We next leveraged data from a published study in which neuropsychological and behavioral measures were collected in adult drug (cannabis) dependent and non-dependent subjects30. In more details, rs12765063 significantly associated with increased impulsivity (β=3.21, t97=3.33, p=0.001) and decreased persistence (β=−12.12, t97=−2.25, p=0.027, Fig. 4e), with the association with impulsivity particularly strong in dependent individuals (β=3.71, t48=3.46, p=0.001, Supplementary Fig. 9a). Based on statistical mediation modeling, impulsivity mediated the association between CREM and dependence severity (PM=77%, Z=2.88, p=0.004, Fig. 4f, Supplementary Fig. 9b) even after incorporating self-reported race, gender and age as covariates (PM=63%, Z=2.72, p=0.007). No other trait except negative affect (β=3.63, t97=2.55, p=0.013) associated with this polymorphism. Overall, these findings support a genotype-phenotype association between CREM and impulsivity in the genetic link to addiction vulnerability.
