Ethnic-specific Effects of Mitochondrial DNA Variants and Environmental Factors on Cognitive Functioning and Dementia

在75岁以上的美国种族/族裔群体中，非洲裔美国人表现出最高的认知障碍。 患病率（32%）其次是西班牙裔（23%）和非西班牙裔白人（10%）。我们的建议是 多种新的基因组工具，旨在捕获阿尔茨海默病（AD）和相关疾病的种族特异性靶点， 痴呆症（ADRD）的线粒体DNA。我们提案的一个新颖之处在于， 将人类线粒体遗传关联纳入细胞和动物实验范例，并推断 这些mtSNPs修饰了脑源性肽（MDP），MDP是一组微肽， 对代谢和神经退行性疾病过程的深远影响。我们在本提案中提供证据 我们已经在非西班牙裔白人、非洲裔美国人和西班牙裔美国人中发现了三种mtSNPs， 通过MDP以种族特异性方式与AD表型相关。在这份提案中，我们将 几种新的遗传分析：（1）线粒体全基因组关联研究（MiWAS），（2）线粒体 全基因组GxE和GxG相互作用研究（MiWIS），以及（3）线粒体RNASeq差异表达 分析（线粒体转录组学），在三个大的纵向多种族队列中进行比较， 认知能力下降的测量以及生活方式和代谢因素（例如，体重指数，糖尿病， 体力活动）。使用健康和退休研究（HRS）以及地理和种族的原因 卒中（REGARDS）队列的差异，我们将对非西班牙裔进行MiWAS和MiWIS发现 白人（n~ 14，300）、非洲裔美国人（n~ 13，400）和西班牙裔美国人（n~ 2，420）。我们将测试结果的重复性 来自HRS和REGARDS的关于认知下降和使用不同Rush阿尔茨海默氏症诊断临床AD的研究 疾病中心（RADC）队列（n~ 4，500）。我们将对HRS的所有种族群体进行线粒体转录组学研究 （n~ 4，000;白色血细胞）和RADC（n~640;大脑前额皮质）中。我们的核心假设是 线粒体单核苷酸多态性和线粒体基因表达将预测临床AD诊断和认知能力下降的不同， 种族在这个项目中，我们组建了一个跨学科的团队：1）识别种族特异性的mtSNPs 预测认知能力下降、ADRD和AD。2)识别与生活方式因素相互作用的种族特异性mtSNP 或核SNP影响认知衰退、ADRD和AD。3)研究是否有基因编码 在不同种族中，相对于AD或ADRD状态，脑源性肽的表达存在差异。 该项目允许发现线粒体遗传靶点，这些靶点可以作为基于精确度的， 种族特异性，潜在的ADRD治疗靶点，以来源于线粒体的微肽的形式。 这项提案的结果将有助于AD治疗发现，因为国家的组成 人口在种族上变得更加多样化。

Among U.S race/ethnic groups over 75 years of age, African Americans exhibit the highest cognitive impairment prevalence (32%) followed by Hispanics (23%) and Non-Hispanic Whites (10%). Our proposal implements multiple novel genomic tools designed to capture ethnic-specific targets of Alzheimer's disease (AD) and related dementias (ADRD) within the mitochondrial DNA. A novel aspect of our proposal is that we can rapidly translate human mitochondrial genetic associations into cellular and animal experimental paradigms and infer whether these mtSNPs modify mitochondrial-derived peptides (MDPs), which are a group of micro-peptides that display profound effects on metabolic and neurodegenerative disease processes. We provide evidence in this proposal that we have already identified three mtSNPs in Non-Hispanic Whites, African Americans, and Hispanics that associate with AD phenotypes in an ethnic-specific fashion through MDPs. In this proposal, we will conduct several novel genetic analyses: (1) Mitochondrial Genome Wide Association Studies (MiWAS), (2) Mitochondrial Genome Wide GxE and GxG Interaction Studies (MiWIS), and (3) mitochondria RNASeq differential expression analysis (mito-transcriptomics), in three large, longitudinal multi-ethnic cohorts with comparable repeated measures of cognitive decline as well as lifestyle and metabolic factors (e.g., body mass index, diabetes, and physical activity). Using the Health and Retirement Study (HRS) and REasons for Geographic And Racial Differences in Stroke (REGARDS) cohorts, we will conduct discovery MiWAS and MiWIS for Non-Hispanic Whites (n~14,300), African Americans (n~13,400), and Hispanics (n~2,420). We will test replication of findings from HRS and REGARDS on cognitive decline and diagnosis of clinical AD using the diverse Rush Alzheimer's Disease Center (RADC) cohorts (n~4,500). We will conduct mito-transcriptomics for all ethnic groups in HRS (n~4,000; white blood cells) and in RADC (n~640; brain prefrontal cortex). Our central hypothesis is that specific mtSNPs and mitochondrial gene expression will predict clinical AD diagnosis and cognitive decline differently by ethnicity. For this project, we have assembled an interdisciplinary team to: 1) Identify ethnic-specific mtSNPs that predict cognitive decline, ADRD, and AD. 2) Identify ethnic-specific mtSNPs that interact with lifestyle factors or nuclear SNPs to affect cognitive decline, ADRD, and AD. 3) Investigate whether genes that encode mitochondrial-derived peptides are differentially expressed relative to AD or ADRD status in different ethnicities. This project permits discovery of mitochondrial genetic targets that can be explored as precision-based, ethnic-specific, potential ADRD treatment targets, in the form of micro-peptides derived from the mitochondria. Findings from this proposal will be instrumental to AD therapeutic discovery because the makeup of the national population is becoming more ethnically diverse.