# Project 1 - Novel gene networks modulating progressive ethanol consumption in DO mice

> **NIH NIH P50** · VIRGINIA COMMONWEALTH UNIVERSITY · 2024 · $185,345

## Abstract

Project Summary – Project 1
Over the last four years of P50 funding to the VCU Alcohol Research Center (VCU ARC), our laboratory used
Diversity Outbred (DO) mouse mice from Jackson Laboratories (http://do.jax.org) for behavioral genetics and
initial genomic studies on progressive ethanol consumption. DO mice originate from 8 progenitor mouse strains
chosen to maximize genetic diversity and utilize a breeding scheme producing a high degree of heterozygosity
for fine mapping complex traits such as ethanol consumption. As such, DO mice more faithfully mimic genetic
aspects seen with alcohol use disorder (AUD). As expected, based upon preliminary work in DO progenitor
strains, behavioral studies using a progressive ethanol consumption model (intermittent ethanol access, IEA)
on over 600 DO mice showed a broad distribution of consumption values (~0.5–38 g/kg/24h) that shifted to
significantly higher intake over the 4 week experiment. Genotyping identified 10 genome-wide significant or
suggestive QTL with LOD ≥ 6 and support intervals generally < 2 Mb. Strikingly, quantitative trait loci (QTL) for
the first week of drinking differed from those during the last week of consumption. Ongoing haplotype analysis
and integration of RNAseq data from prefrontal cortex have identified provisional candidate genes, including
two that have been implicated in human genome-wide association studies on alcohol consumption or
dependence. We hypothesize in this renewal that extension of this DO behavioral QTL and genomic data will
identify novel candidate genes and gene networks contributing to ethanol consumption behaviors in mice and
that such data will inform existing and future human genetic studies and therapeutic efforts on AUD.
Our specific aims thus describe: 1) Further expression genetics analysis in nucleus accumbens, allele specific
expression analysis, and chromatin 3D conformation analyses to identify and refine a list of positional
candidate genes for behavioral QTL associated with initial ethanol intake vs. progressive consumption; 2)
Gene network analysis of RNAseq data in both prefrontal cortex and nucleus accumbens across 200 DO mice
to identify networks and possible mechanisms tightly associated with consumption differing between first and
last week; and 3) Validation of candidate genes or network hubs as functioning in ethanol behaviors, including
initial or progressive ethanol consumption, using invertebrate models (collaboration with Projects 2 and 3 of
this Center proposal), rodent models (this project and Rodent Behavioral Core). Further, the work of this
project will inform and be informed by novel human genetic studies described in Projects 4 and 5. Throughout
this project, the VCU ARC Bioinformatics and Analysis Core will provide critical support for analysis of RNAseq
data and Capture-C chromatin conformation studies, and the choice of candidate genes and networks. This
novel gene discovery and network analysis effort will have major interacti...

## Key facts

- **NIH application ID:** 10857149
- **Project number:** 5P50AA022537-10
- **Recipient organization:** VIRGINIA COMMONWEALTH UNIVERSITY
- **Principal Investigator:** MICHAEL F MILES
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $185,345
- **Award type:** 5
- **Project period:** 2014-08-05 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10857149

## Citation

> US National Institutes of Health, RePORTER application 10857149, Project 1 - Novel gene networks modulating progressive ethanol consumption in DO mice (5P50AA022537-10). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10857149. Licensed CC0.

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