Unravelling Polygenic Risk and Environmental Interactions in Adolescent Polysubstance Use: a U.S. Population-Based Observational Study

BackgroundPolysubstance use (PSU), defined as the use of multiple psychoactive substances, often begins during adolescence. Since PSU is associated with heightened risk of subsequent health issues, including substance use disorders, understanding its antecedents could ultimately have significant public health impacts. We investigated how genetic susceptibility, and environmental exposures together influence the initiation of PSU in adolescents. MethodsWe analyzed data from 11,868 adolescents (aged 11-15 years) in the Adolescent Brain and Cognitive Development study. PSU was assessed through interviews and toxicology. We examined the associations of polygenic scores (PGSs) for addiction, derived from GenomicSEM analysis, environmental factors, and their interactions, with the initiation of PSU, while controlling for multiple covariates. OutcomesOur sample included 7,898 adolescents (mean age 12.9 [0.6] years; 4,150 [53%] male). Overall, 541 (6.8%) had initiated single substance use (SSU), and 162 (2.1%) reported PSU. PGSs for general addiction risk were significantly associated with PSU (Odds Ratios [OR]=1.62, 95% CI=1.30-2.01) but not with SSU. Key environmental risk factors for PSU included prenatal substance use and peer victimization, while planned pregnancy and positive family dynamics acted as protective factors. Notably, gene-environment interaction analyses showed that peer victimization (OR=2.4, 95% CI=1.4-4.2), prenatal substance use (OR=2.1, 95% CI=1.2-3.6), and substance availability (OR=2.3, 95% CI=1.3-3.9) increased PSU risk among adolescents with high genetic susceptibility but had negligible effects at low genetic risk levels (all p < 0.05 after multiple testing correction). InterpretationThis study provides the first evidence linking polygenic risk to PSU in early adolescence and demonstrates that PSU represents more severe manifestation of substance use liability, driven by heightened genetic vulnerability and adverse environmental exposures. This underscores the importance of studying PSU explicitly, identifying high-risk individuals early, and implementing tailored interventions to mitigate the risk of escalating substance use behaviors. FundingNational Institutes of Health. Research in ContextO_ST_ABSEvidence before this studyC_ST_ABSWe conducted a literature search on PubMed for research articles published in English from inception to August 30, 2024, using the search terms: ("polygenic risk" OR "polygenic score" OR "genetic risk") AND ("adolescents" OR "adolescence") AND ("polysubstance use" OR "multiple substance use" OR "number of substances"). This search yielded no studies examining the relationship between polygenic risk of substance use and polysubstance use (PSU) in adolescence, revealing a critical gap in the field. To investigate environmental factors, we searched PubMed using the terms: (("environmental risk" OR "environmental factor" OR "social determinants") AND ("adolescents" OR "adolescence") AND ("polysubstance use" OR "multiple substance use" OR "number of substances")). This search highlighted consistent associations between adolescent PSU and adverse social determinants, such as socioeconomic disadvantage, prenatal exposure, parental monitoring, peer influence, and trauma experience. However, evidence for interactions between genetic and environmental factors was limited to a small number of candidate gene studies, with largely inconclusive findings. Added value of this studyThis study offers several important contributions to the field. First, to our knowledge, it is the first population-based study in the U.S. to examine PSU in early adolescence within a large, diverse cohort, leveraging data from the Adolescent Brain Cognitive Development (ABCD) Study. The ABCD studys comprehensive and inclusive sampling enables analyses across socioeconomic and racial/ethnic backgrounds, strengthening the generalizability of findings. Second, our results reveal a previously unreported association between polygenic risk and PSU in adolescents. Specifically, we show that genetic risk shared across five adult substance use disorders (SUDs) including alcohol, nicotine, cannabis, cocaine, and opioid use disorders, significantly relates to PSU outcomes among adolescents aged 11-15 years. Third, the ABCD studys in-depth characterization of participants allows us to examine a wide array of contributory individual and socio-environmental factors. Finally, this study highlights specific environmental contexts--such as prenatal substance use, family dynamics, and peer relationships--that interact with genetic predisposition to shape PSU behaviors in adolescence. This integrative approach provides insights into gene-environment (GxE) interactions that contribute to PSU, offering a more nuanced understanding of the mechanisms underlying health disparities in adolescent substance use outcomes. Implications of All Available EvidenceOur study shows that integrating polygenic risk with assessments of environmental factors in adolescent population improves understanding of PSU risk. Adolescents exposed to adverse social determinants are particularly vulnerable to PSU, especially when they have a higher genetic predisposition to SUDs. These insights support more explicit study of PSU and targeted early prevention strategies addressing both genetic vulnerabilities and environmental stressors to reduce PSU risk in preadolescence.