Accepted_test

Background: Alcohol use disorder (AUD) impacts over 200 health conditions, causing approximately 3 million deaths annually. Meta-analysis of twin and adoption studies suggests AUD is about 50% heritable.

Methods: We conducted the largest East Slavs cohort genome-wide association study (GWAS) on self-reported alcohol consumption (AUDIT score) with 41 575 participants. Genetic correlations with diverse phenotypes were assessed, and a polygenic risk score (PRS) for alcohol dependence was developed and tested in an independent clinical cohort. GWAS and PRS associations were validated in various ethnic groups.

Results: The East Slavs GWAS identified a significant association (p-value = 2.5 x 10^-18) between rs1229984 SNP and AUD. This SNP showed significant associations in several ethnic groups, including Russians, Ukrainians, and Tatars, with consistent positive effect sizes. Other notable associations (p-value < 10^-6) involved SNPs within KIF26, OCA2, DLGAP2, and miRNA AL161421 gene regions. Genetic correlations showed strong positive associations with psychiatric traits.

The PRS, trained using external summary statistics on our cohort, matched the performance of the original study's PRS and outperformed others. Validation in an independent clinical cohort (AUC = 0.6, 95% CI = 0.56-0.64) and integration into non-genetic models increased AUC by 1.33%, resulting in 0.762 (p-value = 8 × 10^-5).

Conclusions: Our findings suggest a genetic basis for AUD involving genes related to alcohol metabolism, dopamine pleasure, and the reward system. The cross-ethnic applicability of the PRS supports its integration into non-genetic models to enhance AUD prediction accuracy in diverse populations.