Format

Send to

Choose Destination
Lancet Respir Med. 2015 Oct;3(10):769-81. doi: 10.1016/S2213-2600(15)00283-0. Epub 2015 Sep 27.

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

Author information

1
Department of Health Sciences, University of Leicester, Leicester, UK.
2
Division of Respiratory Medicine, Queen's Medical Centre, University of Nottingham, Nottingham, UK.
3
University of British Columbia Centre for Heart Lung Innovation, St Paul's Hospital, Vancouver, BC, Canada.
4
Institut universitaire de cardiologie et de pneumologie de Québec, Department of Molecular Medicine, Laval University, Québec, QC, Canada.
5
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Icahn Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Respiratory Medicine, Shanghai Tenth People's Hospital, Tongji University, Shanghai, China.
6
Department of Pulmonary Medicine and Tuberculosis, University of Groningen, University Medical Center Groningen, Groningen, Netherlands.
7
Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK; Department of Medical and Molecular Genetics, King's College London, London, UK; Jenner Institute, University of Oxford, Oxford, UK.
8
Estonian Genome Center, University of Tartu, Tartu, Estonia.
9
Institute of Environmental Medicine, Karolinska Institutet and Sachs' Children's Hospital, Stockholm, Sweden.
10
Department of Statistics, University of Oxford, Oxford, UK; Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
11
Department of Statistics, University of Oxford, Oxford, UK; Centre for Statistics in Medicine, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK.
12
Department of Statistics, University of Oxford, Oxford, UK; Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland.
13
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
14
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK; Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK.
15
William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University London, London, UK; Princess Al-Jawhara Al-Brahim Centre of Excellence in Research of Hereditary Disorders (PACER-HD), King Abdulaziz University, Jeddah, Saudi Arabia.
16
Faculty of Medicine and Health Sciences, School of Medicine, University of Nottingham, Nottingham, UK.
17
Respiratory Medicine, University of Oxford, Oxford, UK.
18
UK Small Area Health Statistics Unit, MRC-PHE Centre for Environment and Health, School of Public Health, Imperial College London, London, UK; Imperial College Healthcare NHS Trust, St Mary's Hospital, Paddington, London, UK.
19
Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, UK.
20
Wellcome Trust Sanger Institute, Hinxton, Cambridgeshire, UK.
21
Department of Biostatistics, University of Liverpool, Liverpool, UK.
22
Population Health Research Institute, St George's, University of London, London, UK.
23
Department of Health Sciences, University of Leicester, Leicester, UK; National Institute for Health Research, Leicester Respiratory Biomedical Research Unit, Glenfield Hospital, Leicester, UK. Electronic address: mt47@leicester.ac.uk.
24
Division of Respiratory Medicine, Queen's Medical Centre, University of Nottingham, Nottingham, UK. Electronic address: ian.hall@nottingham.ac.uk.

Erratum in

  • Lancet Respir Med. 2016 Jan;4(1):e4.

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<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.

PMID:
26423011
PMCID:
PMC4593935
DOI:
10.1016/S2213-2600(15)00283-0
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center