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.

摘要 识别阿尔茨海默病和相关痴呆（AD/ADRD）病理学的分子驱动因素是一项重要的研究。 紧急公共卫生优先事项。这一点对非洲人来说尤其重要。的总目标 这项研究的目的是鉴定驱动AD/ADRD共同病理特征的基因和蛋白质。 我们以前使用多水平组学来鉴定非拉丁裔AD/ADRD病理特征的分子驱动因素， 白人根据NOT-AG-18-053提交的拟议研究将通过利用 在巴西圣保罗进行的一项独特的、正在进行的、多样化的研究，名为“病理学、阿尔茨海默氏症和 相关痴呆症研究”（PARDoS）和美国其他五个不同的队列，全基因组 测序（WGS）对1350多名不同的尸检参与者进行了研究。PARDoS正在前瞻性地生成 神经病理学和临床AD/ADRD特征，以及欧洲和非洲混合巴西人的DNA，以及 巴西原住民血统。该提案的目的如下。 目标1将与阿尔茨海默氏病研究所合作，为另外7650人提供WGS 测序项目（ADSP）。目标2将对阿尔茨海默病的已知SNP进行深度混合作图 痴呆，以确定其与AD/ADRD神经病理表型在6500混合 巴西人的大脑随后对来自美国的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。 巴西人随后推广到2000个不同的样本在美国。目标3将通过计算确定 端粒长度（TL），并检查其与AD/ADRD临床和病理特征的关系。探索性 分析将检查罕见变异与AD/ADRD神经病理学特征的关联。 目标5将审查 线粒体DNA与AD/ADRD性状的关联。