DNA Methylation Signatures of Alcohol Use Disorder – A large-scale Meta-Analysis in the Psychiatric Genomics Consortium
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Despite extensive research on DNA methylation (DNAm) signatures associated with alcohol use disorder (AUD), findings are often inconsistent and not replicated. We conducted a large-scale meta-analysis of epigenome-wide association studies (EWAS) to identify reliable, reproducible epigenetic markers of AUD.
Seven cohorts, comprising 3,775 individuals (1,325 with AUD), contributed to this meta-analysis within the framework of the Psychiatric Genomics Consortium Substance Use Disorders Epigenetics Working Group. Downstream analyses included the identification of differentially methylated regions, overrepresentation analyses, and the construction of a methylation risk score (MRS).
We identified 118 significant CpG sites associated with AUD, with the strongest association found at cg24889777 ( p =5.12×10 -17 ) in the long non-coding RNA LOC100505942. CpG sites were enriched for pathways related to GTPase signaling and transmembrane transporter activity, as well as EWAS signals of alcohol consumption. The MRS explained 10.44% of variance in heavy drinking in an independent cohort (N=2,534, AUC=0.657).
This large-scale meta-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 in AUD.
