Combined Transcriptomics and Genomics to Find Asthma Genes in Admixed Populations

描述（由申请人提供）：非洲裔美国人更容易患哮喘，与欧洲裔美国人相比，非洲裔美国人患严重哮喘并发症的可能性几乎是欧洲裔美国人的三倍。全基因组关联研究已经确定了许多哮喘的遗传风险标记，但在欧洲和欧美患者中观察到的许多关联并没有在非洲裔美国人身上得到复制。这可能是等位基因频率、连锁不平衡或疾病相关基因因祖先而异的结果。转录组的详细特征可以帮助识别哮喘相关基因，通过规避一些上述的问题与基因型关联单独。因此，本研究寻求结合转录组学和基因组学来鉴定哮喘相关基因和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裔美国人的转录组。RNA-seq在定量转录物丰度方面优于传统的微阵列，但该方法迄今尚未在美国少数民族人群中广泛使用。研究哮喘表型和药物基因组相互作用的种族（蓝宝石）队列是一个理想的群体，结合这些分析方法。除了作为美国最大和最具特征的哮喘队列之一外，已经存在大量SAPPHIRE参与者的全基因组基因型数据和全血RNA库。在Specific Aim 1中，我们将使用RNA-seq来确定非裔美国人哮喘状态中先前确定的哮喘相关基因的表达差异。预先存在的基因型数据将用于鉴定这些差异表达的哮喘相关基因的eQTL。在特异性目标2中，我们将使用混合作图来鉴定祖先与哮喘相关的染色体区域。这些区域的基因将被询问哮喘状态的差异表达。由此产生的可能新颖的、祖先特异性的哮喘基因也将用于eQTL评估。由于一部分非裔美国人SAPPHIRE参与者在初始评估和哮喘加重时都收集了RNA，在特异性目标3中，我们将评估在上述目标中鉴定的基因是否也与哮喘加重有关。最后，Specific Aim 4将尝试在一组非裔美国人和非裔美国人身上复制我们的研究结果。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。种族间哮喘并发症的持续不平等强调了改善疾病生物标志物和治疗靶点的必要性。作为朝这个方向迈出的一步，我们提供了一种具有更大统计能力的综合方法来识别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.