In a previous review [21] we asked whether the mean effect size of loci that contribute to psychiatric disease was different from the mean effect size of loci contributing to variation in intermediate phenotypes. We posed this question because larger effect sizes are easier to detect, requiring smaller sample sizes (in other words, the phenotypes are more genetically tractable). Since statistical power is proportional to the square of the effect size, if effect sizes are halved, then four times the sample size is required for their detection. Therefore, if genetic loci contributing to variation in intermediate phenotypes have larger effects sizes than loci contributing to psychiatric disease, it would make sense for genetic studies to focus on intermediate phenotypes (Figure 1). Our conclusion at that time was that the genetic basis of intermediate phenotypes appeared to be at least as complex as that of psychiatric disease, with no clear evidence of substantially larger individual effects [21]. However, we cautioned that we had little reliable data about the genetic architecture of complex traits in humans.
