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

描述（由申请人提供）：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大影响。与欧洲血统的个体相比，非洲血统的哮喘患者往往有更严重的哮喘和更严重的临床症状，但相对较少的研究关注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，但在非洲裔人群中实施哮喘GWAS后的基因发现的下一步需要考虑该种族群体的独特因素，包括足够的样本量，由于混合的人群分层，也许最重要的是，一种认识到目前公共数据库中，特别是商业上可获得的SNP芯片上的常见变异的覆盖率不足以检测非洲混合人群之间的真正遗传关联的方法。在我们自己的GWAS中，来自巴尔的摩-华盛顿特区的1,000名非洲裔美国人哮喘病例和对照组以及来自巴巴多斯的1,000名非洲加勒比哮喘患者及其家庭成员，我们已经确定了在欧洲血统人群中未观察到复制的暗示性关联，支持非洲血统人群可能携带独特易感基因座的假设。我们已经建立了一个代表12,000个DNA样本的研究人员合作，这些样本来自特征良好的非洲裔美国人和非洲加勒比地区哮喘患者和健康对照和/或家庭成员，其中6项研究（5,000个样本）具有可用于荟萃分析的GWAS数据，7个人群（>7,000个样本）可用于复制。在本申请中，我们提出了四个具体目标：（i）我们将利用1，000个基因组计划中的发现，并对非洲和非洲混合人群中的新型SNP进行数据挖掘，开发一种定制的、以非洲血统基因为中心的200 K SNP基因分型阵列（“非洲电源芯片”），以补充目前，商用GWAS芯片，对于常见和罕见的变异没有被现有的SNP充分标记，从而促进对非洲裔人群的GWAS研究;（ii）我们将在“美洲非洲裔人群哮喘联盟”（CAAPA）中使用现有的GWAS数据对DNA样本进行基因分型并检测与哮喘的相关性，然后进行：（iii）深入分析，包括基于估算的哮喘位点相关性作图、拷贝数变异（CNV）分析和混合物作图;（iv）通过CAAPA在独立样本中复制最显著的相关性。这些研究的结果将导致可用于识别与生物医学研究中代表性最不足的少数民族之一非洲血统人群的疾病相关基因的技术取得实质性进步，并将为整个科学界提供成果，无论是作为一个宝贵的数据库还是作为一个经过验证的SNP芯片。 公共卫生相关性：在这项研究中，我们将利用1000个基因组计划的发现，并选择最能代表非洲血统个体基因组的遗传变异。我们将利用这些信息开发一种定制的“SNP”芯片（称为非洲功率芯片），以补充目前的商用芯片，并在12，000人的DNA样本中识别与哮喘风险相关的遗传多态性。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: In this study we will take advantage of discoveries in the 1000 Genomes Project and select genetic variants that best represent the genome of individuals of African descent. We will use this information to develop a custom "SNP" chip (called the African Power Chip) to complement current, commercially available chips, and identify genetic polymorphisms associated with risk of asthma in DNA samples from 12,000 individuals.