The Long Life Family Study

描述（由申请人提供）：我们将利用多中心长寿家族研究（LLFS），这是一种研究人类长寿和健康老龄化的独特资源，以发现与这些特征相关的遗传变异。在当前阶段，我们成功招募了539个两代家庭中的4，953名个体，并对其进行了广泛的表型分析，这些家庭表现出在上一代中异常生存的聚集性。只有不到1%的FHS家族（大致随机的家族样本）符合LLFS中要求的特殊生存率的最低入选标准。因此，我们最不例外的家庭比99%的Fragrance家庭显示出更多的异常长寿的聚集。此外，与FHS相比，儿童一代具有显著较低的老年主要疾病（包括糖尿病、慢性肺病、外周动脉疾病）的发病率，并且显示出显著更有利的健康老龄化的量化指标（诸如血压、血脂、功能表现和认知指数）的概况。这些内在表型在LLFS家族中比在FHS中表现出更大的聚集性（具有高遗传率）。因此，LLFS可能极大地丰富了长寿和健康衰老内表型的任何基因变异的流行率，从而提高了检测能力。最重要的是，LLFS的家族设计提供了额外的力量和分析机会，发现遗传影响，而不是在无关个体的研究中，特别是在罕见等位基因方面。我们的具体目标是：1）通过在储存的样本上测定健康衰老的生物标志物，每年跟踪受试者的新的重大医疗和健康事件，并将Medicare（和丹麦等同物）疾病和利用数据与参考样品; 2）使用GWAS鉴定用于健康老龄化和异常存活的常见遗传变异; 3）通过靶向测序鉴定用于异常存活和健康老龄化的罕见变异;以及4）通过涉及基因网络和途径的系统方法，更清楚地剖析异常生存和健康老龄化的遗传结构，以更好地理解遗传变异、暴露和协变量之间在内表型发展中的复杂相互作用。采取涉及临床医生，人口统计学家，遗传学家，流行病学家和计算科学家的多学科方法，我们建议利用已经在创建这个独特的队列中进行的投资，以进一步了解异常生存和健康老龄化的本质。 公共卫生相关性：异常长寿和健康老龄化在LLFS中登记的家庭中高度富集，从而使我们有独特的机会发现与这些特征的常见和罕见遗传关联。这种关联不仅会显著增强我们对为什么有些人比其他人衰老得更好的理解，而且还会增强对健康和不健康衰老的解释，并可能导致疾病预防策略。

DESCRIPTION (provided by applicant): We will exploit the multicenter Long Life Family Study (LLFS), a unique resource for research on human longevity and healthy aging, to find genetic variants associated with these traits. In the current period, we successfully enrolled and extensively phenotyped 4,953 individuals in 539 two-generational families that demonstrate clustering for exceptional survival in the upper generation. Fewer than 1% of the Framingham Heart Study (FHS) families (a roughly random sample of families) would meet the minimal entrance criteria for exceptional survival required in the LLFS. Thus our least exceptional families show more clustering for exceptional longevity than 99% of the Framingham families. Further, the children's generation have significantly lower rates of major diseases of aging including diabetes, chronic pulmonary disease, peripheral artery disease and show significantly more favorable profiles of quantitative mariners of healthy aging such as blood pressure, lipids, functional performance, and cognitive indices compared to FHS. These endophenotypes show greater clustering (with high heritability) in the LLFS familiesthan in FHS. Thus, LLFS has likely greatly enriched the prevalence of any gene variants for longevity and healthy aging endophenotypes, thereby increasing detection power. Most importantly, the family design of LLFS provides additional power and analytic opportunities to discover genetic influences than would be possible in a study of unrelated individuals, especially with regard to rare alleles. Our specific aims are to: 1) continue phenotyping by assaying biomarkers of healthy aging on stored samples, annually tracking subjects for new significant medical and health events, and comparing Medicare (and Danish equivalent) disease and utilization data with reference samples; 2) identiy common genetic variants for healthy aging and excepional survival using GWAS; 3) identify rare variants for exceptional survival and healthy aging by targeted sequencing; and 4) more clearly dissect the genetic architecture of exceptional survival an healthy aging through a systems approach involving genet networks and pathways, to better understand the complex interplay between genetic variants, exposures, and covariates in the development of endophenotypes. Taking a multidisciplinary approach involving clinicians, demographers, geneticists, epidemiologists, and computational scientists, we propose to capitalize on the investments already made in creating this unique cohort to further our understanding of the nature of exceptional survival and healthy aging. PUBLIC HEALTH RELEVANCE: Exceptional longevity and healthy aging are highly enriched in the families enrolled in the LLFS thus allowing us a unique opportunity to discover both common and rare genetic associations with these traits. Such associations will not only markedly enhance our understanding of why some people age so much better than others, but will also lead to enhanced prognostication for healthy and unhealthy aging and potentially disease prevention strategies.