Drinking motives and alcohol sensitivity mediate multidimensional genetic influences on alcohol use behaviors

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 via uncertain causal links. Here, we explore whether intermediate neurobiological traits mediate the relationship between polygenic scores (PGSs) and multiple AUBs, with the aim to better understand processes captured by different genetic profiles. Methods: We derived four alcohol-related PGSs in participants from Spit for Science, a longitudinal study of college students in the United States (n = 4549). Using linear regression, we tested the relationship between PGSs and 22 potential mediators, including personality, alcohol expectancies, drinking motives, and alcohol sensitivity. Nominally significant effects were carried forward to a multiple mediation model to estimate direct and indirect effects on four measured AUBs (frequency, quantity, alcohol use disorder symptoms [AUDsx], and maximum drinks in 24 h). Results: In univariable regression, PGSs indexing genetic effects on drinks per week (DPW) and problematic alcohol use (PAU) predicted higher levels of impulsivity and drinking motives as well as lower alcohol sensitivity. BeerPref PGSs (indexing a variable pattern of alcohol problems and preference for beer) predicted higher negative urgency and lower alcohol sensitivity. Mediational models indicated direct and indirect effects of DPW PGSs on multiple AUBs via social/enhancement drinking motives and alcohol sensitivity, indirect effects of PAU PGSs on AUDsx, and indirect effects of BeerPref PGS on drinking frequency and AUDsx via the joint effect of mediators including alcohol sensitivity. Conclusions: These findings provide evidence that the genetic influences on 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.