Abstract
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. 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. 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. This study was carried out from May 2023 - September 2024. 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). N/A. 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. 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. 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. Question: Can we advance gene discovery for substance use disorders (SUDs) by incorporating information about correlated outcomes related to behavioral disinhibition?Findings: Combining genetic effects common to SUDs and behavioral disinhibition in a multivariate genome-wide association study of > 2.2 million individuals identified 708 genomic risk loci and accounted for more variance in SUD phenotypes compared with modeling each set of phenotypes separately.Meaning: SUDs and behavioral dysregulation are influenced by a common set of common variants; modeling their joint contributions improves power for genetic discovery and polygenic prediction.
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