Exome-wide analysis of rare coding variation identifies novel associations with COPD and airflow limitation in MOCS3, IFIT3 and SERPINA12

Victoria E Jackson; Ioanna Ntalla; Ian Sayers; Richard Morris; Peter Whincup; Juan-Pablo Casas; Antoinette Amuzu; Minkyoung Choi; Caroline Dale; Meena Kumari; Jorgen Engmann; Noor Kalsheker; Sally Chappell; Tamar Guetta-Baranes; Tricia M McKeever; Colin N A Palmer; Roger Tavendale; John W Holloway; Avan A Sayer; Elaine M Dennison; Cyrus Cooper; Mona Bafadhel; Bethan Barker; Chris Brightling; Charlotte E Bolton; Michelle E John; Stuart G Parker; Miriam F Moffat; Andrew J Wardlaw; Martin J Connolly; David J Porteous; Blair H Smith; Sandosh Padmanabhan; Lynne Hocking; Kathleen E Stirrups; Panos Deloukas; David P Strachan; Ian P Hall; Martin D Tobin; Louise V Wain

doi:10.1136/thoraxjnl-2015-207876

Exome-wide analysis of rare coding variation identifies novel associations with COPD and airflow limitation in MOCS3, IFIT3 and SERPINA12

Thorax. 2016 Jun;71(6):501-9. doi: 10.1136/thoraxjnl-2015-207876. Epub 2016 Feb 25.

Authors

Victoria E Jackson¹, Ioanna Ntalla², Ian Sayers³, Richard Morris⁴, Peter Whincup⁵, Juan-Pablo Casas⁶, Antoinette Amuzu⁷, Minkyoung Choi⁷, Caroline Dale⁷, Meena Kumari⁸, Jorgen Engmann⁹, Noor Kalsheker¹⁰, Sally Chappell¹⁰, Tamar Guetta-Baranes¹⁰, Tricia M McKeever¹¹, Colin N A Palmer¹², Roger Tavendale¹², John W Holloway¹³, Avan A Sayer¹⁴, Elaine M Dennison¹⁵, Cyrus Cooper¹⁴, Mona Bafadhel¹⁶, Bethan Barker¹⁷, Chris Brightling¹⁷, Charlotte E Bolton¹⁸, Michelle E John¹⁸, Stuart G Parker¹⁹, Miriam F Moffat²⁰, Andrew J Wardlaw¹⁷, Martin J Connolly²¹, David J Porteous²², Blair H Smith²³, Sandosh Padmanabhan²⁴, Lynne Hocking²⁵, Kathleen E Stirrups²⁶, Panos Deloukas²⁷, David P Strachan⁵, Ian P Hall³, Martin D Tobin²⁸, Louise V Wain¹

Affiliations

¹ Department of Health Sciences, University of Leicester, Leicester, UK.
² Department of Health Sciences, University of Leicester, Leicester, UK William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
³ Division of Respiratory Medicine, University of Nottingham, Queen's Medical Centre, Nottingham, UK.
⁴ School of Social & Community Medicine, University of Bristol, Bristol, UK Department of Primary Care & Population Health, UCL, London, UK.
⁵ Population Health Research Institute, St George's, University of London, London, UK.
⁶ University College London, Farr Institute of Health Informatics, London, UK Cochrane Heart Group, London, UK.
⁷ Department of Non-communicable Disease Epidemiology, Faculty of Epidemiology and Population Health, London School of Hygiene & Tropical Medicine, London, UK.
⁸ ISER, University of Essex, Colchester, Essex, UK Department of Epidemiology and Public Health, UCL, London, UK.
⁹ Institute of Cardiovascular Science, UCL, London, UK.
¹⁰ School of Life Sciences, University of Nottingham, Nottingham, UK.
¹¹ Division of Epidemiology and Public Health, Nottingham City Hospital, University of Nottingham, Nottingham, UK.
¹² Cardiovascular and Diabetes Medicine, School of Medicine, University of Dundee, Dundee, UK.
¹³ Human Development & Health, Faculty of Medicine, University of Southampton, Southampton General Hospital, Southampton, UK NIHR Southampton Respiratory Biomedical Research Unit, University of Southampton and University Hospital Southampton NHS Foundation Trust, Southampton General Hospital, Southampton, UK.
¹⁴ MRC Lifecourse Epidemiology Unit, University of Southampton, Southampton General Hospital, Southampton, UK NIHR Southampton Biomedical Research Centre, University of Southampton and University Hospital Southampton NHS Foundation Trust, Southampton General Hospital, Southampton, UK.
¹⁵ MRC Lifecourse Epidemiology Unit, University of Southampton, Southampton General Hospital, Southampton, UK Victoria University, Wellington, New Zealand.
¹⁶ Respiratory Medicine Unit, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
¹⁷ Institute for Lung Health, Department of Infection, Immunity and Inflammation, University of Leicester, Leicester, UK National Institute for Health Research Respiratory Biomedical Research Unit, Glenfield Hospital, Leicester, UK.
¹⁸ Nottingham Respiratory Research Unit, University of Nottingham, City Hospital Campus, Nottingham, UK.
¹⁹ Institute for Ageing and Health, Newcastle University, Campus for Ageing and Vitality, Newcastle upon Tyne, UK.
²⁰ Department of Molecular Genetics and Genomics, National Heart and Lung Institute, Imperial College London, London, UK.
²¹ Freemasons' Department of Geriatric Medicine, University of Auckland, New Zealand.
²² Generation Scotland, Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.
²³ Division of Population Health Sciences, University of Dundee, Dundee, UK.
²⁴ Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK.
²⁵ Institute of Medical Sciences, University of Aberdeen, Aberdeen, UK.
²⁶ William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK Department of Haematology, University of Cambridge, Cambridge, UK.
²⁷ William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK Princess Al-Jawhara Al-Brahim Centre of Excellence in Research of Hereditary Disorders, King Abdulaziz University, Jeddah, Saudi Arabia.
²⁸ Department of Health Sciences, University of Leicester, Leicester, UK National Institute for Health Research Respiratory Biomedical Research Unit, Glenfield Hospital, Leicester, UK.

Abstract

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.

Keywords: COPD epidemiology; Tobacco and the lung.

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Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Aged
Airway Obstruction / genetics*
Airway Obstruction / physiopathology*
Exome
Female
Forced Expiratory Volume / genetics
Genome-Wide Association Study
Genotype
Humans
Intracellular Signaling Peptides and Proteins / genetics*
Male
Middle Aged
Nucleotidyltransferases / genetics*
Polymorphism, Single Nucleotide*
Pulmonary Disease, Chronic Obstructive / genetics*
Pulmonary Disease, Chronic Obstructive / physiopathology*
Risk Assessment
Serpins / genetics*
Smoking / epidemiology
Sulfurtransferases / genetics*

Substances

IFIT3 protein, human
Intracellular Signaling Peptides and Proteins
SERPINA12 protein, human
Serpins
MOCS3 protein, human
Nucleotidyltransferases
Sulfurtransferases

Abstract

Publication types

MeSH terms

Substances

Grants and funding