Genomic Characterization of Alzheimer Disease Risk in Admixed Populations with Native American and Southern European Genetic Ancestry

美洲原住民和南欧遗传血统混合人群阿尔茨海默病风险的基因组特征

• 批准号: 10615046
• 负责人: Gary Wayne Beecham
• 金额: $ 226.67万
• 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: 2021-02-01 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10615046
• 关键词: Admixture; African American population; Alzheimer' s Disease; Alzheimer' s disease risk; Alzheimer’s disease biomarker; American; Amerindian; Amyloid beta-Protein; Astrocytes; Awareness; Bioinformatics; Biological; Biological Markers; Brain; Caribbean region; Cell physiology; Code; Collaborations; Collection; Cuban American; Data; Data Set; Dementia; Diagnosis; Disease; Elderly; Ethnic Origin; Ethnic Population; European; European ancestry; Evaluation; Family; Family member; Follow-Up Studies; Genes; Genetic; Genetic Diseases; Genetic Transcription; Genetic Variation; Genetic study; Genomics; Goals; Haplotypes; Health; Heterogeneity; Hispanic Populations; Individual; Investigation; Literature; Maps; Measures; Methods; Mexican; Microglia; Native Americans; Neurocognitive; Neurons; Neuropsychology; Not Hispanic or Latino; Pathway Analysis; Pathway interactions; Peruvian; Plasma; Population; Population Heterogeneity; Prevention; Proteins; Puerto Rican; Risk; Role; Screening procedure; South American; Testing; Tissue Donations; Underrepresented Populations; United States; Variant; admixture mapping; brain tissue; cohort; follow-up; functional genomics; genetic architecture; genetic linkage analysis; genome editing; genome sequencing; genomic data; improved; in silico; induced pluripotent stem cell; mild cognitive impairment; novel; programs; protective factors; protein expression; racial population; rare variant; risk prediction; risk variant; tau Proteins; transcriptomics; whole genome

ABSTRACT Alzheimer disease (AD) is the leading cause of dementia in older adults and occurs in all ethnic and racial groups. Genetic studies of AD have mostly been performed in non-Hispanic Whites (NHW) of Northern European (NE) ancestry. Only recently have efforts in AD started to expand into other populations, such as African-Americans (AA) and Hispanics (HI), and have a ready demonstrated differences in both risk effect size (e.g., APOE in AA and HI) and risk loci (e.g., ABCA7 in AA). Further evaluation demonstrates that genetic ancestry (as opposed to environmental/cultural factors) likely underlie at least part of this heterogeneity. Individuals with the Amerindian (AI) ancestry remain one of the most underrepresented groups in AD. Importantly, the NHW datasets did not differentiate among the Europeans (EU), whereas recent investigations showed that these pan-European results only partially overlap with the findings from populations from the Iberian Peninsula (IP) with Southern European (SE) ancestry. Caribbean and South American Hispanic populations are admixed with both AI and SE, thus making their study a critical scientific objective. Our proposed study enables testing the generalization of findings from NHW to these other ancestries, as well as identify AD risk/protective factors correlated specifically with AI and SE ancestry. Our results will allow for a better and more complete understanding of the genetic architecture of AD which will help improve disease prediction, prevention, diagnosis, and treatment in AI, admixed Hispanic populations, and beyond. To accomplish these goals, we propose three aims. In Aim 1 we will characterize known AD loci in admixed populations with AI and SE ancestry. This includes expanding collections, generalizing known AD loci to AI/SE populations, and variant discovery through admixture mapping and fine-mapping. In Aim 2 we will extend our Puerto Rican dataset by expanding PR multiplex families. This will allow more powerful linkage analyses, longitudinal neurocognitive and biomarker data, and the initiation of a brain donation program. Finally, in Aim 3 we will perform functional follow-up of variants using bioinformatics approaches, assessment of AD biomarkers, and assessment of cellular function using IPSc.

抽象的 阿尔茨海默病（AD）是老年人痴呆的主要原因，发生在所有民族和种族群体中。 AD 的遗传学研究主要在北欧 (NE) 的非西班牙裔白人 (NHW) 中进行 祖先。直到最近，AD 方面的努力才开始扩展到其他人群，例如非洲裔美国人 (AA) 和西班牙裔 (HI)，并且已证明两者风险效应大小存在差异（例如 AA 中的 APOE） 和 HI）和风险位点（例如 AA 中的 ABCA7）。进一步的评估表明，遗传血统（而不是 环境/文化因素）可能至少是这种异质性的一部分的基础。美洲印第安人个体 (AI) 血统仍然是 AD 中代表性最不足的群体之一。重要的是，NHW 数据集并没有 欧洲人（EU）之间存在差异，而最近的调查表明，这些泛欧洲结果 与伊比利亚半岛 (IP) 和南欧人群的研究结果仅部分重叠 (SE) 血统。加勒比海地区和南美洲的西班牙裔人口中同时存在 AI 和 SE，因此 使他们的研究成为一个重要的科学目标。我们提出的研究能够测试研究结果的概括性 从 NHW 到这些其他祖先，以及识别与 AI 特别相关的 AD 风险/保护因素 和SE血统。我们的结果将有助于更好、更全面地了解遗传结构 AD 的研究将有助于改善人工智能中的疾病预测、预防、诊断和治疗，混合西班牙裔 人口，以及其他。为了实现这些目标，我们提出三个目标。在目标 1 中，我们将描述 具有 AI 和 SE 血统的混合群体中已知的 AD 基因座。这包括扩大馆藏、概括 AI/SE 群体的已知 AD 基因座，以及通过混合作图和精细作图发现变异。瞄准 2 我们将通过扩展 PR Multiplex 系列来扩展波多黎各数据集。这将让更强大的 连锁分析、纵向神经认知和生物标志物数据以及大脑捐赠计划的启动。 最后，在目标 3 中，我们将使用生物信息学方法对变异进行功能性随访，评估 AD 生物标志物，以及使用 IPSc 评估细胞功能。