Examining polygenic risk score by environment interaction on the relationship between interpersonal violence exposure and alcohol use in an ancestrally diverse college cohort

Large-scale genome-wide association (GWAS) studies have identified numerous significant single nucleotide polymorphisms (SNPs) for alcohol phenotypes including alcohol consumption (Clarke et al., 2017; Kranzler et al., 2019), problematic drinking (e.g., maximum habitual alcohol intake (Gelernter et al., 2019); problematic alcohol use [PAU] defined as a combination of problem scores and alcohol use disorder [AUD] (Zhou et al., 2020); and alcohol dependence (AD)(Walters et al., 2018) and AUD diagnosis (Kranzler et al., 2019). While early work was conducted primarily in European ancestry (EUR) individuals (Peterson et al., 2019), more recent work has included additional populations and identified loci shared across ancestries as well as ancestry-specific variants (Gelernter et al., 2019). Alcohol phenotypes, like most complex psychiatric traits, are highly polygenic, meaning that many variants of small effect size contribute to their development (Wray et al., 2014). Thus, aggregate genetic methods that capture cumulative common variant genetic risk for a given phenotype, via polygenic risk scores (PRSs), have been increasingly utilized. PRS are an aggregated summation of disorder-associated genetic risk. In general, PRS are calculated for each individual by summing the number of risk variants they carry across the genome (Wray et al., 2021). This approach can improve our understanding of genetic architecture and aggregate genetic risk for alcohol phenotypes. Environmental risk factors are also associated with increased prevalence of alcohol phenotypes. One important environmental risk factor is trauma exposure, particularly interpersonal violence (IPV; experiencing physical or sexual assault). IPV has been associated with increased alcohol consumption (Berenz et al., 2016), greater alcohol misuse (Kilpatrick et al., 2003), and increased AUD risk (Meyers et al., 2018). Importantly, these environmental factors may interact with genetic factors to substantially influence this risk. Indeed, there is growing evidence for the importance of the interaction between genetic and environmental factors on alcohol phenotypes (Prom-Wormley et al., 2017; Pasman et al., 2019). The primary objective of the proposed project extends prior work by detailing the relationships between polygenic risk for alcohol phenotypes, IPV exposure, and alcohol consumption and AUD outcomes. The impact of biological sex and ancestry on these relationships will also be explored. All analyses will be conducted in the Spit for Science study, a large, ancestrally diverse, college-aged cohort with longitudinal behavioral health measures (Dick et al., 2014).