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

Jackson, Victoria E. and Ntalla, Ioanna and Sayers, Ian and Morris, Richard and Whincup, Peter and Casas, Juan-Pablo and Amuzu, Antoinette and Choi, Minkyoung and Dale, Caroline and Kumari, Meena and Engmann, Jorgen and Kalsheker, Noor and Chappell, Sally and Guetta-Baranes, Tamar and McKeever, Tricia M. and Palmer, Colin N.A. and Tavendale, Roger and Holloway, John W. and Sayer, Avan A. and Dennison, Elaine M. and Cooper, Cyrus and Bafadhel, Mona and Barker, Bethan and Brightling, Chris and Bolton, Charlotte E. and John, Michelle E. and Parker, Stuart G. and Moffat, Miriam F. and Wardlaw, Andrew J. and Connolly, Martin J. and Porteous, David J. and Smith, Blair H. and Padmanabhan, Sandosh and Hocking, Lynne and Stirrups, Kathleen E. and Deloukas, Panos and Strachan, David P. and Hall, Ian P. and Tobin, Martin D. and Wain, Louise V. (2016) Exome-wide analysis of rare coding variation identifies novel associations with COPD and airflow limitation in MOCS3, IFIT3 and SERPINA12. Thorax, 71 (6). pp. 501-509. ISSN 1468-3296

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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.

Item Type: Article
Keywords: COPD, Airflow limitation, Low frequency exonic variants
Schools/Departments: University of Nottingham, UK > Faculty of Medicine and Health Sciences > School of Medicine > Division of Epidemiology and Public Health
University of Nottingham, UK > Faculty of Medicine and Health Sciences > School of Medicine > Division of Respiratory Medicine
University of Nottingham, UK > Faculty of Medicine and Health Sciences > School of Life Sciences
Identification Number: https://doi.org/10.1136/thoraxjnl-2015-207876
Depositing User: Eprints, Support
Date Deposited: 05 Apr 2016 08:24
Last Modified: 07 Dec 2016 15:23
URI: http://eprints.nottingham.ac.uk/id/eprint/32631

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