Initial efforts to identify genetic variants associated with psychiatric risk employed a candidate gene approach. This methodology compared candidate genes thought to have large effect across samples of cases and controls. These studies ultimately failed to produce replicable findings due, in part, to extremely low statistical power. This low power reflects the highly polygenic nature of human complex traits, wherein the vast majority of outcomes are influenced by thousands of variants that individually explain a very small portion of the genetic variance in the population (Manolio et al., 2009; Visscher et al., 2017). This issue is further compounded by the observation that the field was generally poor at choosing the candidates. For example, a recent analysis for major depressive disorder found that the most popularly studied candidate genes evinced negligible associations in larger samples and were no more associated with depression phenotypes than genes selected at random (Border et al., 2019).
