A genome-wide association study identifies CDHR3 as a susceptibility locus for early childhood asthma with severe exacerbations

Abstract

Asthma exacerbations are among the most frequent causes of hospitalization during childhood, but the underlying mechanisms are poorly understood. We performed a genome-wide association study of a specific asthma phenotype characterized by recurrent, severe exacerbations occurring between 2 and 6 years of age in a total of 1,173 cases and 2,522 controls. Cases were identified from national health registries of hospitalization, and DNA was obtained from the Danish Neonatal Screening Biobank. We identified five loci with genome-wide significant association. Four of these, GSDMB, IL33, RAD50 and IL1RL1, were previously reported as asthma susceptibility loci, but the effect sizes for these loci in our cohort were considerably larger than in the previous genome-wide association studies of asthma. We also obtained strong evidence for a new susceptibility gene, CDHR3 (encoding cadherin-related family member 3), which is highly expressed in airway epithelium. These results demonstrate the strength of applying specific phenotyping in the search for asthma susceptibility genes.

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Figure 1: Manhattan plot for the discovery genome-wide association analysis.
Figure 2: Cumulative risk of asthma hospitalization during the first 6 years of life stratified on CDHR3 (rs6967330) genotype.
Figure 3: Overview of the CDHR3 protein model.

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Acknowledgements

A full list of acknowledgments for each study is given in the Supplementary Note.

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K.B. was the main author responsible for designing the study, analyzing and interpreting data, writing the manuscript and directing the work. He had full access to the data and final responsibility for the decision to submit the work for publication. H.B. contributed to design of the study, analysis of data and writing of the manuscript. P.S. and H.H. contributed to design of the study and analysis of data in relation to whole-genome genotyping. K.N. performed the GWAS analysis and contributed to regional imputation. E.K.-M., A. Sevelsted, M.A.R., R.Y. and R.G. contributed to data analysis. J.M.M., S.B.-G. and D.T. directed and contributed to regional imputation and data analyses. M.V.H. and D.M.H. were responsible for subject identification, collection of dried blood spots and DNA extraction and amplification. K.B., E.K.-M., L.J.M., R.F. and A.M. contributed to data acquisition. T.B. performed modeling of the CDHR3 protein structure. L.P., C.H. and E.A.N. were responsible for data from the discovery control cohort. H.H. and M.E.M. were responsible for the functional studies of the CDHR3 variant involving flow cytometry. A.H., D.E.S. and D.E.D. were responsible for the experimental studies involving immunofluorescence staining. A. Simpson, A.C. and D.B. were responsible for data from the MAAS cohort. H.T.d.D., L.D. and V.W.V.J. were responsible for data from the Generation R cohort. G.F.-T., P.M.L. and J.W.H. were responsible for the studies of lung tissue. P.F.T. studied the evolutionary aspects of the CDHR3 risk variant (rs6967330). All coauthors provided important intellectual input to the study and approved the final version of the manuscript.

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Correspondence to Klaus Bønnelykke.

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Competing interests

A patent has been filed for CDHR3 as a susceptibility gene for asthma by K.B., H.B. and H.H. on behalf of COPSAC and CHOP. None of the authors report any other conflict of interest relevant to the content of this report.

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Supplementary Figures 1–10, Supplementary Tables 1–11 and Supplementary Note (PDF 2626 kb)

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Bønnelykke, K., Sleiman, P., Nielsen, K. et al. A genome-wide association study identifies CDHR3 as a susceptibility locus for early childhood asthma with severe exacerbations. Nat Genet 46, 51–55 (2014). https://doi.org/10.1038/ng.2830

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