Gene Discovery in Asthma and Allergic Diseases

摘要 哮喘和过敏性疾病是儿童和成人最常见的慢性病之一， 医疗保健系统每年超过800亿美元。在过去的40年里，发病率一直在上升，并具有治疗作用 进展是渐进的。在大型全基因组关联研究中已报告了150多个基因座。 哮喘和过敏性疾病，但它们的个体影响很小，占总人数的很小 遗传风险的一小部分。此外，GWAS的发现中很少有因果关系的发现 导致哮喘和过敏性疾病发病机制的变异或因果基因。后者一直是 尤其具有挑战性，部分原因是这些疾病的显著临床异质性，部分原因是 在开发强大的统计和组学工具以连接从GWAS到基因的轨迹方面存在滞后 发现号。项目1是一个计算项目，在该项目中，我们建议系统地剖析基因 使用强大而全面的策略确定候选哮喘和过敏性疾病的架构 哮喘和过敏性疾病相关基因的因果变异及其靶基因及其特征 表型效应。我们将利用现有数据和(EPI)基因组学核心和项目中生成的数据 2.项目1的结果将为进一步研究肺免疫细胞的变种和基因的选择提供信息 在项目2中，并用于选择基因组区域以用于增强子分析和用于功能研究的变体 (EPI)基因组学核心。我们将通过三个目标实现我们的目标。在目标1中，我们将使用函数注释 在哮喘和过敏性疾病相关的细胞类型中，包括呼吸道上皮细胞、气道平滑肌和 肺免疫细胞以及外周免疫细胞，都处于静息和激活状态，以划分 哮喘和过敏性疾病基因座的遗传度，并指定相关变异和基因座的细胞类型/状态。 在目标2中，我们将使用目标1中的信息来对哮喘和过敏性疾病进行精细定位 使用两种互补的贝叶斯方法来识别假定的因果SNPs及其目标基因。在……里面 目的3，我们将表征因果变异对这两大类别的下游表型的影响 英国生物库中的疾病组以及特定的哮喘和过敏性疾病机械亚型，或 哮喘出生队列中深表型、种族多样化的受试者的内型。这些研究将提供 关于导致哮喘和过敏性疾病的主要细胞类型(S)的新信息 共病以及哮喘和过敏性疾病之间的共同机制，以及可能与 在AIM 3中发现的其他特征。实现这些目标将最终确定原因SNP和原因基因 大多数AAD基因座及其影响表型和内型的原代细胞类型(S) 哮喘和过敏性疾病。总之，这些研究有可能确定新的药物靶点和 最有可能做出反应的个人，并为精准医疗和个性化治疗提供框架 哮喘和过敏性疾病。

SUMMARY Asthma and allergic diseases are among the most common chronic diseases in children and adults, costing our health care system over $80 billion per year. Rates have been increasing over the past 40 years and therapeutic advances have been incremental. Over 150 loci have been reported in large genome-wide association studies (GWAS) of asthma and allergic diseases, but their individual effects are small and account for an overall small fraction of the genetic risk. Moreover, remarkably few of the GWAS findings have led to discoveries of causal variants or causal genes that contribute to asthma and allergic disease pathogenesis. The latter has been particularly challenging due in part to the significant clinical heterogeneity of these diseases, and in part to the lag in the development of powerful statistical and omic tools for bridging the trajectory from GWAS to gene discovery. Project 1 is a computational project in which we propose to systematically dissect the genetic architecture of asthma and allergic diseases using a robust and comprehensive strategy for identifying candidate causal variants and their target genes at asthma- and allergic disease-associated loci and characterizing their phenotypic effects. We will utilize both existing data and those generated in the (Epi)Genomics Core and Project 2. The results of Project 1 will inform the selection of variants and genes for further studies in lung immune cells in Project 2 and for selection of genomic regions for enhancer assays and variants for functional studies in the (Epi)Genomics Core. We will achieve our goals through three aims. In Aim 1, we will use functional annotations in asthma- and allergic disease-relevant cell types, including airway epithelial cells, airway smooth muscle and lung immune cells, as well as peripheral immune cells, all in resting and activated states, to partition the heritability at asthma and allergic diseases GWAS loci and assign cell type/state for associated variants and loci. In Aim 2, we will use information from Aim 1 to perform fine mapping at asthma and allergic disease GWAS loci using two complementary Bayesian approaches to identify putatively causal SNPs and their target genes. In Aim 3, we will characterize the downstream phenotypic effects of causal variants on both broad categories of disease groups in the UK Biobank and on specific asthma and allergic disease mechanistic subtypes, or endotypes, in deeply phenotyped ethnically-diverse subjects in asthma birth cohorts. These studies will provide novel information on the dominant cell type(s) contributing to asthma and allergic disease endotypes and comorbidities, as well as on shared mechanisms between asthma and allergic diseases, and potentially with other traits discovered in Aim 3. Achieving these goals will ultimately identify causal SNPs and causal genes at most AAD loci and the primary cell type(s) in which they exert their effects on phenotypes and endotypes of asthma and allergic diseases. Together, these studies have the potential to identify novel drug targets and the individuals most likely to respond, and to provide a framework for precision medicine and personalized treatment of asthma and allergic diseases.