Epigenome-wide association study and multi-tissue replication of individuals with alcohol use disorder: evidence for abnormal glucocorticoid signaling pathway gene regulation

Falk W. Lohoff, Arunima Roy, Jeesun Jung, Martha Longley, Daniel B. Rosoff, Audrey Luo, Emma O’Connell, Jill L. Sorcher, Hui Sun, Melanie Schwandt, Colin A. Hodgkinson, David Goldman, Reza Momenan, Andrew M. McIntosh, Mark J. Adams, Rosie M. Walker, Kathryn L. Evans, David Porteous, Alicia K. Smith, Jisoo LeeChristine Muench, Katrin Charlet, Toni Kim Clarke, Zachary A. Kaminsky

Research output: Contribution to journalArticlepeer-review

Abstract

Alcohol use disorder (AUD) is a chronic debilitating disorder with limited treatment options and poorly defined pathophysiology. There are substantial genetic and epigenetic components; however, the underlying mechanisms contributing to AUD remain largely unknown. We conducted the largest DNA methylation epigenome-wide association study (EWAS) analyses currently available for AUD (total N = 625) and employed a top hit replication (N = 4798) using a cross-tissue/cross-phenotypic approach with the goal of identifying novel epigenetic targets relevant to AUD. Results show that a network of differentially methylated regions in glucocorticoid signaling and inflammation-related genes were associated with alcohol use behaviors. A top probe consistently associated across all cohorts was located in the long non-coding RNA growth arrest specific five gene (GAS5) (p < 10−24). GAS5 has been implicated in regulating transcriptional activity of the glucocorticoid receptor and has multiple functions related to apoptosis, immune function and various cancers. Endophenotypic analyses using peripheral cortisol levels and neuroimaging paradigms showed that methylomic variation in GAS5 network-related probes were associated with stress phenotypes. Postmortem brain analyses documented increased GAS5 expression in the amygdala of individuals with AUD. Our data suggest that alcohol use is associated with differential methylation in the glucocorticoid system that might influence stress and inflammatory reactivity and subsequently risk for AUD.

Original languageEnglish (US)
Pages (from-to)2224-2237
Number of pages14
JournalMolecular psychiatry
Volume26
Issue number6
DOIs
StatePublished - Jun 2021
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Biology
  • Cellular and Molecular Neuroscience
  • Psychiatry and Mental health

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