Long Life Family Study: University of Pittsburgh Field Center

描述（由申请人提供）：长寿家庭研究（LLFS），成立于2005年，以响应NIA RFA，招募了长寿（EL）丰富的家庭，以发现有助于健康老龄化和生存的因素。从2006年至2009年，LLFS招收了539名兄弟姐妹（G1）、他们的子女（G2）和配偶（总共4 953人）。与参考队列的比较表明，LLFS家庭有很强的例外EL聚类。G2后代具有多种健康老化表型（HAP），定义为与基于人群的队列相比，一种或多种特定疾病或风险因素的年龄特异性患病率异常低，这表明LLFS家族中共享（可能是遗传）保护作用的富集。在第二个资助期（2010-2013年），我们进行了250万个SNP GWAS（dbGaP phs 000397）;开发了一种高通量技术，对约450个候选基因进行了测序，复制了许多变体，并发现了与健康衰老表型（HAP）和长寿相关的其他变体。54%的LLFS G1和92%的G2仍然存活。参与者保留率为94%。我们现在提议在第三个资助期进行第二次面对面检查（V2），以前瞻性研究HAP随年龄的变化率，并确定导致HAP和寿命的遗传和其他因素。我们假设EL和HAP需要常见和罕见的变异，单独具有适度的影响，但在组合中强烈影响寿命和特定的HAP，并且可能仅在富含HAP的家族研究中检测到，如LLFS。在初次亲自访视时评估的HAP显示出强连锁峰，这不能用GWAS询问的常见单倍型来解释（HLOD范围为6.0-45.1）。这些很可能是由罕见的、只有通过对特定家族进行测序才能发现的血统私有等位基因驱动的，并且可能指向重要的新生物学。具体目标1是对所有幸存的LLFS参与者进行第二次家庭检查。具体目标2是分析横截面和纵向表型。我们的目标是通过表征共享和不同的LLFS表型和环境因素来确定EL和HAP的途径。我们将描述HAP的个体纵向模式，以确定显示相似模式和特殊表型的亚组。我们将测试这些HAP是否是可遗传的，并测试与内部和外部参照组的差异。具体目标3是使用a）全外显子组测序以全面搜索与HAP和EL相关的编码变体，和B）显示最强连锁证据的选定家族中HAP的连锁峰下区域的靶向调控测序来发现与横截面和纵向表型相关的基因/变体。具体目标4是在其他衰老研究队列中复制我们的遗传和流行病学发现。这项研究可能会导致影响HAP和EL的途径和潜在的治疗/预防目标的发现。一个数据管理和协调中心和4个现场中心组成了LLFS的主要组成部分。此更新申请由杜克大学提交。/大学南丹麦野战中心

DESCRIPTION (provided by applicant): The Long Life Family Study (LLFS), established in 2005 in response to an NIA RFA, enrolled families enriched for exceptional longevity (EL), to discover factors that contribute to healthy aging and survival. From 2006 to 2009, LLFS enrolled 539 sibships (G1), their offspring (G2) and spouses (total 4,953). Comparison with a referent cohort reveals that LLFS families have strong exceptional clustering of EL. The G2 offspring have a variety of Healthy Aging Phenotypes (HAPs), defined as an unusually low age-specific prevalence of one or more specific conditions or risk factors, compared to population-based cohorts suggesting enrichment of shared (possibly genetic) protective effects in LLFS families. In the second funding period (2010-2013), we conducted a 2.5 million SNP GWAS (dbGaP phs000397); developed a high-throughput technique and sequenced ~450 candidate genes and replicated many variants and found additional ones associated with Healthy Aging Phenotypes (HAP) and longevity. 54% of LLFS G1 and 92% of G2 remain alive. Participant retention has been 94%. We now propose a third funding period to conduct a second in-person examination (V2) to prospectively study rates of change in HAPs with age and identify genetic and other factors contributing to HAPs and longevity. We hypothesize that EL and HAPs entail common and rare variants that individually have modest effects, but which in combinations strongly influence longevity and specific HAPs, and may only be detectable in family studies enriched for HAPs, such as LLFS. HAPs evaluated at the initial in-person visit show strong linkage peaks which are not explained by common haplotypes interrogated by GWAS (HLODs ranging from 6.0-45.1). These are likely driven by rare, lineage-private alleles that will only be found by sequencing specific families, and may point to important new biology. Specific Aim 1 is to conduct a second in-home examination on all surviving LLFS participants. Specific Aim 2 is to analyze cross-sectional and longitudinal phenotypes. The goal is to identify pathways for EL and HAPs by characterizing the shared and distinct LLFS phenotypes and environmental factors. We will characterize individual longitudinal patterns of HAPs to identify subgroups showing similar patterns and exceptional phenotypes. We will test whether these HAPs are heritable, and test for differences with internal and external referent groups. Specific Aim 3 is to find genes/variants associated with cross-sectional and longitudinal phenotypes using a) Whole Exome Sequencing to comprehensively search for coding variants associated with HAPs and EL and b) Targeted Regulatory Sequencing of regions under linkage peaks for HAPs in selected families showing the strongest linkage evidence. Specific Aim 4 is to replicate our genetic and epidemiological findings in other aging study cohorts. This study could lead to the discovery of pathways and potential therapeutic/prevention targets affecting HAPs and EL. A Data Management and Coordinating Center and 4 Field Centers comprise the major components of the LLFS. This renewal application is submitted by the Duke Uni./Uni. of Southern Denmark Field Center.