# Molecular Dissection of Alcohol Use Disorder Through Targeted Brain Multi-omics

> **NIH NIH R01** · YALE UNIVERSITY · 2024 · $594,784

## Abstract

PROJECT SUMMARY
This proposal brings together experts in the genomics of neuropsychiatric disorders and translational
neuroscience to investigate the molecular pathology of alcohol use disorder (AUD). Alcohol use is the fourth
leading cause of preventable death in the United States that affects over 16 million adults. Understanding the
molecular basis for individual differences in susceptibility to alcohol addiction will facilitate the development of
diagnostics and personalized therapeutics. Brain molecular phenotypes, such as gene expression and DNA
methylation can be translated into neurobiological mechanisms by identifying causal disease genes and
pathways. The central goal of this research is to identify novel lasting transcriptomic and epigenetic
changes in biological pathways harboring potential biomarkers and therapeutic targets for AUD. Our
central hypothesis is that genetic and epigenetic variations lead to brain region-specific dysregulation of
transcriptomic networks and disturbances in reward-related genes during AUD. This proposal will perform a
postmortem, multi-omic study of brains from 341 total subjects AUD (n=100), a psychiatric control (MDD;
N = 132) and neurotypical controls (n=109). To test our hypothesis, we will determine differential DNA
methylation and RNA expression across 8 total brain areas of the prefrontal cortex, amygdala, nucleus
accumbens and hippocampus. We will analyze RNA-sequencing of 8 discrete regions to identify transcriptional
changes in etiologically relevant AUD brain regions (Aim 1). Next, we will identify gene regulatory mechanisms
of AUD by integrating whole-genome bisulfite sequencing of matched donors and regions (Aim 2). Finally, we
will prioritize AUD genes and test whether genome-wide significant variants identified from GWAS of AUD and
alcohol-related phenotypes are associated with gene expression or DNA methylation across brain regions
(Aim 3). The expected outcome of this research will be a model of genetic, epigenetic, and transcriptomic
profiles of brain regions from cases versus controls that will allow us to understand the region-specific
molecular effects of AUD. By identifying new molecular mechanisms of AUD using a large number of donors
across many regions, we will be able to explicate the neurobiological mechanisms affected by AUD and
identify novel targets for intervention in the addiction process.

## Key facts

- **NIH application ID:** 10879232
- **Project number:** 1R01AA031017-01A1
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Matthew J Girgenti
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $594,784
- **Award type:** 1
- **Project period:** 2024-07-15 → 2029-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10879232

## Citation

> US National Institutes of Health, RePORTER application 10879232, Molecular Dissection of Alcohol Use Disorder Through Targeted Brain Multi-omics (1R01AA031017-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10879232. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*