DNA Methylation Signatures of Alcohol Use Disorder - A large-scale Meta-Analysis in the Psychiatric Genomics Consortium
Zillich, L.; D'Augello, S.; Avetyan, D.; Delgado, G.; Gizer, I. R.; Jung, J.; Katrinli, S.; Kleber, M. E.; Merrill, N.; Moissl, A. P.; Nunez-Rios, D. L.; Otto, J. M.; Zillich, E.; Friedel, E.; Hancock, D. B.; Johnson, E. O.; Martinez-Magana, J. J.; Nagamatsu, S. T.; Sosnowski, D. W.; White, J. D.; Aberg, K. A.; Copeland, W. E.; Diazgranados, N.; Fani, N.; Gelernter, J.; Goldman, D.; Foo, J. C.; Kranzler, H.; Levey, D. F.; Maerz, W.; Penninx, B. W.; Polimanti, R.; Powers, A.; Smith, A. K.; Spanagel, R.; van den Oord, E. J.; Wilhelmsen, K. C.; Witt, S.; Schiele, M. A.; Domschke, K.; Maher, B.; M
Show abstract
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=5.12x10-17) 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.
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