Genome-wide association study to identify genetic determinants of severe asthma
- Y I Wan1,*,
- N R G Shrine2,*,
- M Soler Artigas2,
- L V Wain2,
- J D Blakey1,
- M F Moffatt3,
- A Bush3,
- K F Chung3,
- W O C M Cookson3,
- D P Strachan4,
- L Heaney5,
- B A H Al-Momani6,
- A H Mansur7,
- S Manney7,
- N C Thomson8,
- R Chaudhuri8,
- C E Brightling9,
- M Bafadhel9,
- A Singapuri9,
- R Niven10,
- A Simpson10,
- J W Holloway11,12,
- P H Howarth12,13,
- J Hui14,
- A W Musk14,
- A L James14,
- the Australian Asthma Genetics Consortium15,
- M A Brown16,
- S Baltic17,
- M A R Ferreira18,
- P J Thompson17,
- M D Tobin2,
- I Sayers1,
- I P Hall1
- 1Therapeutics and Molecular Medicine, University of Nottingham, Nottingham, UK
- 2Department of Health Sciences, University of Leicester, Leicester, UK
- 3National Heart and Lung Institute, Imperial College, London, UK
- 4Division of Community Health Sciences, St George's, University of London, London, UK
- 5Centre for Infection and Immunity, Queen's University of Belfast, Belfast, UK
- 6School of Pharmacy, Queen's University of Belfast, Belfast, UK
- 7Respiratory Medicine, Birmingham Heartlands Hospital and University of Birmingham, Birmingham, UK
- 8Respiratory Medicine, Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow UK
- 9Institute for Lung Health, University of Leicester, Glenfield Hospital, Leicester, UK
- 10The University of Manchester, Manchester Academic Health Science Centre, NIHR Translational Research Facility in Respiratory Medicine, Manchester, UK
- 11Human Genetics and Medical Genomics, Human Development and Health University of Southampton Faculty of Medicine, Southampton, UK
- 12Clinical and Experimental Sciences, University of Southampton Faculty of Medicine, Southampton, UK
- 13Southampton NIHR Respiratory Biomedical Research Unit, University of Southampton Faculty of Medicine, Southampton, UK
- 14Department of Pulmonary Physiology, West Australian Sleep Disorders Research Institute, Western Australia, Australia
- 15A full list of collaborators is available in the web appendix
- 16The University of Queensland Diamantina Institute, Brisbane, Australia
- 17Lung Institute of Western Australia and Centre for Asthma, Allergy and Respiratory Research, University of Western Australia, Perth, Australia
- 18The Queensland Institute of Medical Research, Brisbane, Australia
- Correspondence to Yize I Wan, Division of Therapeutics and Molecular Medicine, University Hospital of Nottingham, Nottingham NG7 2UH, UK;
Contributors YIW, IS and IPH wrote the manuscript. Statistical analyses were carried out by YIW, NGS, MSA, LVW and MDT. Subjects were recruited and phenotype data collected by all authors from individual centres. We would like to acknowledge genotyping by CNG, Paris. The study was conceived by IPH and WOCMC. All authors have read and approved the final version.
- Received 19 October 2011
- Accepted 1 March 2012
- Published Online First 5 May 2012
Background The genetic basis for developing asthma has been extensively studied. However, association studies to date have mostly focused on mild to moderate disease and genetic risk factors for severe asthma remain unclear.
Objective To identify common genetic variants affecting susceptibility to severe asthma.
Methods A genome-wide association study was undertaken in 933 European ancestry individuals with severe asthma based on Global Initiative for Asthma (GINA) criteria 3 or above and 3346 clean controls. After standard quality control measures, the association of 480 889 genotyped single nucleotide polymorphisms (SNPs) was tested. To improve the resolution of the association signals identified, non-genotyped SNPs were imputed in these regions using a dense reference panel of SNP genotypes from the 1000 Genomes Project. Then replication of SNPs of interest was undertaken in a further 231 cases and 1345 controls and a meta-analysis was performed to combine the results across studies.
Results An association was confirmed in subjects with severe asthma of loci previously identified for association with mild to moderate asthma. The strongest evidence was seen for the ORMDL3/GSDMB locus on chromosome 17q12-21 (rs4794820, p=1.03×10(−8) following meta-analysis) meeting genome-wide significance. Strong evidence was also found for the IL1RL1/IL18R1 locus on 2q12 (rs9807989, p=5.59×10(−8) following meta-analysis) just below this threshold. No novel loci for susceptibility to severe asthma met strict criteria for genome-wide significance.
Conclusions The largest genome-wide association study of severe asthma to date was carried out and strong evidence found for the association of two previously identified asthma susceptibility loci in patients with severe disease. A number of novel regions with suggestive evidence were also identified warranting further study.
- Severe asthma
- asthma mechanisms
- asthma epidemiology
- perception of asthma/breathlessness
- respiratory measurement
- respiratory muscles
- COPD mechanisms
- airway epithelium
- allergic lung disease
- COPD epidemiology
- asthma guidelines
- cystic fibrosis
- exhaled airway markers
- lung physiology
- paediatric asthma
- paediatric lung disaese
- asthma pharmacology
- COPD pharmacology
- cytokine biology
- macrophage biology
- clinical epidemiology
- tobacco and the lung
- COPD exacerbations
- asthma in primary care
- bacterial infection
- eosinophil biology
- pulmonary eosinophilia
- respiratory infection
- occupational lung disease
- COPD pathology
YIW and NRGS are joint first authors.
↵* A full list of collaborators is available in the online appendix.
Funding We acknowledge support of Asthma UK, the Wellcome Trust and the Medical Research Council. Specifically, we acknowledge use of phenotype and genotype data from the British 1958 Birth Cohort DNA collection, funded by the Medical Research Council grant G0000934 and the Wellcome Trust grant 068545/Z/02 (http://www.b58cgene.sgul.ac.uk/). Genotyping for the B58C-WTCCC subset was funded by the Wellcome Trust grant 076113/B/04/Z. The B58C-T1DGC genotyping utilised resources provided by the Type 1 Diabetes Genetics Consortium, a collaborative clinical study sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institute of Allergy and Infectious Diseases (NIAID), National Human Genome Research Institute (NHGRI), National Institute of Child Health and Human Development (NICHD), and Juvenile Diabetes Research Foundation International (JDRF) and supported by U01 DK062418. B58C-T1DGC GWAS data were deposited by the Diabetes and Inflammation Laboratory, Cambridge Institute for Medical Research (CIMR), University of Cambridge, which is funded by Juvenile Diabetes Research Foundation International, the Wellcome Trust and the National Institute for Health Research Cambridge Biomedical Research Centre; the CIMR is in receipt of a Wellcome Trust Strategic Award (079895). CEB is funded as a Wellcome Trust Senior Clinical Fellow. MDT has been supported by MRC fellowships G0501942 and G0902313. The Australian Asthma Genetics Consortium is funded by the National Health and Medical Research Council of Australia (613627).
Competing interests None.
Ethics approval Ethics approval was provided by individual study centres during study recruitment.
Provenance and peer review Not commissioned; externally peer reviewed.