The intermediary role of adolescent temperamental and behavioral traits on the prospective associations between polygenic risk and cannabis use among young adults of European Ancestry.

BACKGROUND AND AIMS Cannabis use (CU) is an etiologically complex behavior with several social, temperamental, neurocognitive, and behavioral precursors. Biometrical and molecular studies suggest an interplay of environmental and pleiotropic influences. However, it remains unclear whether identified genetic effects related to behavioral and temperamental characteristics have developmentally direct or indirect mechanisms on CU behavior. The Transmissible Liability Index (TLI) is a measure of continuous liability based on developmental precursors of substance use disorders. This study aimed to examine if the TLI plays a role in understanding genetic risk for CU behaviors. DESIGN Genome-wide association studies [n>10,000; European Ancestry (EA)] of CU, risk tolerance, neuroticism, anxiety, and depression were used to construct polygenic scores (PGSs). Analyses assessed whether PGSs indirectly impacted risk for repeated use via TLI. SETTING USA. PARTICIPANTS From Add Health study, 4077 individuals of EA aged 11-21 during baseline interview collection. MEASUREMENTS Outcomes were initiation and repeated cannabis use (>5x in lifetime). The TLI was parameterized using a latent factor from 21 questions assessing for precursors of disordered use. FINDINGS The marker-based heritability of TLI, initiation, and repeated use were significant, but modest (14%, p=0.033; 15%, p=0.025; and 17%, p=0.008, respectively). TLI and repeated use were genetically correlated (rg = 0.76, p=0.033). The PGS for CU was associated with increased risk for repeated use and PGS for risk tolerance and depression were associated with TLI. Mediation analyses indicated significant, but very weak, indirect effects of PGS for risk tolerance and depression on repeated CU via the TLI. CONCLUSIONS Adolescent behavioral and temperamental characteristics (i.e., the Transmissible Liability Index (TLI)) appear to be early indicators of repeated cannabis use (CU) in adulthood. While polygenic scores (PGSs) for CU directly increased risk for repeated CU, weak evidence was found for the role of PGSs of other internalizing/externalizing traits acting through adolescent derived TLI on CU behavior.