Psychiatric Genetics and the Generation of Mutant Animal Models

Accumulating evidence indicates that the genetic architecture of psychiatric disorders does not strictly conform to the common disease/common allele hypothesis. The contribution of common genetic variants, while likely, may be fundamentally different from those of rare genetic variants. It is possible that common alleles do not increase disease risk per se but are disease modifiers sculpting the psychopathological landscape produced by rare alleles. Unlike common alleles, the statistical association of rare alleles is usually more robust and their functional effects more translatable into etiologically valid animal models. Although rare alleles may not be shared across individuals with the same diagnosis, the comparison of multiple animal models of rare risk alleles can identify common pathogenetic mechanisms. Thus, paradoxically, the cumulative evidence gathered from these animal models is currently poised to offer more insight into common psychiatric disorders than are models of common alleles.