Novel insights into the genetics of smoking behaviour, lung function, and chronic obstructive pulmonary disease (UK BiLEVE): a genetic association study in UK Biobank
Background Understanding the genetic basis of airflow obstruction and smoking behaviour is key to determining the pathophysiology of chronic obstructive pulmonary disease (COPD). We used UK Biobank data to study the genetic causes of smoking behaviour and lung health. Methods We sampled ind...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Published: |
Elsevier
2015
|
| Online Access: | https://eprints.nottingham.ac.uk/32643/ |
| _version_ | 1848794456486051840 |
|---|---|
| author | Wain, Louise V. Shrine, Nick Miller, Suzanne Jackson, Victoria E. Ntalla, Ioanna Artigas, María Soler Billington, Charlotte K. Kheirallah, Abdul Kader Allen, Richard Cook, James P. Probert, Kelly Obeidat, Ma'en Bossé, Yohan Hao, Ke Postma, Dirkje S. Paré, Peter D. Ramasamy, Adaikalavan Mägi, Reedik Mihailov, Evelin Reinmaa, Eva Melén, Erik O'Connell, Jared Frangou, Eleni Delaneau, Olivier Freeman, Colin Petkova, Desislava McCarthy, Mark Sayers, Ian Deloukas, Panos Hubbard, Richard Pavord, Ian Hansell, Anna L. Thomson, Neil C. Zeggini, Eleftheria Morris, Andrew P. Marchini, Jonathan Strachan, David P. Tobin, Martin D. Hall, Ian P. |
| author_facet | Wain, Louise V. Shrine, Nick Miller, Suzanne Jackson, Victoria E. Ntalla, Ioanna Artigas, María Soler Billington, Charlotte K. Kheirallah, Abdul Kader Allen, Richard Cook, James P. Probert, Kelly Obeidat, Ma'en Bossé, Yohan Hao, Ke Postma, Dirkje S. Paré, Peter D. Ramasamy, Adaikalavan Mägi, Reedik Mihailov, Evelin Reinmaa, Eva Melén, Erik O'Connell, Jared Frangou, Eleni Delaneau, Olivier Freeman, Colin Petkova, Desislava McCarthy, Mark Sayers, Ian Deloukas, Panos Hubbard, Richard Pavord, Ian Hansell, Anna L. Thomson, Neil C. Zeggini, Eleftheria Morris, Andrew P. Marchini, Jonathan Strachan, David P. Tobin, Martin D. Hall, Ian P. |
| author_sort | Wain, Louise V. |
| building | Nottingham Research Data Repository |
| collection | Online Access |
| description | Background
Understanding the genetic basis of airflow obstruction and smoking behaviour is key to determining the pathophysiology of chronic obstructive pulmonary disease (COPD). We used UK Biobank data to study the genetic causes of smoking behaviour and lung health.
Methods
We sampled individuals of European ancestry from UK Biobank, from the middle and extremes of the forced expiratory volume in 1 s (FEV1) distribution among heavy smokers (mean 35 pack-years) and never smokers. We developed a custom array for UK Biobank to provide optimum genome-wide coverage of common and low-frequency variants, dense coverage of genomic regions already implicated in lung health and disease, and to assay rare coding variants relevant to the UK population. We investigated whether there were shared genetic causes between different phenotypes defined by extremes of FEV1. We also looked for novel variants associated with extremes of FEV1 and smoking behaviour and assessed regions of the genome that had already shown evidence for a role in lung health and disease. We set genome-wide significance at p<5 × 10−8.
Findings
UK Biobank participants were recruited from March 15, 2006, to July 7, 2010. Sample selection for the UK BiLEVE study started on Nov 22, 2012, and was completed on Dec 20, 2012. We selected 50 008 unique samples: 10 002 individuals with low FEV1, 10 000 with average FEV1, and 5002 with high FEV1 from each of the heavy smoker and never smoker groups. We noted a substantial sharing of genetic causes of low FEV1 between heavy smokers and never smokers (p=2・29 × 10–1⁶) and between individuals with and without doctor-diagnosed asthma (p=6・06 × 10–11). We discovered six novel genome-wide signifi cant signals of association with extremes of FEV1, including signals at four novel loci (KANSL1, TSEN54, TET2, and RBM19/TBX5) and independent signals at two previously reported loci (NPNT and HLA-DQB1/HLA-DQA2). These variants also showed association with COPD, including in individuals with no history of smoking. The number of copies of a 150 kb region containing the 5ʹend of KANSL1, a gene that is important for epigenetic gene regulation, was associated with extremes of FEV1. We also discovered five new genome-wide significant signals for smoking behaviour, including a variant in NCAM1 (chromosome 11) and a variant on chromosome 2 (between TEX41 and PABPC1P2) that has a trans effect on expression of NCAM1 in brain tissue.
Interpretation
By sampling from the extremes of the lung function distribution in UK Biobank, we identified novel genetic causes of lung function and smoking behaviour. These results provide new insight into the specific mechanisms underlying airflow obstruction, COPD, and tobacco addiction, and show substantial shared genetic architecture underlying airflow obstruction across individuals, irrespective of smoking behaviour and other airway disease. |
| first_indexed | 2025-11-14T19:16:29Z |
| format | Article |
| id | nottingham-32643 |
| institution | University of Nottingham Malaysia Campus |
| institution_category | Local University |
| last_indexed | 2025-11-14T19:16:29Z |
| publishDate | 2015 |
| publisher | Elsevier |
| recordtype | eprints |
| repository_type | Digital Repository |
| spelling | nottingham-326432024-08-15T15:32:32Z https://eprints.nottingham.ac.uk/32643/ Novel insights into the genetics of smoking behaviour, lung function, and chronic obstructive pulmonary disease (UK BiLEVE): a genetic association study in UK Biobank Wain, Louise V. Shrine, Nick Miller, Suzanne Jackson, Victoria E. Ntalla, Ioanna Artigas, María Soler Billington, Charlotte K. Kheirallah, Abdul Kader Allen, Richard Cook, James P. Probert, Kelly Obeidat, Ma'en Bossé, Yohan Hao, Ke Postma, Dirkje S. Paré, Peter D. Ramasamy, Adaikalavan Mägi, Reedik Mihailov, Evelin Reinmaa, Eva Melén, Erik O'Connell, Jared Frangou, Eleni Delaneau, Olivier Freeman, Colin Petkova, Desislava McCarthy, Mark Sayers, Ian Deloukas, Panos Hubbard, Richard Pavord, Ian Hansell, Anna L. Thomson, Neil C. Zeggini, Eleftheria Morris, Andrew P. Marchini, Jonathan Strachan, David P. Tobin, Martin D. Hall, Ian P. Background Understanding the genetic basis of airflow obstruction and smoking behaviour is key to determining the pathophysiology of chronic obstructive pulmonary disease (COPD). We used UK Biobank data to study the genetic causes of smoking behaviour and lung health. Methods We sampled individuals of European ancestry from UK Biobank, from the middle and extremes of the forced expiratory volume in 1 s (FEV1) distribution among heavy smokers (mean 35 pack-years) and never smokers. We developed a custom array for UK Biobank to provide optimum genome-wide coverage of common and low-frequency variants, dense coverage of genomic regions already implicated in lung health and disease, and to assay rare coding variants relevant to the UK population. We investigated whether there were shared genetic causes between different phenotypes defined by extremes of FEV1. We also looked for novel variants associated with extremes of FEV1 and smoking behaviour and assessed regions of the genome that had already shown evidence for a role in lung health and disease. We set genome-wide significance at p<5 × 10−8. Findings UK Biobank participants were recruited from March 15, 2006, to July 7, 2010. Sample selection for the UK BiLEVE study started on Nov 22, 2012, and was completed on Dec 20, 2012. We selected 50 008 unique samples: 10 002 individuals with low FEV1, 10 000 with average FEV1, and 5002 with high FEV1 from each of the heavy smoker and never smoker groups. We noted a substantial sharing of genetic causes of low FEV1 between heavy smokers and never smokers (p=2・29 × 10–1⁶) and between individuals with and without doctor-diagnosed asthma (p=6・06 × 10–11). We discovered six novel genome-wide signifi cant signals of association with extremes of FEV1, including signals at four novel loci (KANSL1, TSEN54, TET2, and RBM19/TBX5) and independent signals at two previously reported loci (NPNT and HLA-DQB1/HLA-DQA2). These variants also showed association with COPD, including in individuals with no history of smoking. The number of copies of a 150 kb region containing the 5ʹend of KANSL1, a gene that is important for epigenetic gene regulation, was associated with extremes of FEV1. We also discovered five new genome-wide significant signals for smoking behaviour, including a variant in NCAM1 (chromosome 11) and a variant on chromosome 2 (between TEX41 and PABPC1P2) that has a trans effect on expression of NCAM1 in brain tissue. Interpretation By sampling from the extremes of the lung function distribution in UK Biobank, we identified novel genetic causes of lung function and smoking behaviour. These results provide new insight into the specific mechanisms underlying airflow obstruction, COPD, and tobacco addiction, and show substantial shared genetic architecture underlying airflow obstruction across individuals, irrespective of smoking behaviour and other airway disease. Elsevier 2015-10 Article PeerReviewed Wain, Louise V., Shrine, Nick, Miller, Suzanne, Jackson, Victoria E., Ntalla, Ioanna, Artigas, María Soler, Billington, Charlotte K., Kheirallah, Abdul Kader, Allen, Richard, Cook, James P., Probert, Kelly, Obeidat, Ma'en, Bossé, Yohan, Hao, Ke, Postma, Dirkje S., Paré, Peter D., Ramasamy, Adaikalavan, Mägi, Reedik, Mihailov, Evelin, Reinmaa, Eva, Melén, Erik, O'Connell, Jared, Frangou, Eleni, Delaneau, Olivier, Freeman, Colin, Petkova, Desislava, McCarthy, Mark, Sayers, Ian, Deloukas, Panos, Hubbard, Richard, Pavord, Ian, Hansell, Anna L., Thomson, Neil C., Zeggini, Eleftheria, Morris, Andrew P., Marchini, Jonathan, Strachan, David P., Tobin, Martin D. and Hall, Ian P. (2015) Novel insights into the genetics of smoking behaviour, lung function, and chronic obstructive pulmonary disease (UK BiLEVE): a genetic association study in UK Biobank. Lancet Respiratory Medicine, 3 (10). pp. 769-781. ISSN 2213-2619 http://dx.doi.org/10.1016/S2213-2600(15)00283-0 doi:10.1016/S2213-2600(15)00283-0 doi:10.1016/S2213-2600(15)00283-0 |
| spellingShingle | Wain, Louise V. Shrine, Nick Miller, Suzanne Jackson, Victoria E. Ntalla, Ioanna Artigas, María Soler Billington, Charlotte K. Kheirallah, Abdul Kader Allen, Richard Cook, James P. Probert, Kelly Obeidat, Ma'en Bossé, Yohan Hao, Ke Postma, Dirkje S. Paré, Peter D. Ramasamy, Adaikalavan Mägi, Reedik Mihailov, Evelin Reinmaa, Eva Melén, Erik O'Connell, Jared Frangou, Eleni Delaneau, Olivier Freeman, Colin Petkova, Desislava McCarthy, Mark Sayers, Ian Deloukas, Panos Hubbard, Richard Pavord, Ian Hansell, Anna L. Thomson, Neil C. Zeggini, Eleftheria Morris, Andrew P. Marchini, Jonathan Strachan, David P. Tobin, Martin D. Hall, Ian P. Novel insights into the genetics of smoking behaviour, lung function, and chronic obstructive pulmonary disease (UK BiLEVE): a genetic association study in UK Biobank |
| title | Novel insights into the genetics of smoking behaviour, lung function, and chronic obstructive pulmonary disease (UK BiLEVE): a genetic association study in UK Biobank |
| title_full | Novel insights into the genetics of smoking behaviour, lung function, and chronic obstructive pulmonary disease (UK BiLEVE): a genetic association study in UK Biobank |
| title_fullStr | Novel insights into the genetics of smoking behaviour, lung function, and chronic obstructive pulmonary disease (UK BiLEVE): a genetic association study in UK Biobank |
| title_full_unstemmed | Novel insights into the genetics of smoking behaviour, lung function, and chronic obstructive pulmonary disease (UK BiLEVE): a genetic association study in UK Biobank |
| title_short | Novel insights into the genetics of smoking behaviour, lung function, and chronic obstructive pulmonary disease (UK BiLEVE): a genetic association study in UK Biobank |
| title_sort | novel insights into the genetics of smoking behaviour, lung function, and chronic obstructive pulmonary disease (uk bileve): a genetic association study in uk biobank |
| url | https://eprints.nottingham.ac.uk/32643/ https://eprints.nottingham.ac.uk/32643/ https://eprints.nottingham.ac.uk/32643/ |