This K08 application seeks support for additional research training in modem genetic methods, and their use in unraveling the genetic basis of alcoholism. Specifically, further training is sought in advanced statistical genetic and high-throughput genotyping and mutation detection methods. Training is also sought in the application of genetic methods on the research of endophenotypes of alcoholism, such as differences in interindividual response to alcohol. These training objectives will complement the applicant's previous training in neuropharmacology (Ph.D.), genetics of alcoholism (NIAAA DICBR) and clinical psychiatry (residency, completed 2001), and will make his career goals in research on the genetic basis of alcoholism possible. The training goals will be advanced through two research projects. The first project aims to identify genes for increased risk for alcohol dependence, which have been previously mapped to a specific area of the chromosome 1. Because of the limitations of the genetic linkage techniques in precision, the identified region is very broad and contains several genes. The applicant will fine-map this region using linkage disequilibrium-based techniques, such as the transmission disequilibrium test (TDT), in order to narrow the region containing the gene for predisposition to alcoholism. This is then followed by attempts to identify the gene and its variants using mutation scanning and further mapping. The second project aims to identify the behavioral and neurochemical pathways that connect the Pro7 allele of the functional Neuropeptide Y (NPY) Pro7Leu polymorphism to predisposition for alcohol dependence. Previous large population studies (including one by the applicant) have suggested that the Pro7 allele predisposes to alcohol dependence. We will use a prospective genotyping strategy, and testing for behavioral and neurochemical responses to test doses of alcohol and yohimbine in individuals who carry and who do not carry the Pro7 allele, in order to elucidate the functional differencebetween the Pro7 and L4eu7 Aeles, and their relationship to predisposition for alcoholism. Tne applicant is mentored by Dr. Joel Gelernter (primary) and Dr. John Krystal (co-mentor), who are both exceptionally well-qualified to supervise this type of comprehensive plan, which aims to provide advanced training for an MD, PhD psychiatrist in modem genetic technologies and their application to finding genetic risk factors for alcoholism. Dr. Jeffrey C. Long (University of Michigan) will be the statistical genetics consultant in this project.
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