Background: Genetic influences account for a substantial proportion of individual differences in alcohol use behaviors (AUBs). However, multiple distinct sets of genes are linked to different AUBs, which may explain their dramatic variability in risk factors and manifestations. In this study, we explore whether intermediate neurobiological traits and alcohol-related cognitions mediate the relationship between polygenic scores (PGS) and multiple AUBs, with the aim to better understand processes captured by different genetic profiles. Methods: Using results from prior genome-wide association studies, we derived PGS for 6 AUBs in participants from Spit for Science, a longitudinal study of college students in the U.S. (n=4,549). Self-report measures included personality traits, alcohol expectancies, drinking motivations, and alcohol sensitivity measures as well as drinking frequency, drinking quantity, alcohol use disorder (AUD) symptoms, and maximum drinks in 24 hours. Using linear regression and multiple mediation models, we investigated the direct and indirect effects of PGS on AUBs. Results: In univariable regression results, PGSs indexing broad AUB dimensions such as drinks per week (DPW) and AUD predicted higher levels of sensation-seeking and multiple drinking motives, while BeerPref PGSs (indexing a variable pattern of alcohol problems associated with a preference for beer) predicted higher negative urgency and lower alcohol sensitivity. Mediational models indicated strong direct and indirect effects of DPW PGSs on multiple AUBs via social/enhancement drinking motives and alcohol sensitivity, indirect effects of AUD PGSs on AUD symptoms via coping motives, and indirect effects of BeerPref PGS on all AUBs via the joint effect of mediators including alcohol sensitivity. Conclusions: These findings provide initial evidence that the genetic influences on different AUBs are associated with and partially mediated by intermediate neurobiological and cognitive factors, which may be more amenable to intervention. Greater focus on drinking motives and alcohol sensitivity is warranted in genetic research, as well as attention to the heterogeneous pathways linking genes to alcohol use outcomes.

The authors have declared no competing interest.

This research was funded by a grant to J.E.S. (VI.VENI.201G-064) from The Netherlands Organization for Scientific Research (NWO). The parent study Spit for Science has been supported by Virginia Commonwealth University, P20AA017828, R37AA011408, K02AA018755, P50AA022537, and K01AA024152 from the National Institute on Alcohol Abuse and Alcoholism, UL1RR031990 from the National Center for Research Resources and National Institutes of Health Roadmap for Medical Research, as well as support by the Center for the Study of Tobacco Products at VCU. REDCap support provided by CTSA award UM1TR004360 from the National Center for Advancing Translational Sciences. The content is solely the responsibility of the authors and does not necessarily represent the views of the respective funding agencies. The funding agencies had no role in the study design, data analysis, manuscript preparation, or decision to submit for publication.

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The study involved secondary data analysis of anonymized human subjects data from openly available sources. Data from this study are available to qualified researchers via dbGaP (phs001754.v4.p2) or via spit4science@vcu.edu to qualified researchers who provide the appropriate signed data use agreement.

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Data from this study are available to qualified researchers via dbGaP (phs001754.v4.p2) or via spit4science@vcu.edu to qualified researchers who provide the appropriate signed data use agreement.