Genotype-by-sex interaction analyses for alcohol use disorder across biobanks

Comprehensive Summary

The study being conducted by Zhou et al. aimed to determine the role of genetics and sex-based differences as related to alcohol use disorder (AUD). The study conducted the first large-scale genotype-by-sex (G×S) interaction analysis of AUD. This research utilized data from over 1 million individuals in two major biobanks – the Million Veteran Program (MVP) and the UK Biobank. The research included individuals of European, African, and Admixed American ancestry, providing notable ancestral diversity. AUD cases were defined using medical records and self-reports and genome-wide G×S interaction analyses were performed using REGENIE, a regression analysis model. Four independent genetic loci showed significant genotype-by-sex interaction effects on AUD risk. Two loci were found in individuals of African ancestry, one locus in Admixed American ancestry, and one locus was found in cross-ancestry meta-analysis. For several variants, allele frequencies differed by both sex and AUD prevalence, indicating unequal genetic effects in males vs. females. Functional analyses of ethanol-exposed human neurons linked some variants to genes involved in neuronal development and signaling, cellular metabolism, and transcriptional regulation. Phenome-wide association studies revealed pleiotropic effects, including associations with body weight/BMI and prothrombin time (involved in blood coagulation), which suggests shared biological pathways between AUD and other traits. This study provides important evidence that genetic risk for AUD differs by biological sex and identifies specific loci where genetic effects interact with sex to influence AUD risk.

Outcomes and Implications

Alcohol use disorder (AUD) is a global cause of death and disability with well-established sex differences. Previous studies have indicated that men have higher rates of alcohol use and AUD, while women face greater risks for certain alcohol-related health consequences. However, clinically, AUD is primarily diagnosed and treated without regard to biological sex beyond dosing or pregnancy-related cautions. This strengthens the biological rationale for sex-aware models of AUD risk, progression, and complications, which can provide more precise identification of high-risk individuals. The findings connecting AUD to other health dysregulations support a shared biological basis between AUD and comorbidities frequently seen in clinical practice, such as metabolic disease and liver dysfunction. The research validates sex as a biologically meaningful variable, which can inform drug development, biomarker discovery, and trial design. This data also highlights the need to include women and diverse ancestries in broad AUD research. Overall, this research lays essential groundwork for sex-informed precision medicine, particularly in addiction, which is an area where current care is still largely one-size-fits-all.