Based on prior evidence (a) supporting the role of the eCB system and related genes in cannabis dependence, (b) that childhood adversity confers risk for substance use disorders, and (c) of interactions between the eCB system and neural systems underlying threat and stress responsivity, we first examined whether CSA moderates associations between genetic variation across the eCB system and cannabis dependence symptoms (Sample 1 N = 1,558). Second, we attempted to replicate any interactions with sexual/physical abuse in an independent sample (Sample 2 N = 859). Third, in light of evidence that the eCB system plays a prominent role in fear extinction and amygdala-driven stress reactivity, we examined whether any variants associated with cannabis dependence symptoms in the context of CSA predicted early life stress (ELS)-related differences in amygdala habituation (Sample 3 N = 312). Independent and dependent variables used across studies are described in Table 2. In addition to traditional single-SNP analyses within the eCB system, we employed gene-based analyses in our discovery sample that aggregated effects across SNPs within a gene.
