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

描述(申请人提供)：哮喘是最常见的慢性病之一。其发病机制反映了遗传和环境因素之间复杂的相互作用。我们认为，影响哮喘相关数量性状(QTS)的基因对疾病风险具有性别特异性的影响。在这项申请中，我们建议继续我们对8个QT的研究，其中6个具有性别特定的基因结构，它们与Hutterites人的哮喘有关，Hutterites人是一个共同生活的欧洲血统的创始人群体。我们研究的总体目标是使用最先进的综合方法来表征哮喘的遗传结构，并最终识别哮喘风险等位基因。我们提出了3个具体目标：1)获得96个与我们样本中其他~1200个哈特人亲缘关系最近的相对无关的哈特人的全基因组序列，并利用所有染色体的单倍型和已知同一性将所发现的变异归因于其他个体。我们预计，大量在欧洲人群中罕见的变异将在哈特利人中得到丰富，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)使用RNA测序技术(RNAseq)研究男女哈特族人性别特异性基因调控，以测量500名哈特族人淋巴母细胞系(LCL)中的转录水平，这些哈特族人已被评估为哮喘，并对8个与哮喘相关的QT进行了表型：IgE、淋巴细胞计数、嗜酸性粒细胞、YKL-40、呼出的一氧化氮(ENO)分数、预计FEV1百分比、FEV1/FVC比率和支气管反应指数(BRI)。我们建议识别在高Qt值与低Qt值的哈特人中差异表达的基因，或仅在所有个体中与Qt值相关的基因，仅在男性中，仅在女性中，然后为这些基因定位eQTL(使用Affymetrix基因型以及在Aim 1中发现的变体)，以识别在组合样本中、仅在男性中、仅在女性中作为eQTL的变体。3)整合遗传、基因组、生理和疾病表型以发现哮喘基因。在这个目标中，我们将朝着全面的系统方法前进，以充分整合与哮喘相关的遗传、基因组和表型变异。我们将把这些研究的重点放在500名有基因表达数据的哈特利特人身上，并考虑目标1和目标2中表征的遗传变异，以及Affymetrix基因型、前一次赠款期间测量的生理性QT和哮喘状况。

DESCRIPTION (provided by applicant): 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.