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

项目摘要 这是一项行政补充申请，以提高家长补助金的结果：U01 AG046139“针对阿尔茨海默病先天免疫的系统方法”。本行政副刊旨在 在这个队列中扩展多组学分析，并支持从现有的曝光组变量中精选 脑库记录。在家长奖中我们独特的研究队列的设计使我们能够进行比较 对照(无病理)、路径抗原(病理性衰老，淀粉样蛋白+)、阿尔茨海默病(tau+，淀粉样蛋白+)和PSP的分析 (进行性核上性麻痹，tau+)提供一个框架，以确定在 阿尔茨海默病向不同疾病神经病理阶段的过渡。此外，两个大脑区域之间的比较 (TCX=在AD中受影响，CER=在AD中基本不受影响)以及AD和PSP之间的差异可以帮助区分 确认的分子变化可能是病理的原因或结果。我们收集了多组学 对约350名研究参与者的测量，包括遗传(WGS)、转录(RNAseq)和表观基因组(CHIP- SEQ)数据。与其他联盟成员合作，蛋白质组、代谢组和脂肪组学措施 我们/将也会被收集。家长奖中的研究队列集中在非西班牙裔白人(NHW) 个人。通过AMP-AD多样性倡议补充，我们将这项研究扩展到未被研究 由非洲裔美国人(AA)和拉丁美洲人(LA)参与者组成的种族/少数民族队列。这些 努力已经在200种不同的基因、转录和蛋白质组学方面产生了互补的措施 个人。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。两个队列中的样本都来自梅奥诊所脑库 并接受了深入的神经病理检查。对现有记录进行类似的深入审查，以 整理人口统计、生活方式(教育、吸烟和饮酒)、并存疾病、 以及指示脑血管疾病的特定神经病理结果目前尚不清楚。我们 假设曝光组与表观基因组相互作用，以驱动基因表达变化，这可能 导致神经病理和最终神经退行性变的区域性、细胞性和种族脆弱性 疾病。本附录的目标是分别提取和收集曝光组和DNA甲基化数据 梅奥诊所AMP-AD队列的参与者。我们的具体目标是：1.在一个 用现有的和新的(甲基组)脑多组学建立了多种族参与者的尸检队列 数据。2.发现大脑中与AD/ADRD诊断、神经病理学、 并暴露出一些表型。3.确定阿尔茨海默病、相关神经病理和暴露表型对 阿尔茨海默病关键脑细胞类型的DNA甲基化图谱。我们希望发现差异甲基化 揭示大脑区域和细胞的分子机制的区域(DMR) AD中的漏洞及其与Exposome和种族/民族的交互可能会推动这一点。

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.