New Approaches for Empowering Studies of Asthma in Populations of African Descent

非洲人后裔哮喘研究的新方法

• 批准号: 9256781
• 负责人: Kathleen C Barnes
• 金额: $ 74.8万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-17 至 2017-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9256781
• 关键词: New; Approaches; Empowering; Studies; Asthma

Asthma is a complex disease where the interplay between genetic factors and environmental exposures has significant influence on susceptibility and disease prognosis. Asthmatics of African descent tend to have more severe asthma and more severe clinical symptoms than individuals of European ancestry, but relatively few studies have focused on this underrepresented minority group. Genome-wide association studies (GWAS) have revolutionized gene discovery for multiple complex traits, but implementation of the next step in gene discovery following GWAS of asthma among populations of African descent requires considerations unique to this ethnic group, including adequate sample sizes, population stratification due to admixture, and perhaps most importantly, an approach that recognizes that the current coverage of common variation both in the public database and particularly on commercially available SNP chips is inadequate to detect true genetic association among African admixed populations. In our own GWAS on 1,000 African American asthma cases and controls from Baltimore-Washington, D.C. and 1,000 African Caribbean asthmatics and their family members from Barbados, we have identified suggestive associations for which replication is not observed in populations of European descent, supporting the hypothesis that populations of African descent may carry unique susceptibility loci. We have forged a collaboration of investigators representing 12,000 DNA samples from well-characterized African American and African Caribbean asthmatic patients and healthy controls and/or family members from which six studies (5,000 samples) have GWAS data available for meta-analysis and seven populations (>7,000 samples) are available for replication. In this application, we propose four specific aims: (i) we will leverage discoveries in the 1,000 Genomes Project and data-mine for novel SNPs in African and African admixed populations develop a custom, African-ancestry gene-centric 200K SNP genotyping array (`African Power Chip') to complement current, commercially available GWAS chips, for which common and rare variants are not adequately tagged by the existing SNPs, and thereby facilitate GWAS studies on populations of African descent; (ii) we will perform genotyping on DNA samples with existing GWAS data among the `Consortium on Asthma among African-ancestry Populations in the Americas' (CAAPA) and test for associations with asthma, followed by; (iii) in-depth analyses including imputation-based association mapping of asthma loci, copy number variant (CNV) analyses, and admixture mapping; and (iv) replicate the most significant associations in independent samples available through CAAPA. Results from these studies will lead to substantial advancements in the technology available for identifying genes relevant to disease for what is one of the most underrepresented minorities in biomedical research, African ancestry populations, and will generate deliverables to the scientific community at large, both as an invaluable database and as a validated SNP chip.

哮喘是一种复杂的疾病，遗传因素和环境暴露之间的相互作用 对易感性和疾病预后有重要影响。非洲裔哮喘患者往往有更多 比欧洲血统的个体有严重的哮喘和更严重的临床症状，但相对较少 研究的重点是这个代表性不足的少数群体。全基因组关联研究（GWAS） 彻底改变了多种复杂性状的基因发现，但基因的下一步实施 非洲裔人群哮喘 GWAS 发现后需要考虑独特的因素 这个种族群体，包括足够的样本量、由于混合而造成的人口分层，也许 最重要的是，这种方法认识到当前公共变化的覆盖范围 数据库，特别是市售的 SNP 芯片数据库不足以检测真正的遗传关联 非洲混血人群中。我们自己的 GWAS 对 1,000 名非裔美国人哮喘病例和对照进行了研究 来自巴尔的摩-华盛顿特区的 1,000 名非洲加勒比哮喘患者及其家人 巴巴多斯，我们已经确定了在人群中未观察到复制的暗示性关联 欧洲血统，支持非洲血统人群可能携带独特的假设 易感位点。我们与代表 12,000 个 DNA 样本的研究人员建立了合作关系 特征明确的非裔美国人和非洲加勒比哮喘患者和健康对照和/或 六项研究（5,000 个样本）具有可用于荟萃分析的 GWAS 数据的家庭成员 七个群体（>7,000 个样本）可用于复制。在此应用中，我们提出了四个具体的 目标：(i) 我们将利用 1,000 基因组计划的发现和非洲新 SNP 的数据挖掘 和非洲混合人群开发了一种定制的、以非洲血统基因为中心的 200K SNP 基因分型阵列 （“非洲电源芯片”）以补充当前的商用 GWAS 芯片，该芯片的常见和 现有的 SNP 没有充分标记罕见变异，从而促进了 GWAS 研究 非洲人后裔； (ii) 我们将利用现有的 GWAS 数据对 DNA 样本进行基因分型 加入“美洲非洲裔人群哮喘联盟”(CAAPA) 并进行测试 与哮喘的关联，其次是； (iii) 深入分析，包括基于估算的关联映射 哮喘基因座、拷贝数变异 (CNV) 分析和混合图谱； (iv) 复制最多 CAAPA 提供的独立样本中存在显着关联。这些研究的结果将导致 技术的重大进步可用于识别与疾病相关的基因 生物医学研究中代表性最不足的少数群体之一，非洲血统人口，并且将 为整个科学界提供可交付成果，既作为宝贵的数据库，又作为经过验证的 SNP 芯片。