In interpreting these results, it is important to note that, consistent with prior behavioral, psychiatric, and neuro-genetics studies (Duncan & Keller, 2011; Flint & Munafo, 2013; Hibar et al., 2015), the effects reported in this study are small, explaining only 0.5-1.3% of variation in our outcome phenotypes. As such, these findings alone will not be practically informative at an individual level. Additionally, evidence suggests that many published GxE results may represent type-I errors, leading to low replication rates (Duncan & Keller, 2011). Interactions between genes and environment, relative to main effects of genotype, are particularly susceptible to increased rates of false positives due to low prior probabilities of interaction, reduced variance of the interaction term, and the potential for unmodeled nonlinearity (see Dick et al., 2015, for review). However, within the current study, the convergence of evidence across three samples implicating rs604300 in individual differences in both cannabis dependence symptoms and a psychiatrically relevant neural phenotype in the context of childhood adversity pinpoints a target within the endocannabinoid system worthy of future replication and extension.
