A large-scale DNA methylation study of alcohol use identified robust associations and cell-type specific insights

The biological mechanisms linking alcohol consumption to health outcomes are not fully understood, but growing evidence suggests a role for DNA methylation (DNAm). In this study, we conducted the largest and most comprehensive methylome-wide association study (MWAS) of alcohol using a cohort of 13,970 participants and, through epigenomic deconvolution, investigated cell-type specific associations in 12 different blood cell-types. We then replicated our whole blood findings using summary statistics from an existing alcohol MWAS and characterized our findings using bioinformatic analyses. We identified 1,266 methylome-wide significant (p -08) findings in whole blood. Fewer significant associations were found in the cell-types: 8 in both neutrophils and CD8+ naïve T-cells, 3 in both CD8+ memory T-cells and eosinophils, and 1 in T regulatory cells. The top replicating finding in whole blood was in SLC7A11 (p = 1.19×10-150) and was previously implicated in other alcohol MWASs. In the cell-type specific results, the top finding was in PDIA5 in CD8+ naïve T-cells (p = 2.83×10-12). Whole blood and cell-type specific findings tended to show significant overlap with genome-wide association studies of problematic alcohol use but not those based on alcohol consumption. In summary, we observed considerable overlap with previous alcohol MWASs and GWASs suggesting robust associations. Further, our novel DNAm findings, such as the involvement of Rho GTPase pathways, implicate new therapeutic targets that warrant further investigation. Due to the large number of findings in whole blood and coordinated changes across cell-types, we hypothesize results may capture alcohol exposure effects. Future work should use novel design to disentangle exposure versus liability effects.