Time-Varying Environmental and Polygenic Predictors of Substance Use Initiation in Youth: A Survival and Causal Modeling Study in the ABCD Cohort

Original Abstract

Early initiation of alcohol, nicotine, cannabis, and other substances predicts later substance use disorders and related psychopathology. We integrate time-varying environmental factors with polygenic risk scores (PRS) in a longitudinal framework to identify determinants of substance initiation in adolescence. Using data from the Adolescent Brain Cognitive Development (ABCD) Study with repeated assessments over approximately four years, we defined time-to-event outcomes for first use of alcohol, nicotine, cannabis, and any substance. We constructed high-dimensional panels of time-varying environmental covariates across family, school, neighborhood, behavioral, and health domains, alongside time-invariant covariates and PRS for alcohol, cannabis, nicotine, and general substance use disorders. Time-varying Cox models with clustered standard errors were applied. Univariate analyses showed broad associations between earlier initiation and multiple environmental domains, including impulsivity, sleep disturbance, parental monitoring, caffeine use, and school functioning. In multivariable models, a smaller set of predictors remained robust, particularly impulsivity traits, parental monitoring, and selected health and lifestyle factors. PRS were positively associated with earlier initiation, with the strongest and most consistent effects for nicotine-related genetic risk. Secondary analyses using marginal structural models suggested that higher parental monitoring is protective, whereas higher impulsivity and caffeine exposure are associated with increased risk. These results demonstrate that integrating dynamic environmental exposures with genetic liability can identify key risk factors for adolescent substance initiation and highlight actionable targets for prevention.