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 substantial gap between its heritability and findings from genome-wide association studies. One potential factor contributing to this gap may be genetic interactions, or epistasis, a largely unexplored aspect in the context of AUD. The aim of this study was to investigate the role of epistasis in AUD susceptibility and severity among American Indians, a population that exhibits the highest rates of AUD among all ethnic groups in the U.S. We began by identifying genes previously linked to alcohol dependence and AUD, then expanded this gene set through biological networks, ultimately comprising 3,736 genes and regulatory elements. The final gene set was mapped to over 476K variants in an American Indian cohort of 742 individuals. We performed a pairwise genetic interaction association analysis on the variant set, followed by a bi-clustering procedure to group the interacting SNP pairs into interacting intervals. A total of 114 interacting pairs of genes and regulatory elements were identified to be significantly associated with AUD severity. These genes were enriched for immune system, cell adhesion, neuronal, and disease pathways. Their expressions were particularly enriched in midbrain GABAergic neurons. Our study represents the first large-scale genetic interaction study of AUD in any population. Our findings suggest that epistasis may significantly contribute to the development and progression of AUD.