Mediation models were subsequently examined to determine whether behavioral traits mediated the genetic association with cannabis outcomes. Neuroticism was a notable mediator of the association between rs6277, rs2576573, and rs2609997 and cannabis dependence; 15.3% to 19.5% association between the gene and cannabis dependence was explained by Neuroticism. None of the inhibitory control, reward learning or impulsive temperamental traits met criteria as mediators of the associations between any SNPs and cannabis dependence outcomes. We further examined the potential interaction (moderation) effect of having a genetic and temperamental risk focusing on Neuroticism, which was the most strongly associated with cannabis dependence. We categorized Neuroticism by median score into high and low Neuroticism groups and evaluated four groups: high genetic risk and high Neuroticism; high genetic risk and low Neuroticism, low genetic risk and high Neuroticism; neither risk (reference group). Figure 3 shows a clear evidence for additive interaction with AP being 0.67 (95% CI, 0.62–0.72), indicating 67% increased risk is due to synergy. Relative to the reference group, those with high Neuroticism (OR = 1.3, p = .85) or an at-risk SNP
