Abstract
BACKGROUND: Alcohol use and alcohol use disorder (AUD) are significant contributors to morbidity and mortality, with different prevalences between males and females. Despite the established genetic contribution to AUD, sex as a biological variable and the interplay with genetic factors in the disorder remain largely unexplored. This study aimed to address the key question as to how genetic variations interact with biological sex to influence the AUD risk. METHODS: We conducted genome-wide genotype-by-sex (G × S) interaction analyses using multiancestry datasets from the Million Veteran Program (MVP) and UK Biobank (UKB). In total, 1,039,476 participants were analyzed, comprising 150,429 AUD cases and 889,046 controls. AUD cases were defined using ICD-9/10 codes in the MVP and using ICD-10 codes (field ID 41270) along with self-reported history of alcohol addiction (field ID 20406) in the UKB. RESULTS: In single-ancestry analyses, we identified two loci in African ancestry samples with lead single-nucleotide polymorphisms (SNPs) rs2183020 (p = 1.82 × 10(-8)) and rs9304803 (p = 4.66 × 10(-8)), and one locus in Admixed American ancestry samples with lead SNP rs9527196 (p = 2.83 × 10(-8)). The cross-ancestry meta-analysis identified one additional locus with lead SNP rs62446539 (p = 3.95 × 10(-8)). The deep learning method predicted that rs9304803 has B-cell type-specific enhancer activity. Rs2183020 and rs9304803 exhibited expression quantitative trait locus (eQTL) effects on multiple genes across various tissues, including the brain. Further experiments in ethanol-exposed human neurons confirmed expression changes in several of these genes. Phenome-wide association analyses revealed significant associations between rs2183020 and weight/body mass index, and between rs9304803 and prothrombin time (measured as international normalized ratio). CONCLUSIONS: We believe this is the first genome-wide G × S study of AUD, providing novel insights into the genetic basis of sex differences in AUD and advancing our understanding of its biological underpinnings.