Genome‐Wide Association Studies in Asthma


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.

Keywords: asthma; genome‐wide association study; single nucleotide polymorphism; heritability; atopic march

Figure 1. Asthma gene discovery methods. Positional cloning involves linkage analysis, which follows the transmission of genetic information through families with multiple affected children followed by fine association mapping. Genome‐wide Association Studies (GWAS) look at the frequency of a large number of common variants between cases and controls. Both approaches lead to novel gene discovery. Reproduced with permission from Shaw et al. © Elsevier.
Figure 2. Manhattan (a) and chromosome 17q21 region (b) plots from the GWAS of moderate‐severe asthma. Multiple suggestive signals (p < 10−5) are apparent (red) and closer examination of 17q21 (b) illustrates the complexity of the signal, demonstrating how identification of the causative variant and gene can be a challenge. Reproduced with permission from Wan et al. © BMJ Publishing Group Ltd.
Figure 3. Schematic illustrating genetic loci identified in GWAS for asthma diagnosis or asthma stratified into specific subgroups. Multiple signals identified in different populations are highlighted in the main blue box. A signal specific to the male gender is highlighted in yellow, while genes associated to asthma with comorbidities are highlighted in their respective boxes. Loci associated with a specific subset of asthma are listed in their respective groups atop the main box. Genes that are relevant to different groups presented in box overlaps. Where overlap was not possible, genes presented multiple times in the diagram are highlighted with an asterisk.


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Further Reading

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Portelli, Michael, and Sayers, Ian(Nov 2016) Genome‐Wide Association Studies in Asthma. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0024639]