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

哮喘是一种复杂的疾病，在不同种族和民族之间存在显著差异， 可能部分归因于遗传因素。哮喘联盟的一个主要目标是 美洲非洲裔人口(CAAPA)已经发现了与 非洲血统人群中哮喘的风险。全基因组关联研究 已经成功地识别出与哮喘风险增加相关的基因，但还有 GWAS发现的关联和对这些基因座的理解之间的巨大差距 控制疾病。这种“缺失的遗传性”很大一部分可能是由于带有较小基因的变异 传统的GWA阈值未达到的影响，强调需要过渡到 综合遗传学，其中转录组、蛋白质组、甲基组和代谢组信息 都被纳入一个统一的框架。我们在这次持续更新中的目标是应用 综合的多组学方法来了解哮喘的分子结构， 在为期5年的CAAPA计划的基础上，16,000名哮喘患者和非哮喘患者 已经进行了Gwas基因分型，并且Gwas和/或全基因组测序(WGS)数据 可用于超过100,000个非CAAPA样本。我们建议测试基因变异是否 通过调控基因转录和表达、DNA来控制哮喘的发展 甲基化、代谢谱和蛋白质组变异。这样做的具体目的是 应用程序利用具有多样化但高度集成的国际调查人员团队 专业领域，包括以下内容：(1)扩大和整合多学科资源，以 非洲散居人口中的哮喘研究和识别新的风险基因决定因素 通过将美洲土著和非洲大陆的遗传代表性添加到 非洲散居人口目录，通过新生成的 CAAPA哮喘患者的转录组、甲基组、蛋白质组和代谢组数据 与来自北美和南美7个地点的现有GWAS数据进行的不受影响的对照， 加勒比和非洲，并进行综合分析；(2)广泛传播亚太区域行动方案 结果通过一个基于网络的资源，为哮喘研究社区提供新的 发现；以及(3)开发和应用方法，以确定CAAPA结果在3个健康方面的优先顺序 为美国少数民族人口丰富的系统生物库(纳什维尔、纽约市和 洛基山地区)通过检查基因组学(Phewas)和多组学(PrediXcan) 在CAAPA和非CAAPA数据集中确定的哮喘相关性。这些研究将取得进展 我们对非洲血统人群哮喘的分子基础的理解。

Asthma is a complex disease with striking disparities across racial and ethnic groups, which may be partly attributable to genetic factors. A major goal of the Consortium on Asthma among African-ancestry Populations in the Americas (CAAPA) has been to discover genes conferring risk to asthma in populations of African ancestry. Genome-wide association studies (GWAS) have been successful in identifying genes associated with increased risk of asthma, but there is a substantial gap between associations discovered by GWAS and understanding how these loci control disease. A major portion of the `missing heritability' could be due to variants with smaller effects missed by traditional GWAS thresholds, emphasizing the need for a transition to integrative genetics, where transcriptome, proteome, methylome and metabolome information are brought into a unified framework. Our goal in this continuing renewal is to apply an integrative, multi-omics approach to understand the molecular architecture underlying asthma, building upon the 5-year CAAPA program, where >16,000 asthmatics and non-asthmatics have already been GWAS-genotyped, and GWAS and/or whole genome sequencing (WGS) data are available on more than 100,000 non-CAAPA samples. We propose to test if genetic variants control development of asthma by regulating gene transcription and expression, DNA methylation, metabolic profiles, and proteome variation. The specific aims of this application leverage an international group of investigators with diverse but highly integrated areas of expertise, and include the following: (1) expand and integrate multi-omic resources for asthma research in African Diaspora populations and identify novel genetic determinants for risk of asthma by adding indigenous American and continental African genetic representation in the African Diaspora catalog, building a multi-omic repository through newly generated transcriptome, methylome, proteome, and metabolome data from CAAPA asthmatics and unaffected controls with existing GWAS data from 7 sites in North and South America, the Caribbean and Africa, and performing integrative analyses; (2) broadly disseminate CAAPA results through a web-based resource that empowers the asthma research community for new discoveries; and (3) develop and apply approaches for prioritizing CAAPA results in 3 health systems biobanks enriched for US minority populations (Nashville, New York City, and the Rocky Mountain region) by examining genomics (PheWAS) and multi-omics (PrediXcan) asthma associations identified in CAAPA and non-CAAPA datasets. These studies will advance our understanding of the molecular basis for asthma among populations of African ancestry.