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<p>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 (<i>P</i> = 5.12 × 10<sup>−17</sup>). 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 (<i>N</i> = 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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月29日

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  • Lea Zillich,
  • Sofia D’Augello,
  • Diana Avetyan,
  • Graciela E. Delgado,
  • Ian R. Gizer,
  • Jeesun Jung,
  • Seyma Katrinli,
  • Marcus E. Kleber,
  • Natalie Merrill,
  • Angela P. Moissl-Blanke,
  • Diana L. Núñez-Rios,
  • Jacqueline M. Otto,
  • Eric Zillich,
  • Eva Friedel,
  • Dana B. Hancock,
  • Eric O. Johnson,
  • José Jaime Martínez-Magaña,
  • Sheila T. Nagamatsu,
  • David W. Sosnowski,
  • Julie D. White,
  • Karolina A. Aberg,
  • William E. Copeland,
  • Nancy Diazgranados,
  • Negar Fani,
  • Joel Gelernter,
  • David Goldman,
  • Jerome C. Foo,
  • Henry R. Kranzler,
  • Daniel F. Levey,
  • Winfried März,
  • Brenda W. J. H. Penninx,
  • Renato Polimanti,
  • Abigail Powers,
  • Alicia K. Smith,
  • Rainer Spanagel,
  • Edwin J. C. G. van den Oord,
  • Kirk C. Wilhelmsen,
  • Stephanie H. Witt,
  • Katharina Domschke,
  • Miriam A. Schiele,
  • Brion S. Maher,
  • Janitza L. Montalvo Ortiz,
  • Shaunna L. Clark,
  • Falk W. Lohoff

摘要

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.