GRIK1 and GABRA2 Variants Have Distinct Effects on the Dose-Related Subjective Response to Intravenous Alcohol in Healthy Social Drinkers

Abstract

Background

The heritable risk for alcohol use disorder (AUD) is expressed partly through alterations in subjective alcohol response. In this study, we investigated the effects of two AUD risk-associated single nucleotide polymorphisms (SNPs), GABRA2 rs279858 and GRIK1 rs2832407, on the subjective response to alcohol administered intravenously to healthy social drinkers in a laboratory setting.

Methods

93 self-identified European American social drinkers underwent three blinded lab sessions in which they received intravenous infusions of ethanol at three target blood alcohol levels (0.00mg%, 40mg%, 100mg%) using a “clamp” procedure. The self-reported Biphasic Alcohol Effects Scale (BAES) stimulation and sedation subscales were the primary outcome measures. We examined the effects of these two genetic variants on subjective response to alcohol.

Results

For the BAES stimulation subscale scores, adjusting for age, baseline scores, and time effects, individuals with two copies of the GABRA2 rs279858 C “risk” allele for AUD exhibited the greatest stimulant responses to high dose alcohol compared to the other risk allele counts (dose-by-allele count interaction effect, p=0.001, post-hoc contrast for C-allele p=0.012). For the BAES sedation subscale scores, adjusting for the same covariates, we detected a dose-by-allele count interaction effect ( p=0.0044) such that subjects with two copies of the GRIK1 C “risk” allele reported the greatest sedative response to the higher alcohol dose.

Conclusions

This study suggests that gene variants contributing to the risk for AUD may alter features of the alcohol dose-response relationship in specific ways. GABRA2 rs279858*C enhances stimulant responses to higher levels of alcohol, while the GRIK1 rs2832407*C allele increases sedative responses. In summary, GRIK1 and GABRA2 variants have distinct effects on the dose-related subjective response to intravenous alcohol in humans.