Extensive genetic interactions (epistasis) linked to alcohol use disorder in a high-risk population.

Alcohol use disorder (AUD) is known to have a significant genetic component, yet there remains a gap between its heritability and findings from genome-wide association studies. One potential explanation for this could be genetic interactions, or epistasis, which remain largely unexplored in the context of AUD. We investigated the role of epistasis in AUD susceptibility among 742 American Indians. By analyzing 467 K variants in 3,736 genes and regulatory elements linked to AUD, we identified 97 interacting gene pairs significantly associated with AUD severity in an American Indian cohort. Five of these gene pairs: CNTNAP2-GRM8, CSMD1-DLGAP1, CSMD1-ERBB4, CSMD1-MAML2, and KCNQ5-ROBO2 - were replicated in All of Us research American Indian cohort (N = 5,037). These genes were enriched for immune system, cell adhesion, neuronal, and disease pathways. Their expressions were particularly enriched in midbrain GABAergic neurons. This large-scale epistasis study of AUD suggests that epistasis may contribute to the development of AUD.