Combined Transcriptomics and Genomics to Find Asthma Genes in Admixed Populations

描述（由申请人提供）：非裔美国人更容易患哮喘，与欧洲裔美国人相比，发生严重哮喘并发症的可能性几乎是三倍。全基因组关联研究已经确定了许多哮喘的遗传风险标志物，但在欧洲和欧洲美国患者中观察到的许多关联在非洲裔美国人中并没有复制。这可能是由于等位基因频率，连锁不平衡，或疾病相关基因的祖先不同。转录组的详细特征可以帮助识别哮喘相关基因，避免了上述与基因型相关的一些问题。因此，本研究试图将联合收割机转录组学和基因组学相结合来鉴定哮喘相关基因和似乎调控这些基因的表达数量性状位点（eQTL）。我们建议使用RNA测序（RNA-seq）来表征患有和不患有哮喘的非洲裔美国人的转录组。RNA-seq在定量转录本丰度方面上级传统的微阵列，但这种方法迄今尚未在美国少数民族人群中广泛使用。SAPPHIRE队列研究是联合收割机结合这些分析方法的理想群体。除了是美国最大和最具特征的哮喘队列之一，对于大量的SAPPHIRE参与者，已经存在全基因组基因型数据和库存的全血RNA。在具体目标1中，我们将使用RNA-seq来确定哮喘状态的非裔美国人个体中先前确定的哮喘相关基因的表达差异。现有的基因型数据将被用于鉴定这些差异表达的哮喘相关基因的eQTL。在具体目标2中，我们将使用混合物图谱来确定与哮喘相关的祖先的染色体区域。这些区域中的基因将被哮喘状态询问差异表达。还将评估所得的潜在新的祖先特异性哮喘基因的eQTL。由于非裔美国人SAPPHIRE参与者的一个子集在其初始评估和哮喘急性发作时都收集了RNA，因此在特定目标3中，我们将评估在前述目标中鉴定的基因是否也与哮喘急性发作相关。最后，具体目标4将试图在一组单独的非裔美国人参与者中复制我们的研究结果，无论他们是否患有哮喘。总之，哮喘是一种复杂的疾病，具有潜在的不同遗传预测因子。哮喘并发症在种族间的持续不平等强调了对改善疾病生物标志物和治疗靶点的需求。作为这个方向的一步，我们提供了一个综合的方法，更大的统计能力，以确定哮喘相关基因及其调控元件。

DESCRIPTION (provided by applicant): African American individuals are more likely to develop asthma and are nearly three times as likely to experience serious asthma complications when compared with European American individuals. Genome wide association studies have identified a number of genetic risk markers for asthma, but many of the associations observed in European and European American patients have not replicated in African American individuals. This may be the result of allele frequencies, linkage disequilibria, or disease-related genes which differ by ancestry. Detailed characterization of the transcriptome can aid in the identification of asthma-related genes by circumventing some of the aforementioned problems associated with genotype association alone. Therefore, this proposal seeks to combine transcriptomics and genomics to identify asthma-related genes and the expression quantitative trait loci (eQTL) which appear to regulate these genes. We propose using RNA sequencing (RNA-seq) to characterize the transcriptome of African American individuals with and without asthma. RNA-seq is superior to traditional microarrays at quantifying transcript abundance, but this method has not been widely used in U.S. minority populations to date. The Study of Asthma Phenotypes and Pharmacogenomic Interactions by Race-ethnicity (SAPPHIRE) cohort is an ideal group in which combine these analytic approaches. In addition to being one of largest and best characterized asthma cohorts in the U.S., genome wide genotype data and banked whole blood RNA already exist for a large number of SAPPHIRE participants. In Specific Aim 1, we will use RNA-seq to identify expression differences in previously identified asthma-related genes among African American individuals by asthma status. Pre-existing genotype data will then be used to identify eQTL for these differentially expressed, asthma-associated genes. In Specific Aim 2, we will use admixture mapping to identify chromosomal regions where ancestry is associated with asthma. The genes in these regions will be interrogated for differential expression by asthma status. The resulting potentially novel, ancestry-specific asthma genes will also be assessed for eQTL. As a subset of African American SAPPHIRE participants have RNA collected at both their initial evaluation and the time of an asthma exacerbation, in Specific Aim 3 we will assess whether the genes identified in the preceding aims are also associated with asthma exacerbations. Lastly, Specific Aim 4 will attempt to replicate our findings in a separate group of African American participants with and without asthma. In summary, asthma is a complex disease with potentially distinct genetic predictors by ancestry. Persisting inequitie in asthma complications by race-ethnicity underscore the need for improved disease biomarkers and therapeutic targets. As a step in this direction, we proffer an integrative approach with greater statistical power to identify asthma-related genes and their regulatory elements.