Most cases of psychiatric disorders are thought to result from complex interactions between multiple genes of mostly small to modest effect and the environment [1]. The identification of these genes and their function has proven to be an extraordinarily challenging endeavor, even using the popular and biologically agnostic genome-wide association (GWA) approach, which results in the potential identification of genes whose mechanisms of risk association are almost always unknown. This approach, as with earlier linkage and candidate gene approaches, has not produced incontrovertible evidence of association of common genetic variation with clinical diagnosis, though a few promising loci have been found. As psychiatric disorders are syndromal, analogous to most common medical illnesses, it is rational to assume that genetic association is stronger at the level of biological substrates related to syndromal risk. This is analogous to evidence that genes for common medical syndromal disorders show much stronger association to the biological substrates that contribute to risk. Examples include lipid levels and risk for heart disease [2], sodium homeostasis and risk for hypertension [3], and body mass index (BMI) and risk for diabetes [4].
