Characterizing Genetic Risks for Asthma

Abstract

Asthma is a disease of the airways with significant clinical heterogeneity regarding age-of-onset, co-occurrence with allergic diseases, lung function measures, and more. Genome-wide association studies (GWAS) have successfully reported over 150 asthma susceptibility loci. However, uncovering the causal genes and mechanisms underlying its pathogenesis has been challenging in part due to extensive linkage disequilibrium (LD), which makes it difficult to uncover the specific causal variants and genes, and in part because most asthma GWAS are often conducted in populations of European ancestries with limited information on asthma subtypes and associated traits. In this thesis, I address these gaps through complementary approaches that identify putatively genes in two major subtypes of asthma and in asthma-associated quantitative traits. First, I examined one of the most highly associated asthma loci on chromosome 6p21, encoding the human leukocyte antigen (HLA) genes in childhood-onset asthma and adult-onset asthma. Using Bayesian approaches for fine mapping both GWAS loci and gene expression in three different asthma-relevant cell types, I identified putatively causal childhood- and adult-onset asthma variants that are both shared and distinct to each type of asthma and highlight roles for both gene expression and protein coding variation in the HLA genes for asthma risk. In the second project I examine the contribution of rare variants to specific asthma-associated quantitative phenotypes in a population of children of diverse ancestries. I examined whole genome sequencing data and detailed clinical information reflecting the major allergic, pulmonary, and immune components of asthma. I performed gene-based variant set tests and followed up associations with independent, predicted gene expression and mouse knockout resources. Overall, I report novel associations between genes and allergic and inflammatory phenotypes. Together, these studies build on the results of asthma GWASs, identifying novel variants and genes associated with asthma and its associated phenotypes