Leveraging genetic data to investigate molecular targets and drug repurposing candidates for treating alcohol use disorder and hepatotoxicity

Abstract

Novel treatments for alcohol use disorder (AUD) and alcohol-related liver disease (ALD) are greatly needed. We utilized a recently developed Bayesian approach, Integrative Risk Gene Selector (iRIGS), to identify high-confidence risk genes (HRGs) for alcohol consumption using SNPs from the largest alcohol consumption GWAS to date (N = 941,280). We subsequently used the Target Central Resource Database (TCRD) to search for drug-protein interactions for these HRGs and previously identified risk genes for alcohol consumption. We identified several HRGs for alcohol consumption that are novel contributions to the previously published alcohol consumption GWAS. Namely, ACVR2A, codes for activin receptor type-2A, which is critical for liver function, and PRKCE, codes for protein kinase C epsilon, which has been linked to alcohol consumption. Furthermore, several previously identified risk genes for alcohol consumption code for proteins that are implicated in liver function and are targeted by drugs that are promising candidates for managing hepatotoxicity (e.g., metformin), highlighting potential candidates for drug repurposing. This study demonstrates the value of incorporating regulatory information and drug-protein interaction data to highlight promising molecular targets and drugs for treating AUD and ALD.