Plasma beta-amyloid in long lived families: genetics and risk of AD

描述(由申请者提供)：长寿家庭研究(LLFS)是应NIA RFA的要求于2005年建立的，旨在发现有助于健康老龄化和生存的因素。从2006年到2009年，LLFS登记了539名兄弟姐妹(G1)、他们的后代(G2)和配偶(总计4953人)。与参考队列的比较表明，LLFS家族具有很强的EL异常聚集性。与基于人群的队列相比，G2后代具有各种健康老龄化表型(HAP)，其定义为一种或多种特定条件或风险因素的特定年龄段的异常低患病率，这表明LLFS家庭中共享的(可能是遗传的)保护作用丰富。在第二个资助期(2010-2013年)，我们进行了250万个SNP GWA(DBGaP Phs000397)；开发了一种高通量技术，对约450个候选基因进行了测序，并复制了许多变体，发现了更多与健康衰老表型(HAP)和长寿相关的基因。54%的LLFS G1和92%的G2仍然活着。参与者保留率为94%。我们现在建议第三个资助期进行第二次面对面检查(V2)，以前瞻性地研究HAPS随年龄的变化率，并确定导致HAPS和寿命的遗传和其他因素。我们假设，EL和HAPS包含常见和罕见的变异，单独影响不大，但组合在一起强烈影响寿命和特定的HAP，可能只在富含HAPS的家系研究中可检测到，如LLFS。在最初的面对面访问中评估的HAP显示出强烈的连锁峰，这些峰不能用GWAS询问的常见单倍型(HLOD范围为6.0-45.1)来解释。这些可能是由稀有的、谱系私有的等位基因驱动的，这些等位基因只有通过对特定的家族进行测序才能找到，并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。目标是通过表征共有的和不同的LLFS表型和环境因素来确定EL和HAPS的途径。我们将对HAP的个别纵向模式进行表征，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是否可遗传，并测试与内部和外部参照组的差异。具体目标3是使用a)全外显子组测序来全面搜索与HAPS和EL相关的编码变异体，以及b)在显示最强连锁证据的选定家系中对HAPS连锁峰下的区域进行定向调控测序，以寻找与横截面和纵向表型相关的基因/变体。具体目标4是在其他老龄化研究队列中复制我们的遗传和流行病学发现。这项研究可能导致发现影响HAPS和EL的途径和潜在的治疗/预防靶点。1个数据管理和协调中心和4个外地中心是LLFS的主要组成部分。本续展申请书由杜克大学提交。位于丹麦南部赛场中心。

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.