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.
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