Depression negatively impacts health more than any other chronic disease2 and is a leading cause of total disease burden worldwide.3 Both genetic and environmental factors influence depression;4 research on the etiology of depression suggests substantial heritability of 40–50%.4–9 Only recently have genome-wide association studies (GWAS) begun to identify and replicate specific loci associated with depression.10–12 The findings from these studies suggest that (1) the effects of individual single nucleotide polymorphisms (SNPs) on major depressive disorder (MDD) are small in magnitude (requiring large sample sizes to detect), and (2) candidate genes generally do not show evidence of association in either GWAS or subsequent large-scale meta-analyses.13 Gene-environment interactions (G×E) (e.g., genetic variants whose influence on depression risk is only seen under specific environmental exposures) are one mechanism that may contribute to the complexity of identifying genetic associations with depression.14, 15
