Gene Discovery in Asthma and Allergic Diseases

总结 哮喘和过敏性疾病是儿童和成人最常见的慢性疾病之一，给我们带来了巨大的损失 医疗保健系统每年超过800亿美元。在过去的40年里， 进展是渐进的。在大型全基因组关联研究中，已经报道了超过150个位点 （GWAS）的哮喘和过敏性疾病，但他们的个人影响很小，占整体小 遗传风险的一部分。此外，GWAS的发现很少导致因果关系的发现， 导致哮喘和过敏性疾病发病机制的变异或致病基因。危险工作据 特别具有挑战性，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到基因的轨迹方面滞后 的发现项目1是一个计算项目，我们建议系统地剖析遗传 哮喘和过敏性疾病的结构，使用一个强大的和全面的战略，以确定候选 哮喘和过敏性疾病相关基因座的致病变异体及其靶基因，并表征其 表型效应我们将利用现有的数据和（Epi）基因组学核心和项目中产生的数据 2.项目1的结果将为肺免疫细胞的进一步研究提供变异和基因的选择 在项目2中，以及用于选择用于增强子测定的基因组区域和用于功能研究的变体， （Epi）Genomics Core.我们将通过三个目标来实现我们的目标。在目标1中，我们将使用函数式注释 在哮喘和过敏性疾病相关的细胞类型中，包括气道上皮细胞、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，以分配 哮喘和过敏性疾病GWAS基因座遗传性，并为相关变体和基因座分配细胞类型/状态。 在目标2中，我们将使用目标1中的信息对哮喘和过敏性疾病GWAS位点进行精细定位 使用两种互补的贝叶斯方法来识别pupiruscasual SNP及其靶基因。在 目的3，我们将描述因果变异体对两大类疾病的下游表型效应。 英国生物库中的疾病组和特定哮喘和过敏性疾病机制亚型，或 内源型，在哮喘出生队列中的深表型种族多样性受试者中。这些研究将提供 关于导致哮喘和过敏性疾病内源型的主要细胞类型的新信息， 共病，以及哮喘和过敏性疾病之间的共同机制，并可能与 目标3中发现的其他特征。实现这些目标将最终确定因果SNP和因果基因， 大多数AAD基因座和它们对表型和内源型产生影响的原代细胞类型， 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， 最有可能做出反应的个体，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.