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

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

doi:10.1038/s41380-020-0734-4

Cited by 38 publications

(22 citation statements)

References 65 publications

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“…Genomic study on brain tissue samples from MDD and BD patients revealed increased mRNA expression of inflammatory genes in frontal region, reward related brain region ( 25 , 26 ). Furthermore, epigenome-wide association studies (EWAS) have revealed epigenetic associations between inflammatory genes like GAS5 and phenotypes such as fear conditioning and extinction in chronic alcohol drinkers ( 27 ). These studies provide a basis for the transcriptional regulation of neuroendophenotypes in mood and substance use disorders by inflammatory genes.…”

Section: Introductionmentioning

confidence: 99%

Inflammatory Markers in Substance Use and Mood Disorders: A Neuroimaging Perspective

et al. 2022

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Chronic exposure to addictive drugs in substance use disorders and stressors in mood disorders render the brain more vulnerable to inflammation. Inflammation in the brain, or neuroinflammation, is characterized by gliosis, microglial activation, and sustained release of cytokines, chemokines, and pro-inflammatory factors compromising the permeability of the blood-brain barrier. There is increased curiosity in understanding how substance misuse and/or repeated stress exposure affect inflammation and contribute to abnormal neuronal activity, altered neuroplasticity, and impaired cognitive control, which eventually promote compulsive drug-use behaviors and worsen mood disorders. This review will emphasize human imaging studies to explore the link between brain function and peripheral markers of inflammation in substance use disorders and mood disorders.

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Section: Introductionmentioning

confidence: 99%

Inflammatory Markers in Substance Use and Mood Disorders: A Neuroimaging Perspective

et al. 2022

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“…Several intronic γ-aminobutyric acid β1 (GABA β1) subunit (GABR β1)single nucleotide polymorphisms that may directly influence alcohol dependence risk have been recently identified ( 1 ). DNA methylation of growth arrest specific five gene is implicated in alcohol use ( 2 ). In addition, carriers of the rs1789891 A allele reportedly consume more alcohol and have a higher risk of relapse than individuals that are homozygous for the C allele ( 3 ).…”

Section: Introductionmentioning

confidence: 99%

Exploration of the Role of Serine Proteinase Inhibitor A3 in Alcohol Dependence Using Gene Expression Omnibus Database

Zhang

Wang²,

Huang

et al. 2022

Front. Psychiatry

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Background: Alcohol dependence is an overall health-related challenge; however, the specific mechanisms underlying alcohol dependence remain unclear. Serine proteinase inhibitor A3 (SERPINA3) plays crucial roles in multiple human diseases; however, its role in alcohol dependence clinical practice has not been confirmed.Methods: We screened Gene Expression Omnibus (GEO) expression profiles, and identified differentially expressed genes (DEGs). Protein-protein interaction (PPI) networks were generated using STRING and Cytoscape, and the key clustering module was identified using the MCODE plugin. SERPINA3-based target microRNA prediction was performed using online databases. Functional enrichment analysis was performed. Fifty-eight patients with alcohol dependence and 20 healthy controls were recruited. Clinical variables were collected and follow-up was conducted for 8 months for relapse.Results:SERPINA3 was identified as a DEG. ELANE and miR-137 were identified after PPI analysis. The enriched functions and pathways included acute inflammatory response, response to stress, immune response, and terpenoid backbone biosynthesis. SERPINA3 concentrations were significantly elevated in the alcohol dependence group than in healthy controls (P < 0.001). According to the median value of SERPINA3 expression level in alcohol dependence group, patients were divided into high SERPINA3 (≥2677.33 pg/ml, n = 29) and low SERPINA3 groups (<2677.33 pg/ml, n = 29). Binary logistic analysis indicated that IL-6 was statistically significant (P = 0.015) Kaplan-Meier survival analysis did not indicate any difference in event-free survival between patients with low and high SERPINA3 levels (P = 0.489) after 8 months of follow-up. Receiver characteristic curve analysis revealed that SERPINA3 had an area under the curve of 0.921 (P < 0.0001), with a sensitivity and specificity of 93.1 and 80.0%, respectively. Cox regression analysis revealed that aspartate transaminase level was a negative predictor of relapse (β = 0.003; hazard ratio = 1.003; P = 0.03).Conclusions:SERPINA3 level was remarkably elevated in patients with alcohol dependence than healthy controls, indicating that SERPINA3 is correlated with alcohol dependence. However, SERPINA3 may not be a potential predictive marker of relapse with patients in alcohol dependence.

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“…We searched major studies of alcohol consumption for all of the genes replicated in three AUD studies. 26 , 42 , 43 Heterogenous Nuclear Ribonucleoprotein A1 ( HNRNPA1 ) was significantly hypomethylated in AUD cases in three studies that included saliva, lymphocytes and blood, 29 , 44 , 45 and HNRNPA1 methylation was inversely associated with alcohol consumption in blood 42 , 46 and saliva. 26 HNRNPA1 regulates RNA processing, including transcription, translation, splicing, stability and export.…”

Section: Recent Molecular Discoveriesmentioning

confidence: 99%

Epigenetics of alcohol use disorder—A review of recent advances in DNA methylation profiling

et al. 2021

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Alcohol use disorder (AUD) is a major contributor to morbidity and mortality worldwide. Although there is a heritable component, the etiology of AUD is complex and can involve environmental exposures like trauma and can be associated with many different patterns of alcohol consumption. Epigenetic modifications, which can mediate the influence of genetic variants and environmental variables on gene expression, have emerged as an important area of AUD research. Over the past decade, the number of studies investigating AUD and DNA methylation, a form of epigenetic modification, has grown rapidly. Yet we are still far from understanding how DNA methylation contributes to or reflects aspects of AUD. In this paper, we reviewed studies of DNA methylation and AUD and discussed how the field has evolved. We found that global DNA and candidate DNA methylation studies did not produce replicable results. To assess whether findings of epigenome‐wide association studies (EWAS) were replicated, we aggregated significant findings across studies and identified 184 genes and 15 gene ontological pathways that were differentially methylated in at least two studies and four genes and three gene ontological pathways that were differentially methylated in three studies. These genes and pathways repeatedly found enrichment of immune processes, which is in line with recent developments suggesting that the immune system may be altered in AUD. Finally, we assess the current limitations of studies of DNA methylation and AUD and make recommendations on how to design future studies to resolve outstanding questions.

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

Cited by 38 publications

References 65 publications

Inflammatory Markers in Substance Use and Mood Disorders: A Neuroimaging Perspective

Inflammatory Markers in Substance Use and Mood Disorders: A Neuroimaging Perspective

Exploration of the Role of Serine Proteinase Inhibitor A3 in Alcohol Dependence Using Gene Expression Omnibus Database

Epigenetics of alcohol use disorder—A review of recent advances in DNA methylation profiling

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