Background: Alcohol 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.
Methods: Illumina 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.
Results: At 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.
Conclusions: Our 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.
Keywords: Epigenetics; Epigenome-wide association study; Gene regulation; Postmortem human brain; Substance use.
Alcohol use disorder (AUD) has a profound public health impact, but understanding of the molecular mechanisms that underlie its development and progression remains limited. In the current study, which is the largest of its kind, we examined DNA methylation changes in the brains of 119 individuals with and without AUD. In 2 brain regions key to the addiction cycle, the nucleus accumbens and dorsolateral prefrontal cortex, we identified 105 methylation markers (CpGs) associated with AUD across 120 genes. We also integrated these results with previously published genetic and epigenetic studies, highlighting potential targets for better understanding how AUD develops, progresses, and someday may be treated.
© 2024 The Authors.