@article{8f2672f85d114f888dfb1054c1d892c3,
title = "Epigenome-wide association study and multi-tissue replication of individuals with alcohol use disorder: evidence for abnormal glucocorticoid signaling pathway gene regulation",
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.",
author = "Lohoff, {Falk W.} and Arunima Roy and Jeesun Jung and Martha Longley and Rosoff, {Daniel B.} and Audrey Luo and Emma O{\textquoteright}Connell and Sorcher, {Jill L.} and Hui Sun and Melanie Schwandt and Hodgkinson, {Colin A.} and David Goldman and Reza Momenan and McIntosh, {Andrew M.} and Adams, {Mark J.} and Walker, {Rosie M.} and Evans, {Kathryn L.} and David Porteous and Smith, {Alicia K.} and Jisoo Lee and Christine Muench and Katrin Charlet and Clarke, {Toni Kim} and Kaminsky, {Zachary A.}",
note = "Funding Information: Acknowledgements This research was supported by the National Institutes of Health (NIH) intramural funding ZIA-AA000242 (Section on Clinical Genomics and Experimental Therapeutics; to FWL), Division of Intramural Clinical and Biological Research of the National Institute on Alcohol Abuse and Alcoholism (NIAAA). Dr. Charlet acknowledges funding from the German Research Foundation (DFG CH1936/1-1). The authors are grateful to the families who took part in GS, the GPs and Scottish School of Primary Care for their help in recruiting them, and the whole GS team that includes academic researchers, clinic staff, laboratory technicians, clerical workers, IT staff, statisticians and research managers. Generation Scotland received core support from the Chief Scientist Office of the Scottish Government Health Directorates (CZD/16/6) and the Scottish Funding Council (HR03006). Genotyping of the GS samples was carried out by the Genetics Core Laboratory at the Wellcome Trust Clinical Research Facility, Edinburgh, Scotland, and was funded by the Medical Research Council UK and the Wellcome Trust (Wellcome Trust Strategic Award {\textquoteleft}STratifying Resilience and Depression Longitudinally{\textquoteright} (STRADL) Reference 104036/Z/14/Z). Publisher Copyright: {\textcopyright} 2020, This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.",
year = "2021",
month = jun,
doi = "10.1038/s41380-020-0734-4",
language = "English (US)",
volume = "26",
pages = "2224--2237",
journal = "Molecular psychiatry",
issn = "1359-4184",
publisher = "Nature Publishing Group",
number = "6",
}