Translational genetic analysis in human and mouse gwas to identify the genomic architecture of alcohol sensitivity and tolerance

Active Project Grant Awarded Last action

Award ID
R01AA031176
Recipient
Awarding agency
Obligated
$1,646,833

Award facts

Assistance listing
93.273 Alcohol Research Programs
Completion date 44% complete
Place of performance
Indianapolis, IN 46202, USA

Award details come from USAspending.gov.

Description

As the agency reported it.

Abstract
Alcohol use disorder (AUD) is a major U.S. Health problem with 12-month and lifetime prevalence being 13.9% and 29.1%, respectively. AUD is partly caused by genetic factors with the estimated heritability being about 50%. Therefore, identification of genes related AUD can help US elucidate the genetic mechanisms of AUD and develop novel prevention and treatment strategies. While recent large-scale genome wide association studies (GWAS) have identified multiple AUD-associated genes, these genes only explain a small portion of heritability, indicating that many additional genes with small effects remain to be discovered. AUD is a heterogeneous disorder with multiple interacting genetic and environmental influences. Therefore, two individuals could receive the same AUD diagnosis, but have multiple different symptoms. One strategy to interrogate heterogeneous disorders is the inclusion of more homogenous endophenotypes, which deconstruct diagnostic categories into component features that may be more amenable to genetic research and provide a cost-effective way to increase statistical power without dramatically increasing the sample size. Alcohol sensitivity and tolerance are two important contributing features to the development and maintenance of AUD in humans, can be effectively measured in mice, and are known to be at least partly genetically mediated in both species. In this study, we propose a systematic and translational strategy to identify and validate variants and genes related to alcohol sensitivity and tolerance using both human and diversity outbred (do) mice. In aim 1, we will perform GWAS of alcohol sensitivity and tolerance in both european and african ancestry populations after adjusting for the effects of alcohol metabolism genes. Next, we will use high throughput reporter assays in multiple cell lines representing four major brain cells to identify functional variants with sub-threshold P values. We will then use a mendelian randomization framework to identify target genes of those functional variants. In aim 2, we will perform QTL, eqtl, and gene expression-trait correlation analyses to identify genetic variants associated with ethanol sensitivity and tolerance in do mice. Do mice are genetically heterogeneous with large amounts of recombination that provide high mapping resolution approximating that of a human GWAS, but with a much smaller sample size. In aim 3, we will employ our newly developed variantgraph database to identify variants and genes with shared regulatory effects across mouse and human. The findings will advance our knowledge of the genetic architecture of alcohol sensitivity and tolerance and will shed light on AUD etiologies.

Transactions

Action Obligated Date
Amendment $537,641
Amendment $534,384
Original award $574,808

Subawards

Subrecipient Amount Awarded
Jackson Laboratory We will use the VariantGraph to identify variants and genes with shared regulation by integrating results from human and mouse GWAS and meta-analyses,… $84,812
University Of Missouri The goal of this study is to gain a better understanding of the genetic influences that contribute to alcohol sensitivity. The proposed study will conduct… $54,410
University Of California, San Diego For UCSD subaward for the project entitled: Translational genetic analysis in human and mouse GWAS to identify the genomic architecture of alcohol sensitivity… $112,972
President And Fellows Of Middlebury College Dr. Parker will oversee the phenotyping of 1600 DO mice for ethanol sensitivity and tolerance to the ataxic, hypothermic, and sedative effects of ethanol. In… $655,059

Quick answers

Who received award R01AA031176?

R01AA031176 was awarded to Trustees Of Indiana University by National Institute on Alcohol Abuse and Alcoholism (National Institutes of Health) on September 9, 2024.

How much is award R01AA031176 worth?

$1,646,833 has been obligated on R01AA031176.

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