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 识别阿尔茨海默氏病的分子驱动因素和相关痴呆症（AD/ADRD）病理学是一种 紧急公共卫生优先事项。这在非洲血统的人中尤其重要。总体目标 拟议的研究是确定驱动常见AD/ADRD病理特征的基因和蛋白质。 我们以前使用多层次的OMICS鉴定非Latinx中AD/ADRD病理性状的分子驱动因素 白人。提出的针对NOT-AG-18-053提交的拟议研究将通过利用一个 在巴西的圣保罗进行的独特，持续的，多元化的研究称为“病理学，阿尔茨海默氏症和 相关痴呆症研究”（帕尔多斯）和美国其他五个潜水员队列，全基因组 在1350多名潜水员尸体尸体参与者中进行测序（WGS）。帕尔多斯可能正在产生 神经病理学和临床广告/ADRD特征，以及对欧洲和非洲的巴西混合性的DNA，以及 较小的巴西本地血统。该提案具有以下目标。 AIM 1将与阿尔茨海默氏病合作，在另外7650人身上生成WGS 测序项目（ADSP）。 AIM 2将对阿尔茨海默氏症的已知SNP进行深层混合映射 痴呆症，确定其与6500中的AD/ADRD神经病理表型的关联 巴西大脑遵循美国的300名潜水大脑的概括，并进行了5500的发现分析 巴西人随后对美国的2000名潜水员样本进行了概括。 AIM 3将在计算上确定 端粒长度（TL）并检查其与AD/ADRD临床和病理特征的关联。探索性 分析将检查与AD/ADRD神经病理学特征的罕见变体关联。 AIM 5将检查 线粒体DNA与AD/ADRD性状的关联。