A large-scale meta-analysis of DNA methylation signatures of alcohol use disorder in the Psychiatric Genomics Consortium

Abstract

Despite extensive research on DNA methylation signatures associated with alcohol use disorder (AUD), findings are often inconsistent. Here we conducted a large-scale meta-analysis of epigenome-wide association studies (EWASs) to identify reliable, reproducible epigenetic markers of AUD. Seven cohorts, comprising 3,775 individuals (1,325 with AUD), contributed to this meta-analysis. Downstream analyses included differentially methylated regions, overrepresentation analyses and the construction of a methylation risk score. We identified 118 significant CpG sites associated with AUD, with the strongest association found at cg24889777 (P = 5.12 × 10⁻¹⁷). CpG sites were enriched for pathways related to GTPase signaling, transmembrane transporter activity and EWAS signals of alcohol consumption. The methylation risk score explained 2.06% of the variance in alcohol consumption and predicted heavy drinking in an independent cohort (N = 2,534, area under the curve = 0.657). This analysis offers key insights into the epigenetic mechanisms of AUD and lays the groundwork for future research on methylation risk scores for the diagnosis, prognosis and treatment of AUD.