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.

摘要 阿尔茨海默病（AD）是老年人痴呆症的主要原因，发生在所有种族和种族群体中。 AD的遗传学研究主要在北方欧洲（NE）的非西班牙裔白人（NHW）中进行 祖先直到最近，AD的研究才开始扩展到其他人群，如非洲裔美国人 (AA)和西班牙裔（HI），并且在风险效应大小（例如，AA中的APOE 和HI）和风险基因座（例如，AA中的ABCA 7）。进一步的评估表明，遗传祖先（而不是 环境/文化因素）可能是这种异质性的至少一部分的基础。与美洲印第安人的个人 (AI)祖先仍然是AD中代表性最低的群体之一。重要的是，NHW数据集没有 区分欧洲人（欧盟），而最近的调查显示，这些泛欧洲的结果， 仅部分与伊比利亚半岛（IP）和南欧人群的结果重叠 (SE)祖先加勒比海和南美西班牙裔人口与AI和SE混合，因此 使他们的研究成为重要的科学目标。我们提出的研究能够测试结果的概括性 从NHW到这些其他祖先，以及确定与AI特别相关的AD风险/保护因素 的祖先。我们的研究结果将有助于更好更全面地了解遗传结构 这将有助于改善AI的疾病预测、预防、诊断和治疗， 人口，超越。为了实现这些目标，我们提出了三个目标。在目标1中， 已知的AD基因座与AI和SE血统的混合人群。这包括扩大收藏， 已知的AD基因座到AI/SE人群，并通过混合作图和精细作图发现变体。在Aim中 2我们将通过扩展PR多重家族来扩展我们的波多黎各数据集。这将使更强大的 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体进行功能随访，评估 AD生物标志物和使用IPSc的细胞功能评估。