title: Exome-wide analysis of rare coding variation identifies novel associations with COPD and airflow limitation in MOCS3, IFIT3 and SERPINA12.
abstract: Several regions of the genome have shown to be associated with COPD in genome-wide association studies of common variants.
  
  
  
  To determine rare and potentially functional single nucleotide polymorphisms (SNPs) associated with the risk of COPD and severity of airflow limitation.
  
  
  
  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.
  
  
  
  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)).
  
  
  
  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.
authors.affiliation: Department of Health Sciences, University of Leicester, Leicester, UK.
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authors.affiliation: 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.
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authors.affiliation: Division of Respiratory Medicine, University of Nottingham, Queen's Medical Centre, Nottingham, UK.
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authors.affiliation: Population Health Research Institute, St George's, University of London, London, UK.
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authors.affiliation: Department of Non-communicable Disease Epidemiology, Faculty of Epidemiology and Population Health, London School of Hygiene & Tropical Medicine, London, UK.
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authors.affiliation: Department of Non-communicable Disease Epidemiology, Faculty of Epidemiology and Population Health, London School of Hygiene & Tropical Medicine, London, UK.
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authors.affiliation: School of Life Sciences, University of Nottingham, Nottingham, UK.
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authors.affiliation: School of Life Sciences, University of Nottingham, Nottingham, UK.
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authors.affiliation: 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.
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authors.identifier: 0000-0002-9993-2478
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authors.affiliation: 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.
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authors.affiliation: 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.
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authors.affiliation: Department of Health Sciences, University of Leicester, Leicester, UK National Institute for Health Research Respiratory Biomedical Research Unit, Glenfield Hospital, Leicester, UK.
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authors.initials: MD
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authors.affiliation: Department of Health Sciences, University of Leicester, Leicester, UK.
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mesh_terms: D000368:Aged; D000402:Airway Obstruction / Q000235:genetics* / Q000503:physiopathology*; D059472:Exome; D005260:Female; D005541:Forced Expiratory Volume / Q000235:genetics; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009713:Nucleotidyltransferases / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D029424:Pulmonary Disease, Chronic Obstructive / Q000235:genetics* / Q000503:physiopathology*; D018570:Risk Assessment; D015843:Serpins / Q000235:genetics*; D012907:Smoking / Q000453:epidemiology; D013466:Sulfurtransferases / Q000235:genetics*
chemical_list: C116468:IFIT3 protein, human; D047908:Intracellular Signaling Peptides and Proteins; C507339:SERPINA12 protein, human; D015843:Serpins; C502790:MOCS3 protein, human; D009713:Nucleotidyltransferases; D013466:Sulfurtransferases
keywords: COPD epidemiology; Tobacco and the lung