We have also reviewed some of the potential explanations for the lack of success to date for GWAS and GxE studies of depression. Given the established heritability of depression, there is every reason to expect that increasingly well-powered studies will indeed identify risk loci. However, the genetic and phenotypic complexity of depression may mean that such successes will require samples on the order of tens of thousands of participants. Efforts to parse the heterogeneity of depression and validate phenotypic subtypes may also be essential to facilitate gene identification. Further, as we have noted, potentially important areas of the genetic basis of depression--specifically, rare variation and GxE--remain relatively unexplored on a large-scale. It remains to be seen how much of the “missing heritability” of depression will be revealed thorough studies of these components.
