Importance: Substance use disorders (SUDs) frequently co-occur with each other and with other traits related to behavioral disinhibition, a spectrum of outcomes referred to as externalizing. Nevertheless, genome-wide association studies (GWAS) typically study individual SUDs separately. This single-disorder approach ignores genetic covariance between SUDs and other traits and may contribute to the relatively limited genetic discoveries to date. Objective: To identify the most effective model for capturing genetic relationships between SUDs and externalizing phenotypes, optimizing the detection of genetic influences on SUDs while maintaining specificity. Design: We used Genomic SEM to estimate SNP effects on a broad factor representing liability to externalizing and SUDs, on factors representing liability to behavioral disinhibition and SUDs separately, and on residualized SUDs. Subsequent gene-based, tissue expression, and polygenic score (PGS) analyses were used to compare the ability of these alternative approaches to identify genetic influences on SUDs. Setting: This study was carried out from May 2023 - September 2024. Participants: We used GWAS summary statistics based on samples of European ancestry from previous studies of externalizing and SUD phenotypes in the main multivariate GWAS (N > 2.2 million). We used two independent samples to estimate polygenic associations, a family-based sample enriched for substance use problems (COGA; N = 7,530) and a population-based sample representative of the United States, (All of Us; N = 77,442). Exposures: N/A Main Outcomes and Measures: Across the three factors (Externalizing; SUDs; Behavioral Disinhibition) and four residualized SUDs (alcohol, tobacco, opioid, and cannabis), we compared the number, putative function, previous associations of significant genomic risk loci and genes, and variance explained by polygenic scores in substance use outcomes. Results: We identified genomic risk loci and genes uniquely associated with Externalizing that are relevant to the neurobiology of substance use. Genes identified for residual SUDs were involved in substance-specific processes (e.g., metabolism). The Externalizing PGS accounted for the most variance in substance outcomes relative to the PGS for the other factors and residual PGS appeared to capture substance specific signals. Conclusions and Relevance: Our findings suggest that modeling both a broad genetic liability to externalizing behaviors and substance-specific liabilities enhances the detection of genetic effects related to SUDs and explains more variance in substance use outcomes.

The authors have declared no competing interest.

The Externalizing Consortium has been supported by the National Institute on Alcohol Abuse and Alcoholism (R01AA015416 administrative supplement to DMD), and the National Institute on Drug Abuse (R01DA050721 to DMD). Additional funding for investigator effort has been provided by K02AA018755, U10AA008401, P50AA022537 to DMD, as well as a European Research Council Consolidator Grant (647648 EdGe). Additional funding was provided by The National Institute on Drug Abuse (DP1DA054394 to SSR), Tobacco-Related Disease Research Program (T32IR5226 to SSR) and the National Institute on Alcohol Abuse and Alcoholism (T32AA028254 to HEP).

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