Genetic analysis of alcohol use disorder: GWAS of alcohol use disorders identification test (AUDIT) and polygenic risk scores in an east slavic population.

BACKGROUND

Alcohol use disorder (AUD) significantly affects over 200 health conditions, causing about 3 million deaths annually worldwide and is approximately 50 % heritable.

METHODS

We conducted a genome-wide association study (GWAS) on self-reported alcohol consumption and alcohol-related challenges (AUDIT score) in a large East Slavs cohort (N = 41,575). Genetic correlations with diverse phenotypes were assessed, and a polygenic risk score (PRS) for alcohol use disorder (AUD) was built and tested in an independent clinical cohort. GWAS and PRS associations were validated across various genetic ancestries.

RESULTS

The East Slavs GWAS identified a highly significant association (p = 2.5 ×10-18) between the rs1229984 SNP and AUD. Transancestral modeling revealed significant associations in Ashkenazi Jews, Tatars, Siberian, and other populations. Additional subthreshold associations (p < 10-6) were found in SNPs within KIF26, OCA2, DLGAP2, and miRNA AL161421 gene regions. SNP-based heritability was estimated at hg = 6.4 % (SE = 1.1 %). Genetic correlation analysis revealed the strongest positive associations with psychiatric traits. We trained the PRS using external summary statistics and individual-level genomic data from our cohort (R2 = 0.013). It outperformed other external PRSs included in the analysis. Validation in the independent clinical cohort showed an AUC of 0.6 (95 % CI = 0.56-0.64), and integrating PRS with non-genetic models increased the AUC by 1.33 %, resulting in 0.762 (p = 8 × 10⁻⁵).

CONCLUSIONS

Our findings suggest a genetic basis for AUD involving genes related to alcohol metabolism and the reward system. The applicability of the PRS across diverse genetic ancestries supports its integration into non-genetic prediction models, enhancing AUD prediction accuracy in diverse populations.