Genomic Studies of Sex-Specific Architecture of Asthma-Associated Traits

哮喘是最常见的慢性疾病之一。其发病机制反映了 遗传和环境因素。我们认为，影响哮喘相关的定量基因 性状（QTs）对疾病风险具有性别特异性影响。在这份申请中，我们建议继续我们的研究 8个QT，6个具有性别特异性遗传结构，与Hutterites的哮喘有关，Hutterites是一个创始人， 起源于欧洲的共同生活的人口。我们的研究的总体目标是利用国家的- 本领域的综合方法来表征哮喘的遗传结构，并最终确定 哮喘危险等位基因我们提出了3个具体目标：1）获得96个相对无关的基因组全序列 在我们的样本中，哈特派被选为与其他约1200名哈特派关系最密切的人，并将其归因于 发现变异的其他个人使用的单倍型和已知的身份，通过血统结构的所有 染色体我们预计，在欧洲人群中罕见的大量变异将在 在哈特分子中富集，使我们能够研究罕见与常见变异对哮喘风险的影响。（二） 使用RNA测序（RNAseq）研究男性和女性哈特人的性别特异性基因调控，以测量 来自500名已评估哮喘的赫特人的淋巴母细胞样细胞系（LCL）中的转录水平 并对8种哮喘相关QT进行表型分析：IgE、淋巴细胞计数、嗜酸性粒细胞、YKL-40、呼气分数 一氧化氮（eNO）、%预计FEV 1、FEV 1/FVC比值和支气管反应性指数（BRI）。我们提出 鉴定在具有高QT值与低QT值的哈特人中差异表达或与QT相关的基因 值，然后定位eQTL（使用Affyssin基因型 以及Aim 1）中发现的变异，以鉴定这些基因中的eQTL变异。 样品，仅在雄性中，仅在雌性中。3)整合遗传、基因组、生理和疾病 表型来发现哮喘基因为此，我们将采取全面系统的方法， 完全整合与哮喘相关的遗传、基因组和表型变异。我们将集中这些 研究了500个哈特人的基因表达数据，并考虑了遗传变异的特点， 目的1和2，除了Affyssine基因型，在前一个资助期测量的生理QT， 和哮喘状态。

Asthma is one of the most common, chronic diseases. Its pathogenesis reflects complex interactions between genetic and environmental factors. We propose that the genes that influence asthma-associated quantitative traits (QTs) have sex-specific effects on risk for disease. In this application, we propose to continue our studies of 8 QTs, 6 with sex-specific genetic architecture, that are associated with asthma in the Hutterites, a founder population of European origins that lives communally. The overall objectives of our studies are to use state-of- the art, integrative approaches to characterize the genetic architecture of asthma and ultimately to identify asthma risk alleles. We propose 3 specific aims: 1) Obtain the full genome sequence for 96 relatively unrelated Hutterites selected to be most closely related to the other ~1200 Hutterites in our sample, and impute the discovered variation to the other individuals using the haplotype and known identity by descent structure of all chromosomes. We expect a significant number of variants that are rare in European populations will be enriched in the Hutterites and allow us to study the effects of rare vs. common variants on asthma risk. 2) Study sex-specific gene regulation in male and female Hutterites using RNA sequencing (RNAseq) to measure transcript levels in lymphoblastoid cell lines (LCLs) from 500 Hutterites that have been evaluated for asthma and phenotyped for 8 asthma-associated QTs: IgE, lymphocyte count, eosinophils, YKL-40, fractional exhaled nitric oxide (eNO), %predicted FEV1, FEV1/FVC ratio, and bronchial responsiveness index (BRI). We propose to identify genes that are differentially expressed in Hutterites with high vs. low QT values or correlated with QT values in all individuals, in males only, and in females only, and then map eQTLs (using Affymetrix genotypes as well as variants discovered in Aim 1) for those genes to identify variants that are eQTLs in the combined sample, in males only, and in females only. 3) Integrate genetic, genomic, and physiologic and disease phenotypes to discover asthma genes. In this aim we will move toward a comprehensive systems approach to fully integrate genetic, genomic, and phenotypic variation that is relevant to asthma. We will focus these studies on the 500 Hutterites with gene expression data and consider the genetic variation characterized in Aims 1 and 2, in addition to Affymetrix genotypes, physiologic QTs measured during the previous grant period, and asthma status.