Protective genetic factors of Alzheimer disease in PSEN1 Mutation Carriers in Puerto Rico

波多黎各 PSEN1 突变携带者阿尔茨海默病的保护性遗传因素

基本信息

批准号：
10414433
负责人：
Joseph Hyungwoo Lee
金额：
$ 40.4万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-15 至 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10414433
关键词：
Address Administrative Supplement Affect African Age Alleles Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease patient Alzheimer&apos s disease risk Amyloid Amyloid beta-Protein Autophagocytosis Autopsy Biological Assay Brain Candidate Disease Gene Caribbean Hispanic Caucasians Cell Line Cell model Cells Code Cognition Collaborations Colombian Data Dementia European Family Family member Fibroblasts Functional disorder General Population Genes Genetic Genome Goals Hela Cells Hispanics Human Human Cell Line Individual Institutes Investigation Late Onset Alzheimer Disease Learning Literature Lysosomes Memory Memory Loss Memory impairment Methods Multiomic Data Mutation Neurons Not Hispanic or Latino Outcome Pathogenesis Pathway interactions Performance Persons Phenotype Population Presenile Alzheimer Dementia Production Proteins Puerto Rican Puerto Rico Reporting Role Sampling Specific qualifier value Structure System Technology Testing Tissue-Specific Gene Expression Untranslated RNA Variant age related amyloid precursor protein processing apolipoprotein E-4 base brain tissue clinically relevant cohort exome sequencing founder mutation genetic architecture genetic resource genetic variant genome sequencing genome-wide genomic data high dimensionality high risk population induced pluripotent stem cell knock-down mutation carrier novel parent grant phenotypic data presenilin-1 prevent protective allele protective effect recruit therapeutic target trafficking trait transcriptomics whole genome

项目摘要

ABSTRACT The main goal is to identify protective genetic variants from a group of high-risk PSEN1-G206A mutation carriers. If successful, we may be able to learn how these protective variants may delay the age at onset (AAO) of dementia or 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 was as prevalent as APOE ε4, but, unlike APOE ε4 carriers who have a 2- to 3- fold increased risk of AD, most PSEN1 carriers will develop Alzheimer disease (AD) eventually. Our pilot whole exome sequencing (WES) study identified 6 candidate genes that may harbor variants that alter the AAO of AD, and these variants accounted for as much as 15-20 year differences in AAO of AD [2]. We then showed that 3 out of 6 genes had SNPs that were associated with variable AAO in individuals with late onset AD (LOAD), suggesting that these may be generalizable to LOAD, the most common form of AD. This study proposes to integrate whole genome sequencing (WGS) data with genome wide SNP (GWAS) data to identify genetic modifiers of AAO or memory traits by focusing on this set of the G206A carrier families. To date, we have recruited and examined over 75 extended EOAD families that have at least one person who carry the G206A mutation. Most individuals have in-depth phenotype data and GWAS data. Further, we have established collaboration with Dr. Kosik who study a Colombian cohort with a different PSEN1 (E280) mutation which will allow independent confirmation. In addition, we will be able to employ the high dimensional multi- omic data of ROS/MAP from the collaboration with Dr. De Jager’s group. To assess generalizability, we will be able to access independent sets of unrelated Caribbean Hispanics and non-Hispanic Whites to further confirm the allelic association, and then to examine how clinically relevant these variants are in general populations. Lastly, we will use cell based systems to test the role of modifiers in the Aβ pathway. Taking all the genetic resources together, we will be able to interrogate the genomes of this unique cohort with a founder mutation to identify protective variants and genes. We will: (1) conduct a WGS study to identify novel variants; (2) characterize the relations between novel modifier variants and AAO or memory through examination of transcriptomic and external genomic data of EOAD and LOAD; and (3) investigate the mechanisms of action of modifiers of PSEN1 using human fibroblast and iPSC-derived neuronal cultures. If successful, it may be possible to identify a potential therapeutic target(s) that might delay or prevent AD or maintain healthy cognition.

抽象的主要目标是从一组高风险 PSEN1-G206A 突变中识别保护性遗传变异如果成功，我们也许能够了解这些保护性变异如何延迟发病年龄。 2001 年，我们发现了 PSEN1 的一个创始人突变。 (G206A) 来自八个来自波多黎各的加勒比西班牙裔家庭的家庭成员的平均值。这种突变的发病年龄异常晚（平均：55.6 岁），并且在在这组波多黎各家庭中，有多个受影响的家庭，年龄从 22 岁到 77 岁不等。在家庭成员中，这种突变与 APOE ε4 一样普遍，但与具有 2 至 3- 基因的 APOE ε4 携带者不同患 AD 的风险成倍增加，大多数 PSEN1 携带者最终会患上阿尔茨海默病 (AD)。我们的试点全外显子组测序 (WES) 研究确定了 6 个可能含有变异的候选基因改变 AD 的 AAO，这些变异导致 AD 的 AAO 长达 15-20 年的差异[2]。然后我们发现，6 个基因中有 3 个具有与患有 AAO 的个体中的可变 AAO 相关的 SNP。迟发性 AD (LOAD)，表明这些可能可以推广到 LOAD，这是最常见的 AD 形式。本研究建议将全基因组测序 (WGS) 数据与全基因组 SNP (GWAS) 数据整合通过关注这组 G206A 携带者家族来识别 AAO 或记忆性状的遗传修饰剂。迄今为止，我们已经招募并审查了超过 75 个 EOAD 大家庭，这些家庭中至少有一个人大多数个体都有深入的表型数据和 GWAS 数据。与 Kosik 博士建立了合作，Kosik 博士研究了具有不同 PSEN1 (E280) 突变的哥伦比亚队列这将允许独立确认。此外，我们将能够采用高维多维。与 De Jager 博士团队合作的 ROS/MAP 组学数据为了评估普遍性，我们将能够访问独立的一组不相关的加勒比西班牙裔和非西班牙裔白人，以进一步确认等位基因关联，然后检查这些变异在一般人群中的临床相关性。最后，我们将使用基于细胞的系统来测试修饰剂在 Aβ 途径中的作用。将所有遗传资源放在一起，我们将能够通过以下方法来探究这个独特群体的基因组：我们将：(1) 进行全基因组测序（WGS）研究来识别新的变异。 (2) 通过以下方式表征新修饰语变体与 AAO 或记忆之间的关系检查 EOAD 和 LOAD 的转录组和外部基因组数据；以及 (3) 研究使用人成纤维细胞和 iPSC 衍生的神经培养物研究 PSEN1 修饰剂的作用机制。成功的话，就有可能识别出可能延迟或预防 AD 的潜在治疗靶点，或者保持健康的认知。

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Rare Variants Imputation in Admixed Populations: Comparison Across Reference Panels and Bioinformatics Tools.

混合人群中的罕见变异插补：参考面板和生物信息学工具之间的比较。

DOI：
发表时间：
2019
期刊：
影响因子：
0
作者：
Sariya, Sanjeev;Lee, Joseph H;Mayeux, Richard;Vardarajan, Badri N;Reyes;Manly, Jennifer J;Brickman, Adam M;Lantigua, Rafael;Medrano, Martin;Jimenez;Tosto, Giuseppe
通讯作者：
Tosto, Giuseppe