Genome‐Wide Association Studies in Asthma

Abstract

Asthma is a complex respiratory disease, with both genetic and environmental factors contributing to disease susceptibility. Genome‐wide association studies (GWAS) have now identified novel risk alleles and loci associated with asthma diagnosis and more recently with clinical subgroups of disease. However, while providing insight into potential disease mechanisms these risk alleles have modest effect sizes and account for a small proportion of the anticipated heritability of asthma. In this article we provide an overview of GWAS in asthma to date including reproducible associations and advances in our understanding of the biology of asthma. In addition we discuss ancestry‐specific findings and how genetics may contribute to the development of multiple allergic conditions known as the ‘atopic march’. Finally, we outline the strengths and weaknesses of GWAS and look to future approaches including a greater focus to functional variation and assessment of gene–gene and gene–environment interactions. Key Concepts Asthma is a common respiratory disease that is heterogeneous with respect to its underlying pathology and clinical presentation. Susceptibility to develop asthma involves both genetic and environmental risk factors. Genome‐wide association is the current method of choice to identify genetic factors underlying complex, multifactorial diseases such as asthma. GWAS of asthma have identified several genetic risk factors and genes with confidence, for example IL33, IL1RL1, ORMDL3 loci. Replication of findings remains the gold standard. GWAS of subgroups of asthma, for example, childhood‐onset disease have identified specific genetic risk factors. The effect sizes identified in GWAS are typically modest for single variants. GWAS have provided a unique insight into the altered biology of asthma including changes in innate and adaptive immune responses, altered airway smooth muscle function and epithelial barrier/function abnormalities. While GWAS of asthma have been successful there remains a large missing heritability. Future approaches include better clinical definition of asthma and greater interrogation of genetic factors not currently addressed, for example, regulatory variants, rare variants, copy number variants and greater attention to gene–environment interactions, gene–gene interactions and epigenetic mechanisms.