Novel insights into the genetics of smoking behaviour, lung function, and chronic obstructive pulmonary disease (UK BiLEVE): a genetic association study in UK Biobank. Issue 10 (October 2015)

• Record Type: Journal Article
• Authors: Wain, Louise V; Shrine, Nick; Miller, Suzanne; Jackson, Victoria E; Ntalla, Ioanna; Artigas, María Soler; Billington, Charlotte K; Kheirallah, Abdul Kader; Allen, Richard; Cook, James P; Probert, Kelly; Obeidat, Ma'en; Bossé, Yohan; Hao, Ke; Postma, Dirkje S; Paré, Peter D; Ramasamy, Adaikalavan; Mägi, Reedik; Mihailov, Evelin; Reinmaa, Eva; Melén, Erik; O'Connell, Jared; Frangou, Eleni; Delaneau, Olivier; Freeman, Colin; Petkova, Desislava; McCarthy, Mark; Sayers, Ian; Deloukas, Panos; Hubbard, Richard; Pavord, Ian; Hansell, Anna L; Thomson, Neil C; Zeggini, Eleftheria; Morris, Andrew P; Marchini, Jonathan; Strachan, David P; Tobin, Martin D; Hall, Ian P; UK Brain Expression Consortium (UKBEC), †; OxGSK Consortium, †;
• Is Part Of: Lancet. Volume 3:Issue 10(2015)
• Page Start: 769
• Page End: 781
• Publication Date: 2015-10
• Subjects: Respiratory organs -- Diseases -- Periodicals; 616.2005
• DOI: 10.1016/S2213-2600(15)00283-0
• Languages: English
• ISSNs: 2213-2600

Abstract

<abstract abstract-type="author" id="ceab10"> <title id="cestitle10">Summary</title> <sec> <title id="cestitle20">Background</title> <p id="spara110">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.</p> </sec> <sec> <title id="cestitle30">Methods</title> <p id="spara120">We sampled individuals of European ancestry from UK Biobank, from the middle and extremes of the forced expiratory volume in 1 s (FEV<sub>1</sub>) 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 FEV<sub>1</sub>. We also looked for novel variants associated with extremes of FEV<sub>1</sub> 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<sup>−8</sup>.</p> </sec> <sec> <title id="cestitle40">Findings</title> <p id="spara130">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 FEV<sub>1</sub>, 10 000 with average FEV<sub>1</sub>, and 5002 with high FEV<sub>1</sub> from each of the heavy smoker and never smoker groups. We noted a substantial sharing of genetic causes of low FEV<sub>1</sub> between heavy smokers and never smokers (p=2·29 × 10<sup>−16</sup>) and between individuals with and without doctor-diagnosed asthma (p=6·06 × 10<sup>−11</sup>). We discovered six novel genome-wide significant signals of association with extremes of FEV<sub>1</sub>, 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 FEV<sub>1</sub>. We also discovered five new genome-wide significant signals for smoking behaviour, including a variant in <italic>NCAM1</italic> (chromosome 11) and a variant on chromosome 2 (between <italic>TEX41</italic> and <italic>PABPC1P2</italic>) that has a <italic>trans</italic> effect on expression of <italic>NCAM1</italic> in brain tissue.</p> </sec> <sec> <title id="cestitle50">Interpretation</title> <p id="spara140">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.</p> </sec> <sec> <title id="cestitle60">Funding</title> <p id="spara150">Medical Research Council.</p> </sec> </abstract>