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 Reinmaa; Erik 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

doi:10.1016/S2213-2600(15)00283-0

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 journal › Article › peer-review

280 Citations (Scopus)

Abstract

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 language	English
Pages (from-to)	769-781
Number of pages	13
Journal	The Lancet Respiratory Medicine
Volume	3
Issue number	10
Early online date	27 Sept 2015
DOIs	https://doi.org/10.1016/S2213-2600(15)00283-0
Publication status	Published - Oct 2015

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Cite this

Wain, L. V., Shrine, N., Miller, S., Jackson, V. E., Ntalla, I., Artigas, M. S., Billington, C. K., Kheirallah, A. K., Allen, R., Cook, J. P., Probert, K., Obeidat, M., Bossé, Y., Hao, K., Postma, D. S., Paré, P. D., Ramasamy, A., Mägi, R., Mihailov, E., ... Francks, C. (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. The Lancet Respiratory Medicine, 3(10), 769-781. https://doi.org/10.1016/S2213-2600(15)00283-0

@article{fb1d1c16dc5d4797899bec1f6c2f1735,

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",

abstract = "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.",

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

year = "2015",

month = oct,

doi = "10.1016/S2213-2600(15)00283-0",

language = "English",

volume = "3",

pages = "769--781",

journal = "The Lancet Respiratory Medicine",

issn = "2213-2600",

publisher = "Elsevier Ltd",

number = "10",

}

Wain, LV, Shrine, N, Miller, S, Jackson, VE, Ntalla, I, Artigas, MS, Billington, CK, Kheirallah, AK, Allen, R, Cook, JP, Probert, K, Obeidat, M, Bossé, Y, Hao, K, Postma, DS, Paré, PD, Ramasamy, A, Mägi, R, Mihailov, E, Reinmaa, E, Melén, E, O'Connell, J, Frangou, E, Delaneau, O, Freeman, C, Petkova, D, McCarthy, M, Sayers, I, Deloukas, P, Hubbard, R, Pavord, I, Hansell, AL, Thomson, NC, Zeggini, E, Morris, AP, Marchini, J, Strachan, DP, Tobin, MD, Hall, IP, Farrall, M, Barroso, I, Anderson, CA, Botía, J, Vandrocova, J, Guelfi, S, D'Sa, K, Ryten, M, Trabzuni, D, Matarin, M, Hardy, JA, Weale, ME, Varghese, V, Forabosco, P , Farmer, A , McGuffin, P, Zgaga, L, Wilson, JF, Wild, SH, Campbell, H, Rudan, I, Smith, C, Walker, R, Liu, JZ, Tozzi, F, Muglia, P, Waterworth, DM, Pillai, SG, Yuan, X, Mooser, V, Middleton, L, Kooner, J, Chambers, JC, Berrettini, W, Knouff, CW, Waeber, G, Vollenweider, P, Preisig, M, Wareham, NJ, Zhao, JH, Loos, RJF, Khaw, KT, Grundy, S, Barter, P, Mahley, R, Kesaniemi, A, McPherson, R, Vincent, JB, Strauss, J, Kennedy, JL, Day, R, Matthews, K, Bakke, P, Gulsvik, A, Lucae, S, Ising, M, Brueckl, T, Horstmann, S, Wichmann, HE, Rawal, R, Wichmann, HE, Lamina, C, Dahmen, N, Polasek, O, Kolcic, I, Huffman, J, Campbell, S, Vitart, V, Hayward, C, Wright, AF, Burnett, MS, Devaney, JM, Pichard, AD, Kent, KM, Satler, L, Lindsay, JM, Waksman, R, Epstein, S, Reilly, MP, Li, M, Qu, L, Wilensky, R, Matthai, W, Hakonarson, HH, Rader, DJ, Ellinghaus, D, Lieb, W, Franke, A, Uda, M, Busonero, F, Terracciano, A, Schlessinger, D, Xiao, X, Scheet, P, St Clair, D, Rujescu, D, Abecasis, GR, Grabe, HJ, Teumer, A, Völzke, H, Petersmann, A, John, U, Wright, BJ, Thompson, JR, Balmforth, AJ, Hall, AS, Samani, NJ, Ahmad, T, Mathew, CG, Parkes, M, Satsangi, J, Caulfield, M, Munroe, PB, Dominiczak, A, Worthington, J, Thomson, W, Eyre, S, Barton, A & Francks, C 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', The Lancet Respiratory Medicine, vol. 3, no. 10, pp. 769-781. https://doi.org/10.1016/S2213-2600(15)00283-0

TY - JOUR

T1 - Novel insights into the genetics of smoking behaviour, lung function, and chronic obstructive pulmonary disease (UK BiLEVE)

T2 - A genetic association study in UK Biobank

AU - Wain, Louise V.

AU - Shrine, Nick

AU - Miller, Suzanne

AU - Jackson, Victoria E.

AU - Ntalla, Ioanna

AU - Artigas, María Soler

AU - Billington, Charlotte K.

AU - Kheirallah, Abdul Kader

AU - Allen, Richard

AU - Cook, James P.

AU - Probert, Kelly

AU - Obeidat, Ma'en

AU - Bossé, Yohan

AU - Hao, Ke

AU - Postma, Dirkje S.

AU - Paré, Peter D.

AU - Ramasamy, Adaikalavan

AU - Mägi, Reedik

AU - Mihailov, Evelin

AU - Reinmaa, Eva

AU - Melén, Erik

AU - O'Connell, Jared

AU - Frangou, Eleni

AU - Delaneau, Olivier

AU - Freeman, Colin

AU - Petkova, Desislava

AU - McCarthy, Mark

AU - Sayers, Ian

AU - Deloukas, Panos

AU - Hubbard, Richard

AU - Pavord, Ian

AU - Hansell, Anna L.

AU - Thomson, Neil C.

AU - Zeggini, Eleftheria

AU - Morris, Andrew P.

AU - Marchini, Jonathan

AU - Strachan, David P.

AU - Tobin, Martin D.

AU - Hall, Ian P.

AU - Farrall, Martin

AU - Barroso, Inês

AU - Anderson, Carl A.

AU - Botía, Juan

AU - Vandrocova, Jana

AU - Guelfi, Sebastian

AU - D'Sa, Karishma

AU - Ryten, Mina

AU - Trabzuni, Daniah

AU - Matarin, Mar

AU - Hardy, John A.

AU - Weale, Michael E.

AU - Varghese, Vibin

AU - Forabosco, Paola

AU - Farmer, Anne

AU - McGuffin, Peter

AU - Zgaga, Lina

AU - Wilson, James F.

AU - Wild, Sarah H.

AU - Campbell, Harry

AU - Rudan, Igor

AU - Smith, Colin

AU - Walker, Robert

AU - Liu, Jason Z.

AU - Tozzi, Federica

AU - Muglia, Pierandrea

AU - Waterworth, Dawn M.

AU - Pillai, Sreekumar G.

AU - Yuan, Xin

AU - Mooser, Vincent

AU - Middleton, Lefkos

AU - Kooner, Jaspal

AU - Chambers, John C.

AU - Berrettini, Wade

AU - Knouff, Christopher W.

AU - Waeber, Gérard

AU - Vollenweider, Peter

AU - Preisig, Martin

AU - Wareham, Nicholas J.

AU - Zhao, Jing Hua

AU - Loos, Ruth J F

AU - Khaw, Kay Tee

AU - Grundy, Scott

AU - Barter, Philip

AU - Mahley, Robert

AU - Kesaniemi, Antero

AU - McPherson, Ruth

AU - Vincent, John B.

AU - Strauss, John

AU - Kennedy, James L.

AU - Day, Richard

AU - Matthews, Keith

AU - Bakke, Per

AU - Gulsvik, Amund

AU - Lucae, Susanne

AU - Ising, Marcus

AU - Brueckl, Tanja

AU - Horstmann, Sonja

AU - Wichmann, H. Erich

AU - Rawal, Rajesh

AU - Wichmann, H. Erich

AU - Lamina, Claudia

AU - Dahmen, Norbert

AU - Polasek, Ozren

AU - Kolcic, Ivana

AU - Huffman, Jennifer

AU - Campbell, Susan

AU - Vitart, Veronique

AU - Hayward, Caroline

AU - Wright, Alan F.

AU - Burnett, Mary Susan

AU - Devaney, Joseph M.

AU - Pichard, Augusto D.

AU - Kent, Kenneth M.

AU - Satler, Lowell

AU - Lindsay, Joseph M.

AU - Waksman, Ron

AU - Epstein, Stephen

AU - Reilly, Muredach P.

AU - Li, Mingyao

AU - Qu, Liming

AU - Wilensky, Robert

AU - Matthai, William

AU - Hakonarson, Hakon H.

AU - Rader, Daniel J.

AU - Ellinghaus, David

AU - Lieb, Wolfgang

AU - Franke, Andre

AU - Uda, Manuela

AU - Busonero, Fabio

AU - Terracciano, Antonio

AU - Schlessinger, David

AU - Xiao, Xiangjun

AU - Scheet, Paul

AU - St Clair, David

AU - Rujescu, Dan

AU - Abecasis, Gonçalo R.

AU - Grabe, Hans Jörgen

AU - Teumer, Alexander

AU - Völzke, Henry

AU - Petersmann, Astrid

AU - John, Ulrich

AU - Wright, Benjamin J.

AU - Thompson, John R.

AU - Balmforth, Anthony J.

AU - Hall, Alistair S.

AU - Samani, Nilesh J.

AU - Ahmad, Tariq

AU - Mathew, Christopher G.

AU - Parkes, Miles

AU - Satsangi, Jack

AU - Caulfield, Mark

AU - Munroe, Patricia B.

AU - Dominiczak, Anna

AU - Worthington, Jane

AU - Thomson, Wendy

AU - Eyre, Steve

AU - Barton, Anne

AU - Francks, Clyde

PY - 2015/10

Y1 - 2015/10

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84943428582&partnerID=8YFLogxK

U2 - 10.1016/S2213-2600(15)00283-0

DO - 10.1016/S2213-2600(15)00283-0

M3 - Article

AN - SCOPUS:84943428582

SN - 2213-2600

VL - 3

SP - 769

EP - 781

JO - The Lancet Respiratory Medicine

JF - The Lancet Respiratory Medicine

IS - 10

ER -

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

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