Novel insights into the genetics of smoking behaviour, lung function, and chronic obstructive pulmonary disease (UK BiLEVE): A genetic association study in UK Biobank

Louise V. Wain, Nick Shrine, Suzanne Miller, Victoria E. Jackson, Ioanna Ntalla, María Soler Artigas, Charlotte K. Billington, Abdul Kader Kheirallah, Richard Allen, James P. Cook, Kelly Probert, Ma'en Obeidat, Yohan Bossé, Ke Hao, Dirkje S. Postma, Peter D. Paré, Adaikalavan Ramasamy, Reedik Mägi, Evelin Mihailov, Eva ReinmaaErik Melén, Jared O'Connell, Eleni Frangou, Olivier Delaneau, Colin Freeman, Desislava Petkova, Mark McCarthy, Ian Sayers, Panos Deloukas, Richard Hubbard, Ian Pavord, Anna L. Hansell, Neil C. Thomson, Eleftheria Zeggini, Andrew P. Morris, Jonathan Marchini, David P. Strachan, Martin D. Tobin*, Ian P. Hall, Martin Farrall, Inês Barroso, Carl A. Anderson, Juan Botía, Jana Vandrocova, Sebastian Guelfi, Karishma D'Sa, Mina Ryten, Daniah Trabzuni, Mar Matarin, John A. Hardy, Michael E. Weale, Vibin Varghese, Paola Forabosco, Anne Farmer, Peter McGuffin, Lina Zgaga, James F. Wilson, Sarah H. Wild, Harry Campbell, Igor Rudan, Colin Smith, Robert Walker, Jason Z. Liu, Federica Tozzi, Pierandrea Muglia, Dawn M. Waterworth, Sreekumar G. Pillai, Xin Yuan, Vincent Mooser, Lefkos Middleton, Jaspal Kooner, John C. Chambers, Wade Berrettini, Christopher W. Knouff, Gérard Waeber, Peter Vollenweider, Martin Preisig, Nicholas J. Wareham, Jing Hua Zhao, Ruth J F Loos, Kay Tee Khaw, Scott Grundy, Philip Barter, Robert Mahley, Antero Kesaniemi, Ruth McPherson, John B. Vincent, John Strauss, James L. Kennedy, Richard Day, Keith Matthews, Per Bakke, Amund Gulsvik, Susanne Lucae, Marcus Ising, Tanja Brueckl, Sonja Horstmann, H. Erich Wichmann, Rajesh Rawal, H. Erich Wichmann, Claudia Lamina, Norbert Dahmen, Ozren Polasek, Ivana Kolcic, Jennifer Huffman, Susan Campbell, Veronique Vitart, Caroline Hayward, Alan F. Wright, Mary Susan Burnett, Joseph M. Devaney, Augusto D. Pichard, Kenneth M. Kent, Lowell Satler, Joseph M. Lindsay, Ron Waksman, Stephen Epstein, Muredach P. Reilly, Mingyao Li, Liming Qu, Robert Wilensky, William Matthai, Hakon H. Hakonarson, Daniel J. Rader, David Ellinghaus, Wolfgang Lieb, Andre Franke, Manuela Uda, Fabio Busonero, Antonio Terracciano, David Schlessinger, Xiangjun Xiao, Paul Scheet, David St Clair, Dan Rujescu, Gonçalo R. Abecasis, Hans Jörgen Grabe, Alexander Teumer, Henry Völzke, Astrid Petersmann, Ulrich John, Benjamin J. Wright, John R. Thompson, Anthony J. Balmforth, Alistair S. Hall, Nilesh J. Samani, Tariq Ahmad, Christopher G. Mathew, Miles Parkes, Jack Satsangi, Mark Caulfield, Patricia B. Munroe, Anna Dominiczak, Jane Worthington, Wendy Thomson, Steve Eyre, Anne Barton, Clyde Francks

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

274 Citations (Scopus)


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-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 significant 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 5' end 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. Funding: Medical Research Council.

Original languageEnglish
Pages (from-to)769-781
Number of pages13
JournalThe Lancet Respiratory Medicine
Issue number10
Early online date27 Sept 2015
Publication statusPublished - Oct 2015


Dive into the research topics of 'Novel insights into the genetics of smoking behaviour, lung function, and chronic obstructive pulmonary disease (UK BiLEVE): A genetic association study in UK Biobank'. Together they form a unique fingerprint.

Cite this