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

线粒体 DNA 变异和环境因素对认知功能和痴呆的种族特异性影响

• 批准号: 10226908
• 负责人: EILEEN M CRIMMINS
• 金额: $ 76.19万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10226908
• 关键词: Affect; African American; Age-Years; Alzheimer' s Disease; Alzheimer' s disease diagnosis; Alzheimer' s disease related dementia; Alzheimer' s disease risk; Alzheimer' s disease therapeutic; Amino Acid Sequence; Amyloid beta-Protein; Animals; Attenuated; Bioinformatics; Blood Glucose; Body mass index; Brain; Clinical; Cognition; DNA; Data; Dementia; Diabetes Mellitus; Diagnostic; Education; Encephalitis; Environment; Environmental Risk Factor; Ethnic Origin; Ethnic group; Exhibits; Gene Expression; Genes; Genetic; Genetic Variation; Health and Retirement Study; High Fat Diet; Hispanics; Human; Impaired cognition; Individual; Initiator Codon; Leukocytes; Life Style; Measures; Meta-Analysis; Metabolic; Metabolic Diseases; Mitochondria; Mitochondrial DNA; Mus; Nature; Neurodegenerative Disorders; Not Hispanic or Latino; Nuclear; Obesity; Participant; Peptides; Physical activity; Population; Prefrontal Cortex; Prevalence; Process; Publishing; Race; Reasons for Geographic And Racial Differences in Stroke; Reporting; Running; Scanning; Single Nucleotide Polymorphism; Source; Testing; Tissues; Translating; United States; Variant; Weight Gain; base; caregiving; clinical Diagnosis; clinical predictors; cognitive function; cohort; cost; design; differential expression; disease phenotype; effective therapy; ethnic difference; ethnic diversity; gene environment interaction; gene interaction; genetic analysis; genetic association; genome wide association study; genome-wide; genomic tools; humanin; improved; insight; lifestyle factors; lifestyle intervention; mitochondrial genome; multi-ethnic; new therapeutic target; novel; racial and ethnic disparities; therapeutic target; tool; transcriptome sequencing; transcriptomics

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.

在美国75岁以上的种族/族裔群体中，非裔美国人表现出最高的认知障碍