Longevity Genes in Founder Populations

该项目的总体目标是通过研究两个独特的创始人群——旧秩序阿米什人和阿什肯纳兹犹太人——中“最老的老人”及其后代，来定位人类长寿的染色体位点（最终是基因）。这些群体是这些研究的理想选择，因为它们是遗传上相对同质的创始群体，并且以前已经成为成功鉴定疾病基因的基础。该提案汇集了一个强大的多学科研究团队，他们来自老年病学、分子遗传学、流行病学和统计遗传学等领域，具有良好的合作记录，并与这些封闭人群密切合作。首先，我们将招募阿米什人和德系犹太人的先证者（年龄大于95岁）及其家庭成员。其次，我们将通过间隔约10 cM的391个多态短串联重复（STR）标记进行基因分型，并进行“受影响”的连锁分析，在多重阿米什家系中进行长寿保证基因的全基因组搜索。第三，我们将对阿米什人和德系犹太人的研究对象进行详细的表型表征。我们将通过比较先证者后代（病例）和后代配偶（对照组）之间的平均性状差异来确定与衰老相关的中间数量性状。一旦确定了相关的衰老相关性状，我们将在已经招募并进行基因分型的2000多名阿米什受试者中使用方差成分方法进行全基因组搜索，以寻找控制这些数量性状的基因。最后，为了加强连锁和改善连锁信号的定位，我们将在阿米什人中每隔0.5 - 1 cM输入额外的标记，并进行后续的连锁分析和关联分析，包括单倍型共享分析。这些相同的标记将在德系犹太人中进行基因分型，以可能确认该人群中的关联，并有助于进一步缩小联系/关联区域。作为这些研究的结果，我们将(1)描述两个独特的家族集合，丰富了长寿和长寿相关的表型，其中遗传和非遗传（环境）对长寿的影响可以研究；(2)通过定位克隆和定位候选基因的方法，鉴定出可能存在长寿保证基因的特定染色体区域，为后续鉴定提供依据；(3)建立后代队列，进行纵向研究，进一步确定相关的中间长寿表型，并将长寿基因的遗传与其长寿表型联系起来。长寿保证基因的发现将为了解衰老的分子基础以及预防和治疗衰老相关疾病提供重要的见解。这些进步将对美国老年人的健康和生活质量产生重大影响。

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.