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

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...

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Main Authors: Zillich, Lea (Author) , D’Augello, Sofia (Author) , Avetyan, Diana (Author) , Delgado Gonzales de Kleber, Graciela (Author) , Gizer, Ian R. (Author) , Jung, Jeesun (Author) , Katrinli, Seyma (Author) , Kleber, Marcus E. (Author) , Merrill, Natalie (Author) , Moissl-Blanke, Angela P. (Author) , Núñez-Rios, Diana L. (Author) , Otto, Jacqueline M. (Author) , Zillich, Eric (Author) , Friedel, Eva (Author) , Hancock, Dana B. (Author) , Johnson, Eric O. (Author) , Martínez-Magaña, José Jaime (Author) , Nagamatsu, Sheila T. (Author) , Sosnowski, David W. (Author) , White, Julie D. (Author) , Aberg, Karolina A. (Author) , Copeland, William E. (Author) , Diazgranados, Nancy (Author) , Fani, Negar (Author) , Gelernter, Joel (Author) , Goldman, David (Author) , Foo, Jerome Clifford (Author) , Kranzler, Henry R. (Author) , Levey, Daniel F. (Author) , März, Winfried (Author) , Penninx, Brenda W. J. H. (Author) , Polimanti, Renato (Author) , Powers, Abigail (Author) , Smith, Alicia K. (Author) , Spanagel, Rainer (Author) , Oord, Edwin J. C. G. van den (Author) , Wilhelmsen, Kirk C. (Author) , Witt, Stephanie (Author) , Domschke, Katharina (Author) , Schiele, Miriam A. (Author) , Maher, Brion S. (Author) , Ortiz, Janitza L. Montalvo (Author) , Clark, Shaunna L. (Author) , Lohoff, Falk W. (Author)
Format: Article (Journal) Chapter/Article
Language:English
Published: September 02, 2025
In: medRxiv
Year: 2025, Pages: 1-22
DOI:10.1101/2025.08.29.25334705
Online Access:Verlag, kostenfrei, Volltext: https://doi.org/10.1101/2025.08.29.25334705
Verlag, kostenfrei, Volltext: https://www.medrxiv.org/content/10.1101/2025.08.29.25334705v1
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Author Notes: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, 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
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Summary: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.
Item Description:Gesehen am 12.11.2025
Physical Description:Online Resource
DOI:10.1101/2025.08.29.25334705

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