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Exome-wide analysis of rare coding variation identifies novel associations with COPD and airflow limitation in MOCS3, IFIT3 and SERPINA12
  1. Victoria E Jackson1,
  2. Ioanna Ntalla1,2,
  3. Ian Sayers3,
  4. Richard Morris4,5,
  5. Peter Whincup6,
  6. Juan-Pablo Casas7,8,
  7. Antoinette Amuzu9,
  8. Minkyoung Choi9,
  9. Caroline Dale9,
  10. Meena Kumari10,11,
  11. Jorgen Engmann12,
  12. Noor Kalsheker13,
  13. Sally Chappell13,
  14. Tamar Guetta-Baranes13,
  15. Tricia M McKeever14,
  16. Colin N A Palmer15,
  17. Roger Tavendale15,
  18. John W Holloway16,17,
  19. Avan A Sayer18,19,
  20. Elaine M Dennison18,20,
  21. Cyrus Cooper18,19,
  22. Mona Bafadhel21,
  23. Bethan Barker22,23,
  24. Chris Brightling22,23,
  25. Charlotte E Bolton24,
  26. Michelle E John24,
  27. Stuart G Parker25,
  28. Miriam F Moffat26,
  29. Andrew J Wardlaw22,23,
  30. Martin J Connolly27,
  31. David J Porteous28,
  32. Blair H Smith29,
  33. Sandosh Padmanabhan30,
  34. Lynne Hocking31,
  35. Kathleen E Stirrups2,32,
  36. Panos Deloukas2,33,
  37. David P Strachan6,
  38. Ian P Hall3,
  39. Martin D Tobin1,23,
  40. Louise V Wain1
  1. 1Department of Health Sciences, University of Leicester, Leicester, UK
  2. 2William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
  3. 3Division of Respiratory Medicine, University of Nottingham, Queen's Medical Centre, Nottingham, UK
  4. 4School of Social & Community Medicine, University of Bristol, Bristol, UK
  5. 5Department of Primary Care & Population Health, UCL, London, UK
  6. 6Population Health Research Institute, St George's, University of London, London, UK
  7. 7University College London, Farr Institute of Health Informatics, London, UK
  8. 8Cochrane Heart Group, London, UK
  9. 9Department of Non-communicable Disease Epidemiology, Faculty of Epidemiology and Population Health, London School of Hygiene & Tropical Medicine, London, UK
  10. 10ISER, University of Essex, Colchester, Essex, UK
  11. 11Department of Epidemiology and Public Health, UCL, London, UK
  12. 12Institute of Cardiovascular Science, UCL, London, UK
  13. 13School of Life Sciences, University of Nottingham, Nottingham, UK
  14. 14Division of Epidemiology and Public Health, Nottingham City Hospital, University of Nottingham, Nottingham, UK
  15. 15Cardiovascular and Diabetes Medicine, School of Medicine, University of Dundee, Dundee, UK.
  16. 16Human Development & Health, Faculty of Medicine, University of Southampton, Southampton General Hospital, Southampton, UK
  17. 17NIHR Southampton Respiratory Biomedical Research Unit, University of Southampton and University Hospital Southampton NHS Foundation Trust, Southampton General Hospital, Southampton, UK
  18. 18MRC Lifecourse Epidemiology Unit, University of Southampton, Southampton General Hospital, Southampton, UK
  19. 19NIHR Southampton Biomedical Research Centre, University of Southampton and University Hospital Southampton NHS Foundation Trust, Southampton General Hospital, Southampton, UK
  20. 20Victoria University, Wellington, New Zealand
  21. 21Respiratory Medicine Unit, Nuffield Department of Medicine, University of Oxford, Oxford, UK
  22. 22Institute for Lung Health, Department of Infection, Immunity and Inflammation, University of Leicester, Leicester, UK
  23. 23National Institute for Health Research Respiratory Biomedical Research Unit, Glenfield Hospital, Leicester, UK
  24. 24Nottingham Respiratory Research Unit, University of Nottingham, City Hospital Campus, Nottingham, UK
  25. 25Institute for Ageing and Health, Newcastle University, Campus for Ageing and Vitality, Newcastle upon Tyne, UK
  26. 26Department of Molecular Genetics and Genomics, National Heart and Lung Institute, Imperial College London, London, UK
  27. 27Freemasons’ Department of Geriatric Medicine, University of Auckland, New Zealand
  28. 28Generation Scotland, Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK
  29. 29Division of Population Health Sciences, University of Dundee, Dundee, UK
  30. 30Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK
  31. 31Institute of Medical Sciences, University of Aberdeen, Aberdeen, UK
  32. 32Department of Haematology, University of Cambridge, Cambridge, UK
  33. 33Princess Al-Jawhara Al-Brahim Centre of Excellence in Research of Hereditary Disorders, King Abdulaziz University, Jeddah, Saudi Arabia
  1. Correspondence to Victoria E Jackson, Department of Health Sciences, University of Leicester, University Road, Leicester LE1 7RH, UK; vej3{at}


Background Several regions of the genome have shown to be associated with COPD in genome-wide association studies of common variants.

Objective To determine rare and potentially functional single nucleotide polymorphisms (SNPs) associated with the risk of COPD and severity of airflow limitation.

Methods 3226 current or former smokers of European ancestry with lung function measures indicative of Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2 COPD or worse were genotyped using an exome array. An analysis of risk of COPD was carried out using ever smoking controls (n=4784). Associations with %predicted FEV1 were tested in cases. We followed-up signals of interest (p<10−5) in independent samples from a subset of the UK Biobank population and also undertook a more powerful discovery study by meta-analysing the exome array data and UK Biobank data for variants represented on both arrays.

Results Among the associated variants were two in regions previously unreported for COPD; a low frequency non-synonymous SNP in MOCS3 (rs7269297, pdiscovery=3.08×10−6, preplication=0.019) and a rare SNP in IFIT3, which emerged in the meta-analysis (rs140549288, pmeta=8.56×10−6). In the meta-analysis of % predicted FEV1 in cases, the strongest association was shown for a splice variant in a previously unreported region, SERPINA12 (rs140198372, pmeta=5.72×10−6). We also confirmed previously reported associations with COPD risk at MMP12, HHIP, GPR126 and CHRNA5. No associations in novel regions reached a stringent exome-wide significance threshold (p<3.7×10−7).

Conclusions This study identified several associations with the risk of COPD and severity of airflow limitation, including novel regions MOCS3, IFIT3 and SERPINA12, which warrant further study.

  • COPD epidemiology
  • Tobacco and the lung

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