Gene Discovery in Asthma and Allergic Diseases

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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.