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

摘要 确定阿尔茨海默病和相关痴呆(AD/ADRD)病理的分子驱动因素是 紧急公共卫生优先事项。这对非洲血统的人来说尤其重要。的总目标是 这项拟议的研究旨在确定驱动常见AD/ADRD病理特征的基因和蛋白质。 我们以前使用多水平组学来确定非Latinx患者AD/ADRD病理特征的分子驱动因素 白色的。针对NOT-AG-18-053提交的拟议研究将通过利用 巴西圣保罗正在进行一项独特的、正在进行的、多样化的研究，名为《阿尔茨海默病的病理学》S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 对1350多名不同的尸检参与者进行测序(WGS)。帕尔多斯可能会产生 欧洲和非洲混血巴西人的神经病理和临床AD/ADRD特征和DNA 较小程度的巴西原住民血统。该提案有以下目标。 AIM 1将与阿尔茨海默病合作，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SNPs进行深度混合作图 痴呆症与AD/ADRD神经病理表型的相关性 巴西人的大脑对来自美国的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 巴西人随后将其推广到美国的2000个不同的样本。目标3将通过计算确定 端粒长度(TL)及其与AD/ADRD临床和病理特征的关系。探索性的 分析将检查与AD/ADRD神经病理特征相关的罕见变异。 Aim 5将研究 线粒体DNA与AD/ADRD性状的相关性。

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.