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，其中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。非裔哮喘患者往往有更多的 严重哮喘和更严重的临床症状比欧洲血统的个人，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（GWAS） 已经彻底改变了多个复杂性状的基因发现，但基因工程下一步的实施， 在GWAS之后，在非洲裔人群中发现哮喘需要考虑以下独特因素： 这个种族群体，包括足够的样本量，由于混合的人口分层，也许 最重要的是，这种方法认识到，目前的覆盖范围的共同变化，无论是在公众 数据库，特别是商业上可获得的SNP芯片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GWAS中，1,000名非裔美国人哮喘病例和对照组 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，我们已经确定了暗示性的关联，在巴巴多斯的人群中没有观察到复制。 欧洲血统，支持非洲裔人口可能携带独特的假设， 易感基因座我们已经建立了一个代表12,000个DNA样本的调查人员的合作， 充分表征的非洲裔美国人和非洲加勒比人哮喘患者和健康对照和/或 6项研究（5，000份样本）的家族成员具有可用于荟萃分析的GWAS数据， 有7个群体（> 7，000个样本）可供复制。在本申请中，我们提出了四个具体的 目的：（i）我们将利用1,000个基因组计划的发现，并在非洲进行新的SNPs数据挖掘 和非洲混合人群开发了一个定制的，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"），以补充目前的商用GWAS芯片， 罕见的变异没有被现有的SNP充分标记，从而促进了GWAS研究， 非洲裔人群;（ii）我们将使用现有的GWAS数据对DNA样本进行基因分型 在"美洲非洲血统人群哮喘联盟"（CAAPA）中， 与哮喘的相关性，然后是;（iii）深入分析，包括基于插补的关联映射 哮喘基因座、拷贝数变异（CNV）分析和混合物作图;（iv）复制最多的 通过CAAPA获得的独立样本中的显著关联。这些研究的结果将导致 在技术上的实质性进步，可用于识别与疾病相关的基因， 在生物医学研究中代表性最不足的少数民族之一，非洲血统的人口， 作为一个宝贵的数据库和一个经过验证的 SNP芯片