# Distinguishing preexistent and induced epigenetic risk for alcohol use disorders

> **NIH NIH R01** · OREGON HEALTH & SCIENCE UNIVERSITY · 2020 · $711,436

## Abstract

SUMMARY
Nearly 88,000 people die from alcohol-related causes annually, making it the fourth leading preventable cause
of death in the United States. Understanding the molecular mechanisms underlying the neurological changes
that lead to alcohol dependence is crucial for developing new, effective alcohol use disorder (AUD) treatments.
Towards this goal, recent studies have identified genome-wide DNA methylation (DNAm) signals distinguishing
alcoholic and non-alcoholic post-mortem brain tissue. In addition, a subset of the differential DNAm (D-DNAm)
signals was associated with the altered expression of nearby genes, suggesting that DNAm regulates the gene
expression patterns associated with alcoholic dependence. However, it is unknown whether some of the
DNAm signals detected in the post-mortem tissue were preexistent, potentially contributing risk for hazardous
drinking, rather than being induced by chronic alcohol. This study aims to distinguish these two possibilities,
and to pinpoint the functional consequences of alcohol-induced DNAm in the prefrontal cortex (PFC). The
study makes use of the highly relevant and well-characterized nonhuman primate (NHP) alcohol self-
administration model. In this model, voluntary alcohol consumption levels are measured in rhesus macaques
daily for ~12 months, enabling the accurate classification of natural “low” and “heavy” alcohol drinkers. In
addition, a small portion of the PFC is biopsied prior to alcohol access, providing opportunity to establish
baseline measures of DNAm. Genome-wide bisulfite sequencing (GWBS) will be used to identify alcohol-dose
dependent, differentially methylated cytosines (DMCs) and regions (DMRs) in the PFC of the rhesus
macaques. The same approach will be used to compare DNAm in PFC obtained from the macaques prior to
alcohol access, enabling the detection of preexistent, alcohol-dose associated DNAm signatures. In addition,
the macaque D-DNAm signals will be compared to D-DNAm data generated from post-mortem human
alcoholic PFC tissue, identifying alcohol-associated DNAm that is replicated across two primate species. Next,
the expression of DMC/DMR-associated genes, including both whole gene and alternative transcript
expression, will be correlated with the DNAm data. Based on support from the human-macaque DNAm
comparison, and corresponding expression data, a subset of compelling, novel gene targets will be selected
for functional study. Target gene activity will be modulated using pharmacological and gene expression
modification approaches in a murine model. The neural effects of target modulation will be evaluated using
patch-clamp electrophysiological analysis, and alcohol use will be evaluated using intermittent alcohol, 2 bottle
choice models. In total, this work will identify preexistent and alcohol-induced DNAm modifications in the
primate PFC and will clarify the role of a subset of DNAm-linked genes in promoting alcohol use. The findings
of this study will provide funct...

## Key facts

- **NIH application ID:** 9844059
- **Project number:** 5R01AA026278-02
- **Recipient organization:** OREGON HEALTH & SCIENCE UNIVERSITY
- **Principal Investigator:** Rita P Cervera Juanes
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $711,436
- **Award type:** 5
- **Project period:** 2019-01-02 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9844059

## Citation

> US National Institutes of Health, RePORTER application 9844059, Distinguishing preexistent and induced epigenetic risk for alcohol use disorders (5R01AA026278-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9844059. Licensed CC0.

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