An important genetic risk factor for the development of alcoholism is differential sensitivity to an acute dose of alcohol. Using segregating populations derived from selectively bred rat lines, we have mapped quantitative trait loci (QTLs) on rat chromosomes 1 and 2 for an acute response to alcohol, the duration of the loss of righting reflex (LORR). We have subsequently generated congenic and recombinant congenic lines that have confirmed the QTLs while simultaneously reducing their genomic size. We hypothesize that there are one or more genes within the QTL intervals that contribute to genetic variance for LORR through polymorphism- related effects on gene expression and/or on the structure of the genes'products. A second important hypothesis is that these same genes will influence genetic variance in alcohol reward-related behaviors. To address these hypotheses, the project will carry out four Specific Aims: 1) Fine-map the chromosome 1 and 2 QTLs using the recombinant congenic strategy;2) Identify candidate genes in the fine-mapped areas of the chromosome 1 and 2 QTLs;3) Identify enriched functional pathways and gene networks that are affected by the QTLs;and 4) Determine if the chromosome 1 and 2 QTLs are pleiotropic with alcohol reward-related behaviors. Contemporary genetic and genomic methods and analytical approaches, including high-throughput DNA and RNA sequencing, will be used to accomplish the goals of the Aims. We propose that the results of these experiments will offer insight into the nature of genetic variance for acute alcohol sensitivity. This in turn will contribute to a deeper understanding of genetic risk for human alcoholism.

Public Health Relevance

The initiation and maintenance of alcoholism is influenced by both environmental and genetic factors. This project aims to identify genes that influence variation in acute alcohol sensitivity, a trait that is thought to contribute to genetic risk for alcoholism. Such knowledge is essential for a complete understanding of the molecular basis of alcoholism and for the development of new or improved strategies for its treatment.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA018120-03
Application #
8299083
Study Section
Molecular Neurogenetics Study Section (MNG)
Program Officer
Reilly, Matthew
Project Start
2010-07-10
Project End
2015-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
3
Fiscal Year
2012
Total Cost
$315,060
Indirect Cost
$86,775
Name
University of Colorado Denver
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045
Mandt, Bruce H; Larson, Colin; Fay, Tina et al. (2018) Quantitative trait loci for sensitivity to acute ethanol and ethanol consummatory behaviors in rats. Alcohol 66:55-67