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

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos 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

项目摘要

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标是通过研究一组来识别 PSEN1 突变的遗传修饰因子高风险PSEN1-G206A突变携带者如果成功的话，我们也许能够了解这些修饰变体是如何发生的。可以通过延迟发病年龄或减缓与年龄相关的记忆衰退来降低 AD 风险。2001 年，我们发现。在来自八个加勒比西班牙裔家庭的家庭成员中发现了 PSEN1 (G206A) 的创始人突变起源于波多黎各此突变的平均发病年龄异常晚（平均：55.6 岁）在这一群体中，家庭内部和家庭之间的差异并不常见，年龄范围为 22 岁至 77 岁。波多黎各家庭有多名受影响的家庭成员，这种突变与 APOE ε4 一样普遍，但是，与 APOE ε4 携带者 AD 风险增加不同，大多数 PSEN1 携带者最终会发展为 AD 阿尔茨海默病（AD）。为了确定这些PSEN1突变携带者家族是否可以用于鉴定遗传修饰剂，我们使用 31 个 G206A 携带者进行了一项试点全外显子组测序 (WES) 研究，我们确定了 6 个候选者。可能含有改变这些家族中 AD 发病的变异的基因，以及这些基因内的变异 AD 发病年龄差异高达 15-20 岁 [2]，然后我们观察到其中三者。六个基因的 SNP 与晚发 AD 个体的不同发病年龄相关 (LOAD)，表明这些可以推广到 LOAD，这是最常见的 AD 形式。在本研究中，我们建议进行最先进的全基因组测序（WGS）来识别发病年龄或记忆表现的遗传修饰，同时利用这一独特的高风险群体迄今为止，我们已经招募并检查了 75 个具有一个或多个 EOAD 家族。更多携带 PSEN1-G206A 突变的个体，其中大多数具有深度表型。此外，我们还将获得独立的、不相关的加勒比海数据集。西班牙裔和非西班牙裔白人检查这些变异在总体上的临床相关性这项研究的短期目标是确定改变发病年龄和/或年龄的遗传变异。 PSEN1-G206A 携带者的记忆表现，但长期目标是确定潜在的治疗方法可能延迟或预防 AD 的目标。