Lohoff FW, Clarke TK, Kaminsky ZA, et al. - Researchers aimed at determining the underlying mechanisms contributing to the development of alcohol use disorders (AUD).

• This is the largest single-cohort epigenome-wide association study (EWAS) of alcohol consumption to date (N = 8,161).

• The findings were cross-validated in AUD populations with relevant endophenotypes, as well as alcohol-related animal models.

• A significant association of 2,504 CpGs was observed with alcohol consumption with the five leading probes located in SLC7A11, JDP2, GAS5, TRA2B, and SLC43A1.

• Liver and brain function, the cellular response to alcohol and alcohol-associated diseases, including hypertension and Alzheimer’s disease, were noted to involve genes annotated to associated CpG sites.

• The causal relationship of consumption on AUD risk was confirmed in two-sample Mendelian randomization.

• Overall, this study led to an identification of several enriched gene pathways and gene sets.

• In biological validation and endophenotypic studies, SLC7A11 was identified as a top target relevant to liver and brain, and other genes related to often observed clinical comorbidities of chronic heavy alcohol consumption (AC), including hypertension and Alzheimer’s disease.

• This research serves as a proof-of-principle study suggesting direct relevance of upstream phenotypes, such as AC, to underlying disease.