Integrating the exposome and methylome to inform brain molecular changes in ADRD across established diverse cohorts.

项目摘要 这是一个行政补充申请，以提高家长补助金的结果：U 01 AG046139“A Systems Approach to Targeting Innate Immunity in AD”。本行政补充文件旨在 扩展该队列中的多组学分析，并从现有的 大脑银行记录我们在家长奖中独特的研究队列的设计使我们能够进行比较 对照（无病理）、PathAg（病理老化，淀粉样蛋白+）、AD（tau+，淀粉样蛋白+）和PSP的分析 （进行性核上性麻痹，tau+）提供了一个框架，以确定在 向AD的不同疾病神经病理学阶段的转变。此外，比较两个大脑区域 (TCX=受影响，CER=在AD中基本上不受影响）以及AD和PSP之间的差异有助于区分 鉴定的分子变化可能是病理的原因或结果。我们收集了多组学 在约350名研究参与者中进行了测量，包括遗传学（WGS）、转录组学（RNAseq）和表观基因组学（ChIP）。 Seq）数据。与其他联盟成员合作，进行蛋白质组学、代谢组学和脂质组学测量 也将被收集。父母奖的研究队列集中在非西班牙裔白色（NHW） 个体通过AMP-AD多样性倡议补充，我们将本研究扩展到了 种族/少数民族队列，包括非洲裔美国人（AA）和拉丁美洲人（LA）参与者。这些 在超过200个不同的基因组中， 个体然而，目前缺乏来自亲本（NHW）的互补DNA甲基化数据。 和多样性补充（AA，LA）队列。两个队列中的样本均来自马约诊所脑库 并接受了深入的神经病理学检查。对现有记录进行类似的深入审查， 收集人口统计学、生活方式（教育、吸烟和饮酒）、共病数据， 以及目前缺乏指示脑血管疾病的特定神经病理学发现。我们 假设该基因组与表观基因组相互作用以驱动基因表达变化， 是区域性、细胞性和民族性神经病理学脆弱性的基础， 疾病本增刊的目的是分别提取和收集染色体组和DNA甲基化数据 对于马约诊所AMP-AD队列的参与者。我们的具体目标是：1.确定在一个 建立了具有现有和新（甲基化组）脑多组学的多种族参与者的尸检队列 数据2.发现与AD/ADRD诊断，神经病理学， 和麻烦的表型。3.确定AD、相关神经病理学和干扰素组表型对 AD中关键脑细胞类型的DNA甲基化图谱。我们希望能找出差异甲基化的 区域（DMR），揭示大脑区域和细胞的分子机制 AD的脆弱性及其与可能导致这种情况的麻烦和种族/民族的相互作用。

Project Summary This is an application for an administrative supplement to enhance the outcome of the parent grant: U01 AG046139 “A Systems Approach to Targeting Innate Immunity in AD”. This Administrative Supplement aims to expand the multiomics profiling in this cohort and enable curation of exposome variables from existing brain bank records. The design of our unique study cohort in the parent award enables us to perform comparative analysis of control (no pathology), PathAg, (Pathologic Aging, amyloid+), AD (tau+, amyloid+) and PSP (progressive supranuclear palsy, tau+) providing a framework to identify therapeutic targets that play a role in the transition to different disease neuropathologic stages of AD. Further, comparisons between two brain regions (TCX=affected and CER=largely spared in AD) and between AD and PSP can help distinguish whether the molecular changes identified are likely a cause or consequence of pathology. We have collected multiomics measures in ~350 study participants, including genetic (WGS), transcriptomic (RNAseq) and epigenomic (ChIP- Seq) data. In collaboration with other consortia members, proteomic, metabolomic and lipidomic measures were/will also be collected. The study cohort in the parent award is focused on non-Hispanic White (NHW) individuals. Through the AMP-AD diversity initiative supplement, we expanded this study to understudied racial/ethnic minority cohorts comprising African American (AA) and Latin American (LA) participants. These efforts have generated complementary genetic, transcriptomic and proteomic measures on >200 diverse individuals. However, complementary DNA methylation data is currently lacking from both the parent (NHW) and the diversity supplement (AA, LA) cohorts. The samples in both cohorts are from the Mayo Clinic brain bank and have undergone in-depth neuropathological examination. A similarly in-depth review of available records to curate data on demographic, lifestyle (education, smoking and alcohol consumption), comorbid diseases, as well as specific neuropathological findings indicative of cerebrovascular disease is currently lacking. We hypothesize that the exposome interacts with the epigenome to drive gene expression changes which may underlie regional, cellular and ethno-racial vulnerabilities to neuropathology and ultimately neurodegenerative disease. The goal of this Supplement is to extract and collect exposome and DNA methylation data respectively for participants in the Mayo Clinic AMP-AD cohorts. Our specific aims are: 1. Identify exposome variables in an established post-mortem cohort of multi-ethnic participants with existing and new (methylome) brain multi-omics data. 2. Discover differentially methylated regions in brain associated with AD/ADRD diagnosis, neuropathology, and exposome phenotypes. 3. Identify impacts of AD, related neuropathologies and exposome phenotypes on the DNA methylation profile of key brain cell types in AD. We expect to identify differentially methylated regions (DMRs) that reveal the molecular mechanisms underlying brain regional and cellular vulnerabilities in AD and their interactions with exposome and race/ethnicity that may drive this.