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显著影响。非洲人后裔的哮喘患者往往有更多 严重的哮喘和比欧洲血统的人更严重的临床症状，但相对较少 研究的重点是这一代表性不足的少数群体。全基因组关联研究 使多种复杂性状的基因发现发生了革命性变化，但实现了基因的下一步 在GWAS之后发现非洲裔人群中存在哮喘需要考虑以下方面的独特因素 这一种族群体，包括足够的样本量，由于混杂而造成的人口分层，也许 最重要的是，一种方法承认目前公众中共同变异的覆盖面 数据库，特别是商业上可获得的SNP芯片上的数据库不足以检测真正的遗传关联 在非洲混血人群中。在我们自己的关于1000例非裔美国人哮喘病例和对照的GWAS中 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来自 在巴巴多斯，我们已经确定了在巴巴多斯人口中没有观察到的复制的提示性关联 欧洲人后裔，支持非洲人后裔人口可能携带独特的 易感基因座。我们已经伪造了一个调查人员的合作，代表了来自 特征良好的非洲裔美国人和非洲加勒比哮喘患者和健康对照和/或 来自6项研究(5,000个样本)的家庭成员拥有可用于荟萃分析和 有七个群体(&gt；7000个样本)可供复制。在本申请中，我们提出了四个具体的 目标：(I)我们将利用1000基因组计划中的发现和数据挖掘在非洲发现新的SNPs 非洲混血人群形成了定制的、以非洲血统基因为中心的200K SNP基因分型阵列 (‘非洲电力芯片’)，以补充目前商业上可获得的GWAS芯片，对于这些芯片，通用的和 现有的SNPs没有对罕见的变异进行充分的标记，从而促进了GWAS对 非洲人后裔人口；(2)我们将利用现有的全球数据分析系统对DNA样本进行基因分型 在“美洲非洲裔人口中哮喘问题联合会”(CAAPA)和 与哮喘的关联，然后是；(3)深入分析，包括基于归因的关联映射 哮喘基因座、拷贝数变异(CNV)分析和混合图谱；以及(Iv)复制最多 通过CAAPA提供的独立样本中的显著相关性。这些研究的结果将导致 可用于识别与疾病相关的基因的技术的实质性进步 在生物医学研究中代表最少的少数民族之一，非洲血统人口，并将 为整个科学界生成交付成果，既作为宝贵的数据库，也作为经过验证的 SNP芯片。