Alcoholism is the cause of many medical, social and economic problems worldwide. Whereas alcohol is one of the most widely abused substances, individuals vary greatly in alcohol sensitivity and propensity for developing alcohol dependence. However, our understanding of the genetic mechanisms and the environmental triggers responsible for this variation in alcohol-related behavior is far from complete. The difficulty arises because alcohol-related behaviors are complex traits, and individual variation is attributable to multiple interacting genes with small effects, the expression of which depends on environmental factors. The long-term goal of this project is to elucidate the genetic architecture of alcohol sensitivity and tolerance in a powerful genetic model system, Drosophila melanogaster, and to usethis information to gain insights into the genetic factors that predispose to the development of alcohol dependence in people.
The Specific Aims of this proposal are: (1) to characterize prevously identified P-element insertional mutations affecting sensitivity and resistance to the intoxicating effects of ethanol in greater molecular and phenotypic detail, and to determine to what extent these genes interact;(2) to use a systems biology approach, in which whole genome transcriptional profiling is applied to P-element insert lines affecting alcohol sensitivity and resistant and sensitive artificial selection lines, to identify co-regulated genetic networks affecting alcohol sensitivity; (3) to perform a high resolution genome scan for quantitative trait loci affecting naturally occurring variation in alcohol sensitivity between lines selected for increased and decreased alcohol sensitivity, and identify positional candidate genes that contribute to differences in alcohol sensitivity in the selection lines;and (4) to assess the extent to which polymorphisms in candidate genes affecting alcohol sensitivity discovered in the previous specific aims are associated with naturally occurring variation in alcohol sensitivity. Approximately 14 million people in the United States suffer from alcoholism. Chronic alcohol abuse is responsible for a vast number of traffic accidents that result in serious injury or death;neurological, gastrointestinal and cardiovascular disorders;and socio-economic problems, including increasedaggressive behavior with adverse impacts on parenting and marital stability. Determining what genetic factors affect alcohol-related behavior is challenging in humans, but can be addressed more readily in model organisms. Achieving a comprehensive description of the genetic basis of alcohol sensitivity in Drosophila will facilitate a future comparative genomic approach in which we directly incorporate this information in human linkage and association studies to identify genes that confer liability for development of alcohol dependence in human populations.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA016560-04
Application #
7743583
Study Section
Neurotoxicology and Alcohol Study Section (NAL)
Program Officer
Reilly, Matthew
Project Start
2007-01-01
Project End
2011-12-31
Budget Start
2010-01-01
Budget End
2010-12-31
Support Year
4
Fiscal Year
2010
Total Cost
$325,215
Indirect Cost
Name
North Carolina State University Raleigh
Department
Genetics
Type
Schools of Earth Sciences/Natur
DUNS #
042092122
City
Raleigh
State
NC
Country
United States
Zip Code
27695
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Huang, Wen; Carbone, Mary Anna; Magwire, Michael M et al. (2015) Genetic basis of transcriptome diversity in Drosophila melanogaster. Proc Natl Acad Sci U S A 112:E6010-9
Huang, Wen; Massouras, Andreas; Inoue, Yutaka et al. (2014) Natural variation in genome architecture among 205 Drosophila melanogaster Genetic Reference Panel lines. Genome Res 24:1193-208

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