Genetic Studies of Successful Aging in the Amish

描述（由申请人提供）：分子和统计方法的进步极大地促进了老年人常见疾病（如阿尔茨海默病）易感基因的鉴定。同样的方法可以应用于自然衰老过程的研究，以确定与健康长寿有关的基因。识别致病和促进健康的多态性及其与环境的相互作用，有可能极大地改善老年人的健康，老年人是美国人口中增长最快的部分。识别与特定性状相关的基因的一种方法是研究由少数创始成员建立的相对稳定的、孤立的种群，例如印第安纳州北部的阿米什社区。这个社区之前参与了1991-1993年进行的认知障碍横断面调查。在DUMC人类遗传学中心，几个有多个认知障碍个体的家庭被确定并纳入正在进行的痴呆症遗传学研究。我们还在这些家庭中观察到“成功衰老”的明显聚类，这表明这种特征可能在一定程度上受遗传控制。根据这些观察结果，我们建议进行第二次人口调查，以系统地评估80岁及以上的阿米什成年人的认知和功能障碍。我们将确定阿米什社区中成功衰老的家族聚集的流行程度和程度，并进行基因研究以确定与成功衰老相关的基因。为了实现这些目标，我们具体建议：(1)对印第安纳州亚当斯及周边县和俄亥俄州霍姆斯及周边县的80岁及以上阿米什居民进行社区调查；(2)研究成功衰老与长寿相关基因之间的关系；(3)对成功的衰老位点进行完整的基因组筛选；(4)通过定位克隆和候选基因分析方法对基因组筛选结果进行跟踪。

DESCRIPTION (provided by applicant): Advances in molecular and statistical methods have greatly facilitated the identification of susceptibility genes for diseases, such as Alzheimer disease, that are common in older adults. These same methods may be applied to the study of the natural aging process to identify genes that are associated with a long and healthy life. Identification of both disease-causing and health-promoting polymorphisms and their interactions with the environment has the potential to greatly improve the health of older adults, the most rapidly growing segment of the U.S. population. One method of identifying genes associated with a particular trait is to study relatively stable, isolated populations established by a few founding members, such as the Amish community in northern Indiana. This community has previously participated in a cross-sectional survey for cognitive impairment conducted from 1991-1993. Several families with multiple cognitively impaired individuals were identified and included in ongoing studies of the genetics of dementia at the DUMC Center for Human Genetics. We also observed in these families apparent clustering of "successful aging", suggesting that this trait may be, in part, under genetic control. In light of these observations, we propose a second population survey to systematically evaluate Amish adults aged 80 and older for cognitive and functional impairment. We will determine the prevalence and degree of familial aggregation of successful aging in the Amish community and perform genetic studies to identify genes associated with successful aging. To accomplish these goals, we specifically propose to: (1) conduct a community survey of Amish residents aged 80 and older in Adams and surrounding counties in Indiana and Holmes and surrounding counties in Ohio; (2) examine the relationship between successful aging and genes implicated in longevity; (3) perform a complete genomic screen for successful aging loci, and (4) follow-up results of the genomic screen through positional cloning and candidate gene analysis approaches.