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

Background: Early initiation of alcohol, nicotine, cannabis, and other substances is a robust predictor of later substance use disorders and related psychopathology. We integrate time-varying environmental factors with polygenic risk scores (PRS) in a longitudinal framework to identify risk factors influencing substance initiation in adolescents. Methods: with repeated assessments from baseline through approximately four years of follow-up. For each substance (alcohol, nicotine, cannabis, and any substance), we defined a time-to-event outcome indexing age at first use. We assembled a high-dimensional panel of time-varying environmental covariates across multiple domains (family, neighborhood, school, mental health, cognition, and physical health etc.), along with time-invariant covariates and PRS for problematic alcohol use, cannabis use disorder, nicotine use disorder, and any substance use disorder. We constructed individual-level start-stop interval data using interview age in months and fitted time-varying Cox proportional hazards models with robust standard errors clustered by individual ID. First, we conducted univariate models for each predictor. Second, for each outcome, we fitted multivariable Cox models including core covariates (sex, age, site, ancestry principal components), all PRS, and selected predictors. In secondary analyses, we applied marginal structural models with inverse probability of treatment weighting to a subset of modifiable predictors to approximate causal effects under standard assumptions. Results: In univariate models, earlier initiation was broadly associated with multiple time-varying variables, including impulsivity and externalizing behaviors, sleep disturbance, parenting and monitoring, medication and caffeine use, school functioning and absenteeism, and cultural or value-based measures, alongside other mental health and behavioral factors. In multivariable Cox models, a smaller subset of environmental predictors remained robustly associated with the hazard of initiation across alcohol, nicotine, cannabis, and any substance, highlighting consistent signals in impulsivity traits, parental monitoring, and select health and lifestyle factors. PRS for alcohol use disorder (AUD), cannabis use disorder (CUD), nicotine dependence, and any SUD were positively associated with earlier initiation (hazard ratio [HR] > 1), with the strongest and most consistent signal observed for nicotine PRS (e.g., alcohol initiation HR ≈ 2.37; any-substance initiation HR ≈ 2.98). AUD PRS showed weaker associations for alcohol initiation but stronger associations for any-substance initiation. Causal analyses suggested that parental monitoring (PMQ mean), UPPS lack of planning, UPPS sensation seeking, and caffeine exposure may influence time to initiation: higher parental monitoring was protective (odds ratio [OR] ≈ 0.33-0.64), whereas higher impulsivity traits and caffeine exposure were associated with increased risk (OR ≈ 1.47-3.87) across outcomes, with conclusions robust across weighting specifications. Conclusions: Integrating time-varying environmental predictors with polygenic risk in a survival framework helps identify environmental factors most strongly associated with earlier substance use initiation beyond genetic liability. Follow-up causal analyses further highlight potentially actionable pathways, particularly parenting and monitoring and impulsivity-related traits, that may contribute to the developmental trajectory leading to adolescent substance use disorders.