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.
Highlights
Multiple pathways to the development of alcohol use disorder (AUD) exist and include a complex interplay of environmental and genetic risk factors [1]
We identified 69242 CpG probes that were significantly (p ≤ 0.05) associated with AUD in the discovery cohort and 72941 probes in the first replication cohort, using a linear regression model additively controlling for age, sex, and race as covariates
The large number of significant probes identified in our study may derive both from the statistical power inherent in large cohorts as well as widespread epigenetic changes induced by chronic alcohol exposure
Summary
Multiple pathways to the development of alcohol use disorder (AUD) exist and include a complex interplay of environmental and genetic risk factors [1]. The field of epigenetics is rapidly developing in AUD and might help explain some of the environmental components as they interact with the genetic architecture [5,6,7,8]. Some are drug-specific, while others are more generally involved in common pathways that lead to maladaptive and addictive behaviors [1, 10, 11]
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