Whole Genome Sequencing and Admixture Analyses of Neuropathologic Traits in Diverse Cohorts in USA and Brazil

美国和巴西不同群体神经病理特征的全基因组测序和混合分析

• 批准号: 10590405
• 负责人: DAVID ALAN BENNETT
• 金额: $ 367.18万
• 依托单位: RUSH UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-15 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10590405
• 关键词: Address; Admixture; African; African ancestry; Aging; Alzheimer' s Disease; Alzheimer' s disease related dementia; Autopsy; Biological; Black Populations; Blood; Brain; Brazil; Budgets; Cerebrovascular Disorders; Clinical; Clinical Data; Cognition; Collaborations; Communities; DNA; Data; Dementia; European; Genes; Genetic Variation; Goals; Latinx; Length; Lewy Body Disease; Linkage Disequilibrium; Maps; Mitochondrial DNA; Molecular; Participant; Pathologic; Pathology; Persons; Phenotype; Proteins; Public Health; Research; Sampling; Silicon Dioxide; Source; Testing; Tissues; Variant; Work; admixture mapping; causal variant; cohort; genome sequencing; genome wide association study; genome-wide; hippocampal sclerosis; neuropathology; novel; prospective; protein TDP-43; public health priorities; rare variant; response; sex; telomere; trait; whole genome

ABSTRACT Identifying molecular drivers of Alzheimer’s disease and related dementias (AD/ADRD) pathologies is an urgent public health priority. This is especially important in persons of African Ancestry. The overall goal of the proposed study is to identify genes and proteins that drive common AD/ADRD pathologic traits. We previously used multi-level omics to identify molecular drivers of AD/ADRD pathologic traits in non-Latinx whites. The proposed study, submitted in response to NOT-AG-18-053 will extend this work by leveraging an unique, ongoing, diverse study being conducted in Sao Paulo, Brazil, called “Pathology, Alzheimer´s and Related Dementias Study” (PARDoS) and five other diverse cohorts in the USA, with whole genome sequencing (WGS) on more than 1350 diverse autopsied participants. PARDoS is prospectively generating neuropathologic and clinical AD/ADRD traits, and DNA on admixed Brazilians of European and African, and to a lesser extent Native Brazilian ancestry. The proposal has the following Aims. Aim 1 will generate WGS on an additional 7650 persons in collaboration with the Alzheimer’s Disease Sequencing Project (ADSP). Aim 2 will perform deep admixture mapping of known SNPs for Alzheimer’s dementia, to determine their associations with AD/ADRD neuropathologic phenotypes in 6500 admixed Brazilian brains followed generalization to 300 diverse brains from the USA, and discovery analyses for 5500 Brazilians followed by generalization to 2000 diverse samples in the USA. Aim 3 will computationally determine telomere length (TL) and examine their association with AD/ADRD clinical and pathologic traits. An exploratory analysis will examine for rare variant associations with AD/ADRD neuropathologic traits. Aim 5 will examine the association of mitochondrial DNA to AD/ADRD traits.

抽象的 识别阿尔茨海默病和相关痴呆 (AD/ADRD) 病理的分子驱动因素是 紧迫的公共卫生优先事项对于非洲血统的人来说尤其重要。 拟议的研究旨在识别驱动常见 AD/ADRD 病理特征的基因和蛋白质。 我们之前使用多层次组学来识别非拉丁裔 AD/ADRD 病理特征的分子驱动因素 针对 NOT-AG-18-053 提交的拟议研究将通过利用 一项独特的、持续的、多样化的研究正在巴西圣保罗进行，名为“病理学、阿尔茨海默病和 相关痴呆症研究”（PARDoS）和美国其他五个不同的队列，具有全基因组 正在对超过 1350 名不同的尸检参与者进行测序 (WGS)。 欧洲和非洲混血巴西人的神经病理学和临床 AD/ADRD 特征以及 DNA，并 该提案具有以下目标。 目标 1 将与阿尔茨海默氏病合作对另外 7650 人进行全基因组测序 测序项目 (ADSP) 将对阿尔茨海默病的已知 SNP 进行深度混合作图。 痴呆症，以确定它们与 6500 名混合患者的 AD/ADRD 神经病理表型的关联 巴西大脑对美国 300 个不同的大脑进行了概括，并对 5500 个大脑进行了发现分析 巴西人随后将其推广到美国的 2000 个不同样本，然后通过计算确定。 端粒长度 (TL) 并检查其与 AD/ADRD 临床和病理特征的关系。 分析将检查与 AD/ADRD 神经病理特征的罕见变异关联。 目标 5 将检查 线粒体 DNA 与 AD/ADRD 特征的关联。