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. 2024 Aug 13;4(6):100375.
doi: 10.1016/j.bpsgos.2024.100375. eCollection 2024 Nov.

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

Julie D White  1 , Melyssa S Minto  1 , Caryn Willis  1 , Bryan C Quach  1 , Shizhong Han  2 , Ran Tao  2 , Amy Deep-Soboslay  2 , Lea Zillich  3 , Stephanie H Witt  3 , Rainer Spanagel  4 , Anita C Hansson  4 , Shaunna L Clark  5 , Edwin J C G van den Oord  6 , Thomas M Hyde  2 , R Dayne Mayfield  7 , Bradley T Webb  1 , Eric O Johnson  1   8 , Joel E Kleinman  2 , Laura J Bierut  9 , Dana B Hancock  1
Affiliations

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

Julie D White et al. Biol Psychiatry Glob Open Sci. .

Abstract

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.

Plain language summary

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.

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Figures

Figure 1
Figure 1
Overview of all data, analyses, and results. AUD, alcohol use disorder; DLPFC, dorsolateral prefrontal cortex; DMR, differentially methylated region; EWAS, epigenome-wide association study; GO, Gene Ontology; GWAS, genome-wide association study; KEGG, Kyoto Encyclopedia of Genes and Genomes; LDSC, linkage disequilibrium score regression; LIBD, Lieber Institute for Brain Development; NAc, nucleus accumbens.
Figure 2
Figure 2
Overlap of significant probes from the NAc and DLPFC epigenome-wide association study analyses and the corresponding meta-analysis across brain regions. DLPFC, dorsolateral prefrontal cortex; NAc, nucleus accumbens.
Figure 3
Figure 3
Enrichment of genomic features. Proportions of nonsignificant vs. significant CpGs were compared based on (A) CpG contexts and (B) gene-centric contexts. Stars represent significance of a two-sided Fisher’s exact test for count data, based on false discovery rate–corrected p values. ∗∗∗p < .001, ∗∗p < .01, ∗p < .05. DLPFC, dorsolateral prefrontal cortex; NAc, nucleus accumbens; UTR, untranslated region.
Figure 4
Figure 4
Gene-level concordance for statistically significant CpGs among previously published epigenome-wide association studies of alcohol use disorder and alcohol consumption. This UpSet plot shows intersections between genes annotated to significant CpGs from our study (nucleus accumbens, dorsolateral prefrontal cortex, or cross-region meta-analysis) and previously published epigenome-wide association studies. Studies of blood DNA methylation are colored red, while studies of brain methylation are colored blue. For genes annotated to CpGs passing each publication’s significance threshold, the bar plot on the left illustrates the total number of unique genes from each publication, and the bar plot on top shows the number of unique genes annotated to significant CpGs in each intersection set. Clark et al.’s results (11) were not included because no brain methylation or hydroxymethylation sites passed that study’s significance threshold. The comparison between our study and Zillich et al. (12) revealed no overlapping annotated genes.
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References

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