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

TitleNovel insights into the genetics of smoking behaviour, lung function, and chronic obstructive pulmonary disease (UK BiLEVE): a genetic association study in UK Biobank.
Publication TypeJournal Article
Year of Publication2015
AuthorsWain LV, Shrine N, Miller S, Jackson VE, Ntalla I, Soler Artigas M, Billington CK, Kheirallah AKader, Allen R, Cook JP, Probert K, Obeidat M'en, 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
Corporate AuthorsUK Brain Expression Consortium(UKBEC), OxGSK Consortium
JournalLancet Respir Med
Date Published2015 Oct
KeywordsAdolescent, Adult, Aged, Aged, 80 and over, Biological Specimen Banks, Case-Control Studies, Female, Forced Expiratory Volume, Genetic Association Studies, Great Britain, Humans, Lung, Male, Middle Aged, Polymorphism, Single Nucleotide, Pulmonary Disease, Chronic Obstructive, Risk Factors, Smoking, Young Adult

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 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.

Alternate JournalLancet Respir Med
Full Text
PubMed ID26423011
PubMed Central IDPMC4593935
Grant ListP30 CA016672 / CA / NCI NIH HHS / United States
G1000861 / / Medical Research Council / United Kingdom
093707 / / Wellcome Trust / United Kingdom
MC_PC_12010 / / Medical Research Council / United Kingdom
MR/L01341X/1 / / Medical Research Council / United Kingdom
G0501942 / / Medical Research Council / United Kingdom
G0902313 / / Medical Research Council / United Kingdom
WT091310 / / Wellcome Trust / United Kingdom
WT098017 / / Wellcome Trust / United Kingdom
617306 / / European Research Council / International