The overall objective of this project is to localize chromosomal loci (and ultimately genes) for longevity in humans by studying the """"""""oldest old' and their offspring in two unique founder populations, the Old Order Amish and Ashkenazi Jews. These populations are ideal for these studies because they are relatively genetically homogeneous founder populations, and previously have been the basis of successful identification of disease genes. This proposal brings together a strong multidisciplinary team of researchers in the areas of geriatrics, molecular genetics, epidemiology, and statistical genetics who have a proven track record of collaboration and who work closely with these closed populations. First, we will recruit Amish and Ashkenazi probands (age greater than 95 years) and their family members. Second, we will perform a genome-wide search for longevity assurance genes in multiplex Amish pedigrees by genotyping 391 polymorphic short tandem repeat (STR) markers spaced at approximately 10 cM intervals and performing 'affecteds' only linkage analysis. Third, we will perform detailed phenotypic characterization of Amish and Ashkenazi study subjects. We will identify relevant aging-related intermediate quantitative traits by comparing mean trait differences between the probands' offspring (cases) and the offsprings' spouses (controls). Once relevant aging-related traits are identified, we will perform a genome wide search for genes controlling these quantitative traits using variance components methods in over 2000 Amish subjects who have already been recruited and genotyped. Finally, to strengthen linkages and improve localization of linkage signals, we will type additional markers at 0.5 - 1 cM intervals in the Amish, and perform follow-up linkage analysis and association analyses, including haplotype sharing analysis. These same markers will be genotyped in Ashkenazi Jews to possibly confirm associations in this population and also to help narrow regions of linkage/association further. As a result of these studies, we will have (1) characterized two unique family collections enriched for longevity and longevity-related phenotypes in which genetic and nongenetic (environmental) influences on longevity may be studied; (2) identified specific chromosomal regions that are likely to harbor longevity assurance genes for subsequent identification through positional cloning and positional candidate gene approaches, and (3) established an offspring cohort that will be studied longitudinally in order to further define the relevant intermediate longevity phenotypes, and to correlate inheritance of longevity genes to their longevity phenotypes. Discovery of longevity assurance genes will provide critical insights into the molecular basis of aging as well as new strategies for prevention and therapy of aging-related diseases. These advances will impact substantially on the health and quality of life of older Americans.
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