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 lim...
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| Format: | Article |
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BMJ Publishing Group
2016
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| Online Access: | https://eprints.nottingham.ac.uk/32631/ |
| _version_ | 1848794453069791232 |
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| author | 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. Wain, Louise V. |
| author_facet | 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. Wain, Louise V. |
| author_sort | Jackson, Victoria E. |
| building | Nottingham Research Data Repository |
| collection | Online Access |
| description | 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. |
| first_indexed | 2025-11-14T19:16:26Z |
| format | Article |
| id | nottingham-32631 |
| institution | University of Nottingham Malaysia Campus |
| institution_category | Local University |
| last_indexed | 2025-11-14T19:16:26Z |
| publishDate | 2016 |
| publisher | BMJ Publishing Group |
| recordtype | eprints |
| repository_type | Digital Repository |
| spelling | nottingham-326312024-08-15T15:32:18Z https://eprints.nottingham.ac.uk/32631/ Exome-wide analysis of rare coding variation identifies novel associations with COPD and airflow limitation in MOCS3, IFIT3 and SERPINA12 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. Wain, Louise V. 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. BMJ Publishing Group 2016-02 Article PeerReviewed 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). pp. 501-509. ISSN 1468-3296 COPD Airflow limitation Low frequency exonic variants http://thorax.bmj.com/content/71/6/501 doi:10.1136/thoraxjnl-2015-207876 doi:10.1136/thoraxjnl-2015-207876 |
| spellingShingle | COPD Airflow limitation Low frequency exonic variants 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. Wain, Louise V. Exome-wide analysis of rare coding variation identifies novel associations with COPD and airflow limitation in MOCS3, IFIT3 and SERPINA12 |
| title | Exome-wide analysis of rare coding variation identifies novel associations with COPD and airflow limitation in MOCS3, IFIT3 and SERPINA12 |
| title_full | Exome-wide analysis of rare coding variation identifies novel associations with COPD and airflow limitation in MOCS3, IFIT3 and SERPINA12 |
| title_fullStr | Exome-wide analysis of rare coding variation identifies novel associations with COPD and airflow limitation in MOCS3, IFIT3 and SERPINA12 |
| title_full_unstemmed | Exome-wide analysis of rare coding variation identifies novel associations with COPD and airflow limitation in MOCS3, IFIT3 and SERPINA12 |
| title_short | Exome-wide analysis of rare coding variation identifies novel associations with COPD and airflow limitation in MOCS3, IFIT3 and SERPINA12 |
| title_sort | exome-wide analysis of rare coding variation identifies novel associations with copd and airflow limitation in mocs3, ifit3 and serpina12 |
| topic | COPD Airflow limitation Low frequency exonic variants |
| url | https://eprints.nottingham.ac.uk/32631/ https://eprints.nottingham.ac.uk/32631/ https://eprints.nottingham.ac.uk/32631/ |