Admixture mapping in late-onset Alzheimer’s disease

迟发性阿尔茨海默病的混合图谱

• 批准号: 9226309
• 负责人: Giuseppe Tosto
• 金额: $ 20万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-30 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9226309
• 关键词: Admixture; Affect; African; African American; Alleles; Alzheimer' s Disease; Alzheimer' s disease risk; Asthma; Cardiovascular Diseases; Caribbean Hispanic; Chromosomes; Clinical; Data; Dementia; Diagnosis; Disease; Disease susceptibility; Ethnic group; European; Event; Exhibits; Family Study; Family history of; Frequencies; Functional disorder; Genes; Genetic; Genetic Determinism; Genetic Materials; Genetic Risk; Genetic study; Genome; Genomic Segment; Glaucoma; Goals; Hispanics; Incidence; Individual; Inherited; Investigation; Late Onset Alzheimer Disease; Maps; Methods; Modeling; Multicenter Studies; Not Hispanic or Latino; Pathogenesis; Pathway interactions; Phenotype; Population; Prevalence; Probability; Process; Reporting; Risk; Role; Sampling; Socioeconomic Status; Source; Susceptibility Gene; Synapses; Time; Variant; admixture mapping; base; case control; cohort; disorder risk; exome sequencing; genetic profiling; genetic risk factor; genome wide association study; genome-wide; high risk; neglect; neuropsychological; next generation sequencing; novel; offspring; rare variant; risk variant; social; synaptic function; tau Proteins

PROJET SUMMARY Prevalence and incidence of late-onset Alzheimer’s disease (LOAD) are higher in admixed population such as Caribbean Hispanics (CH) and African-Americans (AA) than in non-Hispanic Whites. Admixture occurs when isolated populations begin interbreeding for historical or social events, and their offspring are mixtures of the genetic materials of the founding populations, resulting in mosaic chromosomes. Admixture can be a valuable source of statistical power to map disease-associated genes when the disease has different frequency across populations, such as LOAD. Investigations in other conditions (cardiovascular diseases, glaucoma, asthma) demonstrated the importance of admixture mapping and a recent study on AA showed the significant contribution of African ancestry in LOAD. This has never been performed in Hispanics. In our previous investigation, we performed a large genome-wide association study in Caribbean Hispanics: a novel locus in the FBXL7 gene was found to be associated with LOAD, along with other known-loci previously identified in large GWAS of European ancestry. This new finding implicates additional mechanisms underlying the pathophysiology of LOAD, and demonstrates the valuable asset of admixed populations in advancing the understanding of the disease. Preliminary results indicate that in our Caribbean Hispanic sample, LOAD cases have higher African ancestry as compared to healthy controls, matching previous reports in African Americans. Given these premises, we hypothesize that genetic loci with excess ancestry with respect to LOAD contribute to the observed higher frequency of LOAD in Caribbean Hispanics. This is based on the assumption that causal variants leading to increased risk occur more frequently on chromosomal segments (“ancestral blocks”) inherited from the ancestral population that has higher disease risk. Capitalizing on the large sample of individuals with extensive phenotype and genetic data, a two-layers approach of fine mapping will be carried out: first, we will conduct admixture mapping in GWAS data in order to identify genetic loci with risk profiles for LOAD that differ by ancestry (Aim 1). Secondly, we will conduct analyses in WES data (Aim 2) focusing on those loci prioritize by analyses conducted in the previous aim. Ultimately, we will seek to functionally characterize the newly discovered genetic loci by investigating their role in app processing, tau proteostasis and synaptic function (Aim 3).

项目概要 混合人群中迟发性阿尔茨海默病 (LOAD) 的患病率和发病率较高，例如 加勒比裔西班牙裔 (CH) 和非裔美国人 (AA) 高于非西班牙裔白人。当发生混合时 孤立的种群因历史或社会事件而开始杂交，他们的后代是不同种群的混合体 创始种群的遗传物质，产生嵌合染色体。混合物可能是一种有价值的 当疾病在不同人群中出现不同频率时，绘制疾病相关基因图谱的统计能力来源 人口，例如 LOAD。其他疾病的检查（心血管疾病、青光眼、哮喘） 证明了混合映射的重要性，并且最近对 AA 的研究表明了显着性 非洲血统对 LOAD 的贡献。这从未在西班牙裔中进行过。 在我们之前的调查中，我们对加勒比西班牙裔进行了一项大型全基因组关联研究： FBXL7 基因中的新位点以及先前已知的其他位点被发现与 LOAD 相关 在大型 GWAS 中发现了欧洲血统。这一新发现暗示了潜在的其他机制 LOAD 的病理生理学，并展示了混合人群在推进 LOAD 方面的宝贵资产 对疾病的了解。初步结果表明，在我们的加勒比西班牙裔样本中，LOAD 案例 与健康对照组相比，他们具有更高的非洲血统，这与之前非裔美国人的报告相符。 鉴于这些前提，我们假设具有过多祖先的遗传位点对 LOAD 做出了贡献 观察到加勒比西班牙裔中 LOAD 的频率较高。这是基于以下假设： 导致风险增加的因果变异更频繁地发生在染色体片段（“祖先区块”）上 从具有较高疾病风险的祖先群体遗传而来。充分利用大样本 具有广泛表型和遗传数据的个体，将采用两层精细绘图方法 out：首先，我们将在 GWAS 数据中进行混合作图，以确定具有风险特征的遗传位点 负载因血统而异（目标 1）。其次，我们将对 WES 数据进行分析（目标 2），重点关注 这些位点根据先前目标中进行的分析进行优先排序。最终，我们将寻求在功能上 通过研究新发现的基因位点在应用程序处理、tau 蛋白质稳态中的作用来表征新发现的基因位点 和突触功能（目标 3）。