Associations of transdiagnostic and substance use disorder polygenic scores with substance use milestones in the Adolescent Brain Cognitive Development study
Year: 2026
Type: preprint
Abstract: Background: Genetic influences on transdiagnostic psychopathology dimensions and individual substance use disorders (SUDs) contribute to the emergence of substance use and problems. However, the relative importance of these different types of genetic influence across stages of substance use remains poorly understood. We examined associations of polygenic scores (PGS) indexing psychopathology and SUD genetic propensity with the timing of substance use milestones in adolescence. Methods: We calculated PGS for externalizing (PGSEXT), internalizing (PGSINT), and SUDs for participants in the Adolescent Brain Cognitive Development (ABCD) Study (NMax = 10,387). We used cox proportional hazards models to examine associations between PGS and substance use milestones for alcohol, cannabis, and tobacco. We ran univariable and multivariable models to estimate shared and unique contributions of each PGS. Results: PGSEXT was associated with endorsement of all substance use milestones (HRs = 1.13-1.66) and remained significant after accounting for the PGSINT. In univariable models, PGSINT was also associated with all milestones, though the effect sizes were smaller (HRs = 1.10 to 1.25). In multivariable models, associations of PGSINT were attenuated, but remained significant for many milestones. In contrast, with a few exceptions, individual SUD PGS were not uniquely associated with substance use milestones after jointly accounting for all other PGS. Conclusions: Genetic propensity for externalizing and internalizing, but not individual SUDs, were uniquely associated with substance use milestones in adolescence. These findings highlight the importance of genetic propensity for both externalizing and internalizing in understanding early substance use development in adolescence.
Institution: Virginia Commonwealth University
Subfield: Epidemiology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
OpenAlex ID: W7170196543
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