The EVE Asthma Genetics Consortium: Building Upon GWAS

描述（由申请人提供）： EVE是一个由所有进行过哮喘全基因组关联研究（GWAS）的美国研究者组成的联合体，其主要目的是将个体研究的结果联合收割机，以提高识别哮喘易感位点的总体能力。该联盟包括来自10个美国机构的研究人员，他们对代表欧洲裔美国人、非洲裔美国人、美国西班牙裔和墨西哥裔人口的超过30，000人进行了GWAS结果。作为EVE最初目标的一部分，研究人员的目标是开发一组常见的> 100万个基因分型和插补的SNP，以在该原始样本中测试与哮喘的关联，然后进行关联统计，以组合在哮喘基因发现的大荟萃分析中。在这个GO应用程序中，我们提出了四个具体目标：1）在超过15，000例哮喘病例和欧洲裔美国人，非洲裔美国人和美国西班牙裔美国人的对照中复制最重要的荟萃分析结果; 2）对欧洲裔美国人中与哮喘相关的5-10个基因进行重新测序，但在非洲裔美国人或西班牙裔病例和对照中没有（> 1，500个个体）以鉴定在基因分型平台上未被SNP良好标记的罕见和常见变体; 3）在主要样品中进行哮喘相关表型的额外荟萃分析（例如，肺功能、血清总IgE的测量），并检查与性别、婴儿期烟草烟雾暴露以及基因之间的相互作用;以及4）开发方法，将来自不同类型研究样本（病例对照、三人组、队列）的数据联合收割机用于目标3中描述的荟萃分析，并将网络和途径分析整合到我们的基因发现方法中。哮喘及其相关表型的风险等位基因的发现可能会显著影响公共卫生和医疗保健服务，通过人群筛查来识别风险个体，这些个体可能是早期干预（疾病预防）或基于分子病理学而不是生物学（疾病治疗）的个性化治疗的候选人。 公共卫生相关性： EVE是一个由所有进行过哮喘全基因组关联研究（GWAS）的美国研究者组成的联合体，其主要目的是将个体研究的结果联合收割机，以提高识别哮喘易感位点的总体能力。该联盟包括来自10个美国机构的研究人员，他们对代表欧洲裔美国人、非洲裔美国人、美国西班牙裔和墨西哥裔人口的超过30，000人进行了GWAS结果。在本申请中，我们提出在> 15，000例哮喘病例和欧美裔、非裔美国人和美国西班牙裔种族的对照中复制最显著的GWAS结果，对与欧美裔但非裔美国人或西班牙裔病例和对照中的哮喘相关的5-10个基因进行重测序，以研究其他哮喘相关表型并检查相互作用，并开发出促进基因发现的方法。发现哮喘及其相关表型的风险等位基因可能会对公共卫生和医疗保健服务产生重大影响。

DESCRIPTION (provided by applicant): EVE is a consortium comprised of all U.S. investigators who have conducted genome-wide association studies (GWAS) of asthma and whose main objective is to combine results of individual studies to increase the overall power to identify asthma-susceptibility loci. The consortium includes investigators at 10 U.S. institutions with GWAS results for >30,000 individuals representing European American, African American, U.S. Hispanic, and Mexican populations. As part of the initial goals of EVE, investigators aim to develop a common set of >1 million genotyped and imputed SNPs to be tested for association with asthma in this primary sample followed by association statistics to be combined in a grand meta-analysis for asthma gene discovery. In this GO application, we propose four specific aims: 1) to replicate the most significant meta-analysis results in >15,000 asthma cases and controls of European American, African American, and U.S. Hispanic ethnicities; 2) to resequence 5-10 genes associated with asthma in European Americans but not in African Americans or Hispanic cases and controls (>1,500 individuals) to identify rare and common variants that are not well-tagged by SNPs on the genotyping platforms; 3) to conduct additional meta-analyses in the primary sample for asthma associated phenotypes (e.g., measures of lung function, total serum IgE), and to examine interactions with sex, tobacco smoke exposure in infancy, and between genes; and 4) to develop methods that combine data from different types of study samples (case-control, trios, cohorts) for the meta-analyses described in Aim 3, and integrate network and pathway analyses into our approaches for gene discovery. Discovery of risk alleles for asthma and its associated phenotypes could significantly impact public health and health care delivery by allowing for population screening to identify at-risk individuals who could be candidates for early intervention (disease prevention) or for personalized therapeutics based on molecular pathology rather than on symptomology (disease treatment). PUBLIC HEALTH RELEVANCE: EVE is a consortium comprised of all U.S. investigators who have conducted genome-wide association studies (GWAS) of asthma and whose main objective is to combine results of individual studies to increase the overall power to identify asthma-susceptibility loci. The consortium includes investigators at 10 U.S. institutions with GWAS results for >30,000 individuals representing European American, African American, U.S. Hispanic, and Mexican populations. In this application, we propose to replicate the most significant GWAS results in >15,000 asthma cases and controls of European American, African American, and U.S. Hispanic ethnicities, resequence 5-10 genes associated with asthma in European Americans but not in African Americans or Hispanic cases and controls, to study additional asthma-associated phenotypes and examine interactions, and develop methods to facilitate gene discovery. Discovery of risk alleles for asthma and its associated phenotypes could significantly impact public health and health care delivery.