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

• 批准号: 10381607
• 负责人: Joseph Hyungwoo Lee
• 金额: $ 77.34万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-15 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10381607
• 关键词: Affect; Age; Alleles; Alzheimer' s Disease; Alzheimer' s disease patient; Alzheimer' s disease risk; Amyloid beta-Protein; Biological Markers; Blood; Candidate Disease Gene; Carboxypeptidase; Caribbean Hispanic; Cell model; Cells; Clinical; Clustered Regularly Interspaced Short Palindromic Repeats; Code; Cognition; Collaborations; Colombian; Data; Dementia; Early Onset Alzheimer Disease; Environmental Risk Factor; Family; Family member; Fibroblasts; Funding; Gene Activation; General Population; Genes; Genetic; Genetic Transcription; Genome; Genotype; Goals; Health; Human; Human Genetics; Individual; Joints; Late Onset Alzheimer Disease; Learning; Mediating; Memory; Memory Loss; Memory impairment; Modeling; Multiomic Data; Mutation; Neurons; Not Hispanic or Latino; Pathway interactions; Peptides; Performance; Persons; Phenotype; Puerto Rican; Puerto Rico; Reporting; Resources; Role; SORBS2 gene; Signal Transduction; System; Technology; Testing; Untranslated RNA; Update; Variant; age related; amyloid precursor protein processing; apolipoprotein E-4; base; clinical phenotype; clinically relevant; cognitive function; cohort; exome sequencing; familial Alzheimer disease; founder mutation; gamma secretase; genetic resource; genetic variant; genome sequencing; genome-wide; genomic data; high dimensionality; high risk; high risk population; human model; induced pluripotent stem cell; insight; mutant; mutation carrier; novel; phenotypic data; presenilin-1; prevent; protective allele; recruit; response; risk variant; tau Proteins; therapeutic target; trait; transcriptome sequencing; transcriptomics; whole genome

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的PSEN1-G206A突变中鉴定受保护的遗传变异 载体。如果成功，我们也许可以学习这些受保护的变体如何延迟发病的年龄 （AAO）痴呆或与年龄相关的记忆下降。在2001年，我们确定了PSEN1中的一个创始人突变 （g206a）来自八个加勒比西班牙裔家庭的家庭成员，起源于波多黎各。平均值 这种突变发病时的年龄异常晚（平均：55.6岁），并且在AS内的变化很大 以及整个家庭，范围从22 - 77年。在这组波多黎各家庭中，有多个受影响的 家庭成员，这种突变与apoeε4一样普遍，但是与具有2至3--的ApoEε4载体不同。 倍数增加了AD的风险，大多数PSEN1携带者最终会出现阿尔茨海默氏病（AD）。 我们的飞行员整个外显子组测序（WES）研究确定了6种候选基因，这些基因可能具有变种 更改AA的AAO，这些变体在AAO的AAO [2]中占15 - 20年的差异。 然后我们表明，有6个基因中有3个具有与具有可变AAO相关的SNP 延迟发作AD（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。 这项研究提案将整个基因组测序（WGS）数据与基因组宽SNP（GWAS）数据相结合 通过关注这组G206A载体家族，以识别AAO或记忆性状的遗传修饰符。到 日期，我们已经招募并检查了75个至少有一个人的延长的EOAD家庭 携带G206A突变。大多数人都有深入的表型数据和GWAS数据。此外，我们还有 与Kosik博士建立了合作，他研究了具有不同PSEN1（E280）突变的哥伦比亚人群 这将允许独立确认。此外，我们将能够采用高维度 与De Jager博士合作的ROS/MAP的OMIC数据。为了评估普遍性，我们将 可以访问独立的一组无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，然后检查这些变体在一般人群中是如何相关的。 最后，我们将使用基于细胞的系统来测试修饰符在Aβ途径中的作用。 将所有遗传资源一起汇总在一起，我们将能够与 鉴定受保护变体和基因的创始人突变。我们将：（1）进行WGS研究以识别新颖 变体； （2）表征新颖修饰符变体与AAO之间的关系或通过 检查EOAD和负载的转录组和外部基因组数据； （3）调查 使用人成纤维细胞和IPSC衍生的神经元培养物的PSEN1修饰符作用机理。如果 成功，可能可以确定可能延迟或防止广告或 保持健康的认知。