common variants of a relatively limited number of genes, with each variant having a moderate or larger effect (4). For several diseases—including diabetes, macular degeneration, and Crohn's disease—this approach has been successful, with common variants of three to 100 genes explaining a significant portion of the heritability of the disorder (2). However, genomic contributions to psychiatric diseases have proven more difficult to elucidate. Psychiatric illness risk may be associated with a much larger number of genes, with each gene variant making only a very small contribution to genetic vulnerability. For example, although genetic contributions may account for up to 80% of the risk for schizophrenia, a recent analysis suggests that much of that risk may be explained by common variants of perhaps thousands of genes, each variant of extremely small effect, with even the largest effects accounting at most for 1%–2% of the genetic risk (5). If this is true, it may explain why large genome-wide association studies have failed to replicably identify specific genetic contributions.