Epigenome-wide association study and multi-tissue replication of individuals with alcohol use disorder: evidence for abnormal glucocorticoid signaling pathway gene regulation.
Falk W LohoffArunima RoyJeesun JungMartha LongleyDaniel B RosoffAudrey LuoEmma O'ConnellJill L SorcherHui SunMelanie SchwandtColin A HodgkinsonDavid GoldmanReza MomenanAndrew M McIntoshMark James AdamsRosie M WalkerKathryn L EvansDavid J PorteousAlicia K SmithJisoo LeeChristine MuenchKatrin CharletToni-Kim ClarkeZachary A KaminskyPublished in: Molecular psychiatry (2020)
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.
Keyphrases
- alcohol use disorder
- dna methylation
- genome wide
- long non coding rna
- poor prognosis
- gene expression
- oxidative stress
- room temperature
- signaling pathway
- copy number
- living cells
- resting state
- endoplasmic reticulum stress
- functional connectivity
- cell proliferation
- white matter
- small molecule
- blood brain barrier
- cell death
- brain injury
- cell cycle arrest
- artificial intelligence
- subarachnoid hemorrhage
- machine learning
- chemotherapy induced
- heat shock protein