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

UK Brain Expression Consortium (UKBEC), OxGSK Consortium

Research output: Contribution to journalArticle

155 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 languageEnglish (US)
Pages (from-to)769-781
Number of pages13
JournalThe Lancet Respiratory Medicine
Volume3
Issue number10
DOIs
StatePublished - Oct 1 2015

Fingerprint

Forced Expiratory Volume
Genetic Association Studies
Chronic Obstructive Pulmonary Disease
Smoking
Lung
Genome
Lung Diseases
Health
Chromosomes, Human, Pair 11
Chromosomes, Human, Pair 2
Epigenomics
Genes
Tobacco
Biomedical Research
Asthma
Phenotype
Brain

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine

Cite this

Novel insights into the genetics of smoking behaviour, lung function, and chronic obstructive pulmonary disease (UK BiLEVE) : A genetic association study in UK Biobank. / UK Brain Expression Consortium (UKBEC); OxGSK Consortium.

In: The Lancet Respiratory Medicine, Vol. 3, No. 10, 01.10.2015, p. 769-781.

Research output: Contribution to journalArticle

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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 = "{UK Brain Expression Consortium (UKBEC)} and {OxGSK Consortium} and 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 Grundy, {Scott M}",
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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 - UK Brain Expression Consortium (UKBEC)

AU - OxGSK Consortium

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 - Grundy, Scott M

PY - 2015/10/1

Y1 - 2015/10/1

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.

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