Genetic Modifiers of Alzheimer Disease in PSEN1 Mutation Carriers in Puerto Rico

波多黎各 PSEN1 突变携带者中阿尔茨海默病的遗传修饰

• 批准号: 9353174
• 负责人: Joseph Hyungwoo Lee
• 金额: $ 84.22万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-30 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9353174
• 关键词: Accounting; Affect; Age; Algorithms; Alleles; Alzheimer' s Disease; Alzheimer' s disease risk; Amyloid beta-Protein; Biological Factors; Biological Markers; Candidate Disease Gene; Caribbean Hispanic; Code; Data; Data Set; Environmental Risk Factor; Family; Family member; Gene-Modified; General Population; Genes; Genetic; Genetic study; Goals; Health; Individual; Joints; Late Onset Alzheimer Disease; Lead; Learning; Memory; Memory Loss; Mutation; Not Hispanic or Latino; Parents; Participant; Performance; Phenotype; Pilot Projects; Population; Presenile Alzheimer Dementia; Process; Puerto Rican; Puerto Rico; Recruitment Activity; Reporting; Resources; Signal Transduction; Testing; Time; Untranslated RNA; Update; Variant; age related; base; clinical phenotype; clinically relevant; cohort; exome sequencing; founder mutation; genetic variant; genome sequencing; genome wide association study; genome-wide; genome-wide linkage; high risk; insight; member; mutation carrier; novel; presenilin-1; prevent; tau Proteins; therapeutic target; whole genome

SUMMARY The primary goal of this project is to identify genetic modifiers of the PSEN1 mutation by studying a group of high risk PSEN1-G206A mutation carriers. If successful, we may be able to learn how these modifier variants may lower the risk of AD by delaying age at onset or slowing age-related memory decline. In 2001, we identified a founder mutation in PSEN1 (G206A) in family members from eight Caribbean Hispanic families with origins in Puerto Rico. The average age at onset with this mutation was unusually late (mean: 55.6 years) and was remarkably variable within as well as across families, ranging from 22-77 years. In this group of Puerto Rican families with multiple affected family members, this mutation is as prevalent as APOE ε4, but, unlike APOE ε4 carriers who have an increased risk of AD, most PSEN1 carriers will eventually develop Alzheimer disease (AD). To determine whether these PSEN1 mutation carrier families can be used to identify genetic modifiers, we performed a pilot whole exome sequencing (WES) study. Using 31 G206A carriers, we identified six candidate genes that may harbor variants that alter onset of AD in these families, and variants within these genes accounted for as much as 15-20 years differences in age at onset of AD [2]. We then observed that three out of six genes had SNPs that were associated with variable age at onset in individuals with late onset AD (LOAD), suggesting that these may be generalizable to LOAD, the most common form of AD. In the present study, we propose to perform state of the art whole genome sequencing (WGS) to identify genetic modifiers of age at onset or memory performance, while capitalizing on this unique high risk group with a founder mutation. To date, we have recruited and examined 75 extended EOAD families that have one or more individuals who carry the PSEN1-G206A mutation. Most of these individuals have in-depth phenotype data as well as GWAS data. In addition, we will have access to independent sets of unrelated Caribbean Hispanics as well as non-Hispanic Whites to examine how clinically relevant these variants are in the general populations. The short-term goal of this study is to identify genetic variants that modify the age at onset and/or memory performance in PSEN1-G206A carriers, but the long-term goal is to identify a potential therapeutic target(s) that might delay or prevent AD.

概括 该项目的主要目的是通过研究一组一组，识别PSEN1突变的遗传修饰符 高风险PSEN1-G206A突变载体。如果成功，我们也许能够学习这些修饰符的变体 通过延迟发病时的年龄或与年龄相关的记忆力下降，可能会降低AD的风险。在2001年，我们 在PSEN1（G206A）中确定了来自八个加勒比西班牙裔家庭的家庭成员中的一个创始人突变 起源于波多黎各。这种突变开始时的平均年龄异常迟到（平均：55.6岁） 在整个家庭内和整个家庭之间的变化都非常多，范围从22 - 77年。在这一组 波多黎各人家庭具有多个受影响的家庭成员，这种突变与apoeε4一样普遍，但是， 与APOEε4承运人的AD风险增加不同，大多数PSEN1载体最终都会发展 阿尔茨海默氏病（AD）。 为了确定这些PSEN1突变载体家族是否可以用于识别遗传修饰符，我们 进行了整个外显子组测序（WES）研究。使用31 G206A载体，我们确定了六名候选人 可能具有改变这些家族中AD发作的变体的基因以及这些基因中的变体 AD发作时的年龄差异高达15-20岁[2]。然后我们观察到三个 在六个基因中，有SNP与发病滞后AD的个体发作时的变化年龄相关 （负载），表明这些可能是可以推广到负载的，这是AD的最常见形式。 在本研究中，我们建议执行最先进的整个基因组测序（WGS）以识别 发病或记忆表现时年龄的遗传修饰符，同时利用这个独特的高风险群体 创始人突变。迄今为止，我们已经招募并检查了75个具有一个或一个或 携带PSEN1-G206A突变的更多人。这些人中的大多数都有深入的表型 数据以及GWAS数据。此外，我们将可以访问独立的一组无关的加勒比海 西班牙裔以及非西班牙裔白人，以检查这些变体在临床上的相关性如何 人群。这项研究的短期目标是确定在发作和/或改变年龄的遗传变异体 PSEN1-G206A载体中的内存性能，但长期目标是确定潜在的疗法 可能延迟或阻止AD的目标。