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

Exome-wide analysis of rare coding variation identifies novel associations with COPD and airflow limitation in MOCS3, IFIT3 and SERPINA12
Exome-wide analysis of rare coding variation identifies novel associations with COPD and airflow limitation in MOCS3, IFIT3 and SERPINA12
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.
0040-6376
501-509
Jackson, Victoria E.
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Sayer, Avan A.
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Dennison, Elaine M.
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Cooper, Cyrus
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Bafadhel, Mona
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Bolton, Charlotte E.
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John, Michelle E.
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Parker, Stuart G.
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Moffat, Miriam F.
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Wardlaw, Andrew J.
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Connolly, Martin J.
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Hocking, Lynne
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Jackson, Victoria E.
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Sayers, Ian
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Morris, Richard
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Whincup, Peter
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Casas, Juan-Pablo
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Amuzu, Antoinette
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Choi, Minkyoung
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Dale, Caroline
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Kumari, Meena
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Kalsheker, Noor
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Hocking, Lynne
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Strachan, David P.
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Hall, Ian P.
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Wain, Louise V.
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Jackson, Victoria E., Ntalla, Ioanna, Sayers, Ian, Morris, Richard, Whincup, Peter, Casas, Juan-Pablo, Amuzu, Antoinette, Choi, Minkyoung, Dale, Caroline, Kumari, Meena, Engmann, Jorgen, Kalsheker, Noor, Chappell, Sally, Guetta-Baranes, Tamar, McKeever, Tricia M., Palmer, Colin N.A., Tavendale, Roger, Holloway, John W., Sayer, Avan A., Dennison, Elaine M., Cooper, Cyrus, Bafadhel, Mona, Barker, Bethan, Brightling, Chris, Bolton, Charlotte E., John, Michelle E., Parker, Stuart G., Moffat, Miriam F., Wardlaw, Andrew J., Connolly, Martin J., Porteous, David J., Smith, Blair H., Padmanabhan, Sandosh, Hocking, Lynne, Stirrups, Kathleen E., Deloukas, Panos, Strachan, David P., Hall, Ian P., 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), 501-509. (doi:10.1136/thoraxjnl-2015-207876). (PMID:26917578)

Record type: Article

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.

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Accepted/In Press date: 29 January 2016
e-pub ahead of print date: 25 February 2016
Published date: June 2016
Organisations: Human Development & Health, MRC Life-Course Epidemiology Unit

Identifiers

Local EPrints ID: 388549
URI: http://eprints.soton.ac.uk/id/eprint/388549
ISSN: 0040-6376
PURE UUID: eb0a8c80-f1c4-424a-b751-186df321415a
ORCID for John W. Holloway: ORCID iD orcid.org/0000-0001-9998-0464
ORCID for Elaine M. Dennison: ORCID iD orcid.org/0000-0002-3048-4961
ORCID for Cyrus Cooper: ORCID iD orcid.org/0000-0003-3510-0709

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Date deposited: 29 Feb 2016 14:09
Last modified: 18 Feb 2021 16:49

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Contributors

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

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