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Is DNA methylation in the brain a mechanism of alcohol use disorder?

ABSTRACT: Alcohol use disorder (AUD) is a worldwide problem. Unfortunately, the molecular mechanisms of alcohol misuse are still poorly understood, therefore successful therapeutic approaches are limited. Accumulating data indicate that the tendency for compulsive alcohol use is inherited, suggesting a genetic background as an important factor. However, the probability to develop AUD is also affected by life experience and environmental factors. Therefore, the epigenetic modifications that are altered over lifetime likely contribute to increased risk of alcohol misuse. Here, we review the literature looking for the link between DNA methylation in the brain, a common epigenetic modification, and AUD-related behaviors in humans, mice and rats. We sum up the main findings, identify the existing gaps in our knowledge and indicate future directions of the research.

SUBMITTER: Jarczak J

PROVIDER: S-EPMC9908583 | biostudies-literature | 2023

REPOSITORIES: biostudies-literature

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Is DNA methylation in the brain a mechanism of alcohol use disorder?

Jarczak Justyna J Miszczak Michalina M Radwanska Kasia K

Frontiers in behavioral neuroscience 20230126

Alcohol use disorder (AUD) is a worldwide problem. Unfortunately, the molecular mechanisms of alcohol misuse are still poorly understood, therefore successful therapeutic approaches are limited. Accumulating data indicate that the tendency for compulsive alcohol use is inherited, suggesting a genetic background as an important factor. However, the probability to develop AUD is also affected by life experience and environmental factors. Therefore, the epigenetic modifications that are altered ove ...[more]

PMID: 36778133

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An Exploratory Association Study of Alcohol Use Disorder and DNA Methylation.

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Alcohol Use Disorder-Associated DNA Methylation in the Nucleus Accumbens and Dorsolateral Prefrontal Cortex.

Project description:BackgroundAlcohol use disorder (AUD) has a profound public health impact. However, understanding of the molecular mechanisms that underlie the development and progression of AUD remains limited. Here, we investigated AUD-associated DNA methylation changes within and across 2 addiction-relevant brain regions, the nucleus accumbens and dorsolateral prefrontal cortex.MethodsIllumina HumanMethylation EPIC array data from 119 decedents (61 cases, 58 controls) were analyzed using robust linear regression with adjustment for technical and biological variables. Associations were characterized using integrative analyses of public annotation data and published genetic and epigenetic studies. We also tested for brain region-shared and brain region-specific associations using mixed-effects modeling and assessed implications of these results using public gene expression data from human brain.ResultsAt a false discovery rate of ≤.05, we identified 105 unique AUD-associated CpGs (annotated to 120 genes) within and across brain regions. AUD-associated CpGs were enriched in histone marks that tag active promoters, and our strongest signals were specific to a single brain region. Some concordance was found between our results and those of earlier published alcohol use or dependence methylation studies. Of the 120 genes, 23 overlapped with previous genetic associations for substance use behaviors, some of which also overlapped with previous addiction-related methylation studies.ConclusionsOur findings identify AUD-associated methylation signals and provide evidence of overlap with previous genetic and methylation studies. These signals may constitute predisposing genetic differences or robust methylation changes associated with AUD, although more work is needed to further disentangle the mechanisms that underlie these associations and their implications for AUD.

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Alcohol Use Disorder-Associated DNA Methylation in the Nucleus Accumbens and Dorsolateral Prefrontal Cortex.

Project description:BackgroundAlcohol use disorder (AUD) has a profound public health impact. However, understanding of the molecular mechanisms underlying the development and progression of AUD remain limited. Here, we interrogate AUD-associated DNA methylation (DNAm) changes within and across addiction-relevant brain regions: the nucleus accumbens (NAc) and dorsolateral prefrontal cortex (DLPFC).MethodsIllumina HumanMethylation EPIC array data from 119 decedents of European ancestry (61 cases, 58 controls) were analyzed using robust linear regression, with adjustment for technical and biological variables. Associations were characterized using integrative analyses of public gene regulatory data and published genetic and epigenetic studies. We additionally tested for brain region-shared and -specific associations using mixed effects modeling and assessed implications of these results using public gene expression data.ResultsAt a false discovery rate ≤ 0.05, we identified 53 CpGs significantly associated with AUD status for NAc and 31 CpGs for DLPFC. In a meta-analysis across the regions, we identified an additional 21 CpGs associated with AUD, for a total of 105 unique AUD-associated CpGs (120 genes). AUD-associated CpGs were enriched in histone marks that tag active promoters and our strongest signals were specific to a single brain region. Of the 120 genes, 23 overlapped with previous genetic associations for substance use behaviors; all others represent novel associations.ConclusionsOur findings identify AUD-associated methylation signals, the majority of which are specific within NAc or DLPFC. Some signals may constitute predisposing genetic and epigenetic variation, though more work is needed to further disentangle the neurobiological gene regulatory differences associated with AUD.

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<i>GDAP1</i> Is Dysregulated at DNA Methylation and H3K4me3 Levels in Alcohol Use Disorder.

Project description:Alcohol use disorder (AUD) contributes significantly to the global burden of disease. The susceptibility for AUD is mediated through an interaction of genetic risk factors and environmental influences. These gene × environment (G × E) interactions manifest as epigenetic regulations of gene expression, among other things. Previous research suggests an association between Ganglioside Induced Differentiation Associated Protein 1 (GDAP1) DNA methylation and AUD. Here, we investigate the epigenetic dysregulation of GDAP1 in AUD through comparing DNA methylation in whole blood and saliva, as well as H3K4-trimethylation (H3K4me3) in PBMC (Peripheral Blood Mononuclear Cell) samples of AUD patients and healthy control individuals. Additionally, the effect of abstinence-based therapy was investigated. AUD patients before treatment exhibit significantly lower promoter DNA methylation levels in whole blood and saliva, as well as lower H3K4me3 near the transcription start site. GDAP1 gene expression was not significantly altered. Following treatment, H3K4me3 was significantly increased in patients and no longer differed from control individuals. There was no significant effect of treatment on DNA methylation. We conclude that GDAP1 is epigenetically dysregulated in AUD patients, and is responsive to abstinence-based therapy at the level of H3K4me3. It should be investigated further to establish its potential as a diagnostic biomarker.

| S-EPMC11855626 | biostudies-literature

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