Polygenic prediction of cannabis‐related outcomes: Evidence from the Avon Longitudinal Study of Parents and Children longitudinal cohort and the European gene–environment interaction case–control study

Abstract Background and aims Polygenic risk scores (PRSs) for cannabis use disorder (CUD), major depressive disorder (MDD), insomnia and chronic pain, and early age at cannabis initiation might be linked to problematic cannabis use. We tested whether: (1) higher PRS for CUD, MDD, insomnia and chronic pain are associated with earlier initiation and problematic cannabis use; (2) age at cannabis initiation explains more variance in problematic use than any single PRS; and (3) PRSs moderate the association between early initiation and problematic cannabis use. Design Observational study involving two cohorts: (1) the Avon Longitudinal Study of Parents and Children (ALSPAC) population‐based birth cohort and (2) for conceptual replication, the EUropean Gene–Environment Interaction (EU‐GEI) first‐episode psychosis case–control study. Setting (1) United Kingdom; (2b) 16 population‐based catchment areas in Europe and 1 in Brazil, with FEP cases recruited from mental health services and controls from the general population of the same catchment areas. Participants For ALSPAC, n = 8224 genotyped (51% male); subsamples with Cannabis Abuse Screening Test (CAST) at 17 years ( n = 895), 20y ( n = 1587), 24y ( n = 836) and frequency of use at 24y ( n = 2908). EU‐GEI: n = 776 [controls: mean age 37.2, standard deviation (SD) = 13.5; 47% male] and 491 FEP cases (mean age 31.5, SD = 11.2; 62.5% male). Measurements Outcomes were self‐reported lifetime and frequency of cannabis use and CAST score (problematic use questionnaire). Predictors were PRSs for CUD, MDD, insomnia and chronic pain. Models were adjusted for sex, age and genetic principal components (ALSPAC), and additionally for site and case–control status (EU‐GEI). Results In ALSPAC, CUD PRS was associated with CAST score at 20 [beta coefficient (β) = 0.04, False Discovery Rate‐corrected P ‐value (p FDR ) = 0.03] and CAST at 24 years (β = 0.11, p FDR = 0.005). MDD PRS was associated with CAST scores at 17y (β = 0.1, p FDR = 0.002), 20y (β = 0.06, p FDR = 0.01) and 24y (β = 0.09, p FDR = 0.01). Pain PRS was associated with the CAST scores at 17y (β = 0.09, p FDR = 0.002), 20y (β = 0.07, p FDR < 0.001) and 24y (β = 0.09, p FDR = 0.005). In EU‐GEI, CUD PRS (RRR = 1.82, p FDR = 0.001) and pain PRS (RRR = 1.27, p FDR = 0.007) were associated with weekly‐to‐daily use. The Relative Excess Risk due to Interaction RERI model showed evidence of additive interaction for CUD PRS, RERI = 2.4, P = 0.009, while MDD and schizophrenia PRS showed no evidence of additive interaction. Summary Genetic liability, measured by polygenic risk scores, to cannabis use disorder, major depressive disorder, and chronic pain appears to be associated with heavier and more problematic cannabis use. Age at cannabis initiation explains more variance in problematic cannabis use than polygenic liability.