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

Victoria E. Jackson (Lead / Corresponding author), 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. DennisonCyrus 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

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    22 Citations (Scopus)
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    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.

    Original languageEnglish
    Pages (from-to)501-509
    Number of pages9
    Issue number6
    Early online date25 Feb 2016
    Publication statusPublished - Jun 2016

    ASJC Scopus subject areas

    • Pulmonary and Respiratory Medicine


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