The Origins of Alzheimer Disease in Individuals of African Ancestry

非洲血统个体阿尔茨海默病的起源

• 批准号: 10356488
• 负责人: GOLDIE S. BYRD
• 金额: $ 296.21万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10356488
• 关键词: ATAC-seq; Africa; African; African American; Alzheimer' s Disease; Alzheimer' s disease risk; Alzheimer’s disease biomarker; Astrocytes; Attitude; Autopsy; Awareness; Biological Markers; Brain; CRISPR/Cas technology; Cardiovascular Diseases; Cardiovascular system; Caribbean Hispanic; Cell Nucleus; Cells; Chromatin; DNA; Data; Dementia; Diagnosis; Disease; Education; Elderly; Ethnic group; Etiology; European; Family; GTP-Binding Protein alpha Subunits, Gs; Gene Expression; Gene Frequency; Genes; Genetic; Genetic Diseases; Genetic Predisposition to Disease; Genetic Risk; Genetic Transcription; Genetic Variation; Genetic study; Genomics; Genotype; Ghana; Goals; Heterogeneity; High Prevalence; Individual; Induced pluripotent stem cell derived neurons; Maps; Mendelian randomization; Methods; Microglia; Modeling; Molecular; Neurocognitive; Neuropsychology; Nigeria; Not Hispanic or Latino; Pattern; Phenotype; Plasma; Population; Population Genetics; Prevention; RNA; Race; Recording of previous events; Risk; Rural Community; Sample Size; Sampling; Testing; Uganda; Underrepresented Populations; Underserved Population; Urban Community; Variant; base; brain tissue; cell type; cohort; design; disease phenotype; druggable target; epigenomics; gene discovery; genetic architecture; genetic linkage analysis; genetic risk factor; genome sequencing; genomic locus; improved; induced pluripotent stem cell; mild cognitive impairment; multi-ethnic; novel; precision medicine; programs; rare variant; recruit; risk variant; transcriptome sequencing; transcriptomics; whole genome

ABSTRACT The goal of this proposal is to increase our understanding of the genetic etiology of Alzheimer disease (AD) risk in understudied and underserved populations. Alzheimer disease (AD) is the leading cause of dementia in the elderly and occurs in all ethnic and racial groups, but most genetic studies for AD have been performed in non- Hispanic Whites (NHW) of European ancestry. The lack of diversity in AD genetics studies is problematic as studies in African Americans (AA), who have a higher prevalence of AD compared to NHW, have differences in risk effect sizes in known loci (e.g., APOE; ABCA7), indicating multiple unique patterns of risk. Genetic ancestry (including variability in allele frequencies and novel variants modulating known and novel risk loci), as opposed to only environmental/cultural factors, likely underlies at least part of this heterogeneity. With only a small number of the whole genome sequences in the Alzheimer’s Disease Sequencing Project coming from AA, better characterization of the genetic risk for AD requires increased sample sizes for individuals of African (AF) ancestry. To understand the totality of AD risk, we need to elucidate the pan-population genetic architecture of AD as it will enhance our understanding of the genotype to phenotype relationships for AD, and provide the bases for identifying druggable targets. Using ancestral populations, such as those from Africa, to study risk modifiers is critical to dissecting risk not only in those populations but also among all populations with AF ancestry. Our efforts will allow for improved disease prediction, prevention, diagnosis, and treatment through precision medicine, in AA, AF, and other AF admixed populations (e.g. Caribbean Hispanics). We will accomplish these goals through the following: 1.) expanding existing and recruiting new AA multiplex families for family- based discovery of AD risk loci, 2.) increasing the number of available AA brains for functional studies, 3.) determining the AF origins of genetic variation in AD, 4.) Extending genomic analysis of AD to include cardiovascular phenotypes, 5.) Evaluating the molecular and genomic function of known AD associated variants (e.g., ABCA7) as well as significant variants identified through this project.

抽象的 该提案的目的是增加我们对阿尔茨海默氏病遗传病因（AD）风险的理解 在理解和服务不足的人群中。阿尔茨海默氏病（AD）是痴呆症的主要原因 老年人并发生在所有种族和种族群体中，但是大多数AD遗传研究都是在非 - 欧洲血统的西班牙白人（NHW）。 AD遗传学研究缺乏多样性是有问题的，因为 与NHW相比，非裔美国人的研究（AA）具有更高的AD患病率 已知局部（例如ApoE; ABCA7）中的风险效应大小，表明多种独特的风险模式。遗传血统 （包括等位基因频率的变异性和新型变体调节已知和新型风险基因座），而不是相反 对于只有环境/文化因素，可能至少是这种异质性的一部分。只有少数 阿尔茨海默氏病测序项目中的整个基因组序列来自AA，更好 AD遗传风险的表征需要增加非洲个体的样本量（AF） 祖先。要了解AD风险的整体，我们需要阐明 广告会增强我们对AD表型关系的基因型的理解，并提供 用于识别可吸毒目标的基础。使用祖先人群，例如来自非洲的人口，研究风险 修饰符对于不仅在这些人群中，而且在所有AF的人群中都至关重要 祖先。我们的努力将通过 精密医学，AA，AF和其他AF混合人群（例如加勒比西班牙裔）。我们将完成 通过以下各种目标：1。）扩大现有的并招募新的AA多个家庭为家庭 - 基于AD风险基因座的发现，2。）增加功能研究的可用AA大脑数量，3。） 确定AD中遗传变异的AF起源。4。）扩展AD的基因组分析以包括 心血管表型，5。）评估已知AD相关变体的分子和基因组功能 （例如，ABCA7）以及通过该项目确定的重要变体。