The long range objective of this research project is to identify genes that influence alcohol-seeking behavior. The goal of this proposal is to identify the chromosomal location of genes that are associated with alcohol preference. Numerous family and twin studies in the past years have shown that genetic factors are involved in the genesis of alcoholism. Identification of the genes that influence alcohol-drinking behavior would help our understanding of the mechanisms of this disease and the approaches that need to be taken for treatment and prevention. To better understand the genetics of alcoholism and alcohol preference, animal studies will be used to isolate candidate regions and loci in homogeneous populations developed through selective breeding. Using quantitative trait mapping methods, quantitative trait loci (QTL) with major as well as minor effects on alcohol drinking variability can be identified. First, the selectively bred alcohol-preferring P and alcohol-nonpreferring NP rat lines will be employed in the search for QTL that influence alcohol preference and other traits that are correlated with alcohol preference. Inbreed P and NP rats will be intercrossed to produce 400 F2 animals. The parents and F2 animals will be tested for alcohol preference. The parental lines will then be genotyped using highly polymorphic microsatellite DNA markers. Those markers that are different between the lines will be used to genotype the F2 progeny. Maximum likelihood methods using interval mapping will be used in a genome-wide search to identify candidate QTL for alcohol preference. QTL identified in the P and NP lines will be confirmed using the noninbred first replicate high alcohol drinking (HAD1) and low alcohol drinking (LAD1) liens. HAD1) lines. HAD1 and LAD1 animals will be mated to produce three generational families. The families will be genotyped using highly polymorphic markers in the previously identified candidate regions. Least square regression analysis will be used to determine if the candidate QTL is segregating in these families. These families will also be used for a genome-wide search to identify additional QTL influencing alcohol preference that may not be segregating in the P and NP liens as well as other alcohol-related traits studied by other investigators. Candidate QTL discovered in the HAD1 and LAD1 lines will be confirmed in three- generational families from crosses of the second replicate HAD2 and lAD2 lines. Using two genetically diverse rat lines (P/NP and HAD/LAD) will allow us to identify chromosomal regions that are very likely influencing alcohol preference. The QTL identified in animals can then be tested in human studies to determine their effect on the alcoholism phenotype.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA010707-05
Application #
2894102
Study Section
Special Emphasis Panel (SRCA (49))
Project Start
1995-08-01
Project End
2001-06-30
Budget Start
1999-08-01
Budget End
2001-06-30
Support Year
5
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Indiana University-Purdue University at Indianapolis
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
005436803
City
Indianapolis
State
IN
Country
United States
Zip Code
46202
Spence, John Paul; Reiter, Jill L; Qiu, Bin et al. (2018) Estrogen-Dependent Upregulation of Adcyap1r1 Expression in Nucleus Accumbens Is Associated With Genetic Predisposition of Sex-Specific QTL for Alcohol Consumption on Rat Chromosome 4. Front Genet 9:513
Qiu, Bin; Luczak, Susan E; Wall, Tamara L et al. (2016) The FKBP5 Gene Affects Alcohol Drinking in Knockout Mice and Is Implicated in Alcohol Drinking in Humans. Int J Mol Sci 17:
Yong, Weidong; Spence, John Paul; Eskay, Robert et al. (2014) Alcohol-preferring rats show decreased corticotropin-releasing hormone-2 receptor expression and differences in HPA activation compared to alcohol-nonpreferring rats. Alcohol Clin Exp Res 38:1275-83
Spence, John Paul; Lai, Dongbing; Shekhar, Anantha et al. (2013) Quantitative trait locus for body weight identified on rat chromosome 4 in inbred alcohol-preferring and -nonpreferring rats: potential implications for neuropeptide Y and corticotrophin releasing hormone 2. Alcohol 47:63-7
Bice, Paula J; Liang, Tiebing; Zhang, Lili et al. (2010) Fine mapping and expression of candidate genes within the chromosome 10 QTL region of the high and low alcohol-drinking rats. Alcohol 44:477-85
Liang, Tiebing; Kimpel, Mark W; McClintick, Jeanette N et al. (2010) Candidate genes for alcohol preference identified by expression profiling in alcohol-preferring and -nonpreferring reciprocal congenic rats. Genome Biol 11:R11
Alam, Imranul; Carr, Lucinda G; Liang, Tiebing et al. (2010) Identification of genes influencing skeletal phenotypes in congenic P/NP rats. J Bone Miner Res 25:1314-25
Alam, Imranul; Sun, Qiwei; Koller, Daniel L et al. (2010) Genes influencing spinal bone mineral density in inbred F344, LEW, COP, and DA rats. Funct Integr Genomics 10:63-72
Spence, John P; Liang, Tiebing; Liu, Lixiang et al. (2009) From QTL to candidate gene: a genetic approach to alcoholism research. Curr Drug Abuse Rev 2:127-34
Alam, Imranul; Sun, Qiwei; Koller, Daniel L et al. (2009) Differentially expressed genes strongly correlated with femur strength in rats. Genomics 94:257-62

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