Polygenic Risk Scores for Alcohol Dependence Predict Subjective Response to Alcohol in a Community Sample of Regular Drinkers

Alcohol dependence (AD) is a moderately heritable trait with a highly polygenic genetic architecture. Modeling the cumulative effects of nominally associated variants using polygenic risk scores (PRSs) has been shown to... [ view full abstract ]

Alcohol dependence (AD) is a moderately heritable trait with a highly polygenic genetic architecture. Modeling the cumulative effects of nominally associated variants using polygenic risk scores (PRSs) has been shown to increase the proportion of variance accounted for in substance use phenotypes, but has been largely restricted to the prediction of diagnostic status or quantitative consumption measures. As such, studies of alcohol use and dependence have not focused on intermediate phenotypes underlying risk for these traits, such as a person’s subjective response to alcohol. Therefore, the current study sought to evaluate the ability of a PRS for AD to explain variation in measures of alcohol sensitivity.

Summary statistics from a large-scale genome-wide meta-analysis of AD diagnosis were used to compute PRSs across eight significance thresholds. These scores were used to predict measures of subjective response to alcohol in a community-based sample of regular drinkers (n = 426). Phenotypes included retrospective measures of subjective response to alcohol, and self-reported subjective intoxication and alcohol-related stimulation and sedation following administration of a moderate dose of alcohol during an alcohol challenge session.

PRSs for AD were associated (p < 0.05) with variation in alcohol sensitivity during the alcohol challenge, including higher levels of alcohol-related stimulation and subjective intoxication across ascending and descending limbs of the blood alcohol concentration (BAC) curve, and lower levels of alcohol-related sedation on the descending limb of the blood alcohol concentration curve. This pattern of effects was consistent with the significant associations of the PRSs with retrospective measures of subjective response to the stimulating and sedating effects of alcohol.

These results provide preliminary support that cumulative measures of genetic risk for alcohol dependence may be related to measures of subjective response to alcohol, such as a dampened response to sedating effects and increased sensitivity to the simulating effects of alcohol.