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

哮喘是最常见的慢性病之一。其发病机制反映了复杂的相互作用 遗传和环境因素。我们认为影响哮喘相关数量的基因 性状(QT)对疾病风险有性别特异性的影响。在这份申请中，我们建议继续我们的研究 在8个QT中，有6个具有性别特异的基因结构，与哈特利人的哮喘有关，创始人之一 起源于欧洲的群体，共同生活。我们研究的总体目标是使用状态 描述哮喘遗传结构并最终确定 哮喘风险等位基因。我们提出了三个具体目标：1)获得96个相对无关的全基因组序列 被选为与我们样本中的其他约1200名哈特人关系最密切的哈特人，并将 使用单倍型和所有人的血统结构的已知身份发现了其他个体的变异 染色体。我们预计，大量在欧洲人群中罕见的变异将是 在哈特人中丰富，并使我们能够研究罕见变异与常见变异对哮喘风险的影响。2) 用RNA测序(RNAseq)方法研究哈特族男女性别特异性基因调控 500名接受哮喘评估的哈特族人的淋巴母细胞系(LCL)转录水平 8个哮喘相关QT的表型：IgE、淋巴细胞计数、嗜酸性粒细胞、YKL-40、呼气分数 一氧化氮(ENO)、预测FEV1的百分比、FEV1/FVC比值和支气管反应性指数(BRI)。我们建议 找出在高Qt值与低Qt值或与Qt值相关的哈特族人中差异表达的基因 在所有个体中，仅在男性中，在仅在女性中，然后定位eQTL(使用Affymetrix基因类型 以及在AIM 1)中发现的变体，用于这些基因识别组合中为eQTL的变体 样本，仅限男性，仅限女性。3)将遗传、基因组和生理与疾病结合起来 发现哮喘基因的表型。在这一目标中，我们将走向全面的系统方法，以 充分整合与哮喘相关的遗传、基因组和表型变异。我们将重点关注这些 用基因表达数据对500名哈特人进行研究，并考虑到以 目标1和目标2，除Affymetrix基因型外，还包括在前一次赠款期间测量的生理性QT， 以及哮喘的状况。

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.