Impulsivity behaviors and white matter mediate the relationship between genetic risk for cannabis use disorder and early cannabis use in adolescents

Cannabis use disorder (CUD) is strongly influenced by genetic factors; however the mechanisms underpinning this association are not well understood. This study investigated whether a polygenic risk score (PRS) based on a genome-wide association study for CUD in adults predicts cannabis use in adolescents and whether the association can be explained by inter-individual variation in structural properties of brain white matter or risk-taking behaviors. Longitudinal and cross-sectional analyses using data from the IMAGEN cohort, a European longitudinal study integrating genetic, neuroimaging and behavioral measures. We measured associations between PRS for CUD, novelty and sensation seeking traits and fractional anisotropy (FA) of white matter tracts. Mediation modeling explored whether novelty seeking and FA mediated the association between the PRS and cannabis use. Participants were assessed at 14 (n = 1762), 19 (n = 1175) and 23 (n = 1139) years old. European School Survey Project on Alcohol and Other Drugs, substance use risk profile scale, Fagerstrom Test for Nicotine Dependence, temperament and character inventory, Kirby Monetary Questionnaire, diffusor tensor imaging and CUD-PRS. CUD-PRS was associated with adolescent total cannabis exposure [P