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[Preprint]. 2024 Jan 17:2024.01.17.23300238.
doi: 10.1101/2024.01.17.23300238.

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 , Shaunna L Clark  4 , Edwin J C G van den Oord  5 , Thomas M Hyde  2 , R Dayne Mayfield  6 , Bradley T Webb  1 , Eric O Johnson  1   7 , Joel E Kleinman  2 , Laura J Bierut  8 , Dana B Hancock  1
Affiliations

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

Julie D White et al. medRxiv. .

Update in

Abstract

Background: Alcohol 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).

Methods: Illumina 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.

Results: At 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.

Conclusions: Our 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.

Keywords: epigenome-wide association study; gene regulation; postmortem human brain; substance use.

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Conflict of interest statement

Conflict of Interest The following authors declare no conflict of interest: JDW, MSM, CW, BCQ, SH, RT, AD-S, LZ, SLC, EJCGvdO, TMH, RDM, BTW, EOJ, and DBH. JEK is a member of a drug monitoring committee for an antipsychotic drug trial for Merck. LBJ is listed as an inventor on U.S. Patent 8,080,371, “Markers for Addiction” covering the use of certain SNPs in determining the diagnosis, prognosis, and treatment of addiction.

Figures

Figure 1.
Figure 1.
Overview of all data, analyses, and results.
Figure 2.
Figure 2.
Overlap of significant probes from NAc and DLPFC EWAS analyses and the corresponding meta-analysis across brain regions.
Figure 3.
Figure 3.
Enrichment of genomic features. Proportions of non-significant 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 FDR-corrected p-values; p < 0.001 is ***, p < 0.01 is **, and p < 0.05 is *.
Figure 4.
Figure 4.
Gene-level concordance with previously published EWAS of AUD and alcohol consumption. This UpSet plot shows intersections between genes annotated to significant CpGs from our study (NAc, DLPFC, or meta-analysis) and previously published EWAS, considering only CpGs which passed the original publication’s significance threshold. Clark et al.’s results were not included, as no brain methylation or hydroxymethylation sites passed that study’s significance threshold. The comparison between our study and Zillich et al. did not have any overlapping genes.
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