Genome-wide association study identifies five loci associated with lung function

Journal name:
Nature Genetics
Volume:
42,
Pages:
36–44
Year published:
DOI:
doi:10.1038/ng.501
Received
Accepted
Published online

Abstract

Pulmonary function measures are heritable traits that predict morbidity and mortality and define chronic obstructive pulmonary disease (COPD). We tested genome-wide association with forced expiratory volume in 1 s (FEV1) and the ratio of FEV1 to forced vital capacity (FVC) in the SpiroMeta consortium (n = 20,288 individuals of European ancestry). We conducted a meta-analysis of top signals with data from direct genotyping (n ≤ 32,184 additional individuals) and in silico summary association data from the CHARGE Consortium (n = 21,209) and the Health 2000 survey (n ≤ 883). We confirmed the reported locus at 4q31 and identified associations with FEV1 or FEV1/FVC and common variants at five additional loci: 2q35 in TNS1 (P = 1.11 × 10−12), 4q24 in GSTCD (2.18 × 10−23), 5q33 in HTR4 (P = 4.29 × 10−9), 6p21 in AGER (P = 3.07 × 10−15) and 15q23 in THSD4 (P = 7.24 × 10−15). mRNA analyses showed expression of TNS1, GSTCD, AGER, HTR4 and THSD4 in human lung tissue. These associations offer mechanistic insight into pulmonary function regulation and indicate potential targets for interventions to alleviate respiratory disease.

At a glance

Figures

  1. Manhattan plots of association results for FEV1 and FEV1/FVC (analysis stage 1).
    Figure 1: Manhattan plots of association results for FEV1 and FEV1/FVC (analysis stage 1).

    (a,b) Manhattan plots ordered by chromosome position. SNPs for which −log10P > 5 are indicated in red. The six loci indicated by arrows showed association with FEV1 (a) or FEV1/FVC (b; P < 5 × 10−8) in the meta-analysis of data from stages 1, 2a and 2b.

  2. Regional association plots of six lung function-associated loci.
    Figure 2: Regional association plots of six lung function–associated loci.

    (af) Statistical significance of each SNP on the −log10 scale as a function of chromosome position (NCBI build 36) in the meta-analysis of stage 1 data alone. The sentinel SNP at each locus is shown in blue; the correlations (r2) of each of the surrounding SNPs to the sentinel SNP are shown in the indicated colors. The six loci included are those that showed association with FEV1 or FEV1/FVC (P < 5 × 10−8) in the meta-analysis of data from stages 1, 2a and 2b. The combined P values for all stages are indicated by arrows. The relevant trait (FEV1 or FEV1/FVC ratio) is indicated for each plot. For rs12504628, the plot shows only the association of FEV1/FVC; this SNP was associated (P < 5 × 10−8) with both FEV1 and FEV1/FVC. Fine-scale recombination rate is plotted in blue39. Combined P value from stages 1 and 2a only; SNP rs3995090 had low imputation quality in the CHARGE Consortium data and so was not included in stage 2b.

  3. Forest plots of the stage 1 meta-analysis for the six lung function-associated loci.
    Figure 3: Forest plots of the stage 1 meta-analysis for the six lung function–associated loci.

    Each of the SNPs included in the figure showed genome-wide significant association (P < 5 × 10−8) with either FEV1 or FEV1/FVC in the data from stages 1, 2a and 2b. The plots show the meta-analysis of the stage 1 data for each sentinel SNP. The contributing effect (transformed beta) from each study is shown by a square, with confidence intervals indicated by horizontal lines. The contributing weight of each study to the meta-analysis is indicated by the size of the square. The combined meta-analysis estimate in the stage 1 data is shown at the bottom of each graph.

References

  1. Myint, P.K. et al. Respiratory function and self-reported functional health: EPIC-Norfolk population study. Eur. Respir. J. 26, 494502 (2005).
  2. Schünemann, H.J., Dorn, J., Grant, B.J., Winkelstein, W. Jr. & Trevisan, M. Pulmonary function is a long-term predictor of mortality in the general population: 29-year follow-up of the Buffalo Health Study. Chest 118, 656664 (2000).
  3. Strachan, D.P. Ventilatory function, height, and mortality among lifelong non-smokers. J. Epidemiol. Community Health 46, 6670 (1992).
  4. Young, R.P., Hopkins, R. & Eaton, T.E. Forced expiratory volume in one second: not just a lung function test but a marker of premature death from all causes. Eur. Respir. J. 30, 616622 (2007).
  5. Hubert, H.B., Fabsitz, R.R., Feinleib, M. & Gwinn, C. Genetic and environmental influences on pulmonary function in adult twins. Am. Rev. Respir. Dis. 125, 409415 (1982).
  6. McClearn, G.E., Svartengren, M., Pedersen, N.L., Heller, D.A. & Plomin, R. Genetic and environmental influences on pulmonary function in aging Swedish twins. J. Gerontol. 49, 264268 (1994).
  7. Lewitter, F.I., Tager, I.B., McGue, M., Tishler, P.V. & Speizer, F.E. Genetic and environmental determinants of level of pulmonary function. Am. J. Epidemiol. 120, 518530 (1984).
  8. Palmer, L.J. et al. Familial aggregation and heritability of adult lung function: results from the Busselton Health Study. Eur. Respir. J. 17, 696702 (2001).
  9. Loos, R.J. et al. Common variants near MC4R are associated with fat mass, weight and risk of obesity. Nat. Genet. 40, 768775 (2008).
  10. Pillai, S.G. et al. A genome-wide association study in chronic obstructive pulmonary disease (COPD): identification of two major susceptibility loci. PLoS Genet. 5, e1000421 (2009).
  11. Wilk, J.B. et al. A genome-wide association study of pulmonary function measures in the Framingham Heart Study. PLoS Genet. 5, e1000429 (2009).
  12. McCarthy, M.I. et al. Genome-wide association studies for complex traits: consensus, uncertainty and challenges. Nat. Rev. Genet. 9, 356369 (2008).
  13. Miller, L.-A.D. et al. Role of Sonic hedgehog in patterning of tracheal-bronchial cartilage and the peripheral lung. Dev. Dyn. 231, 5771 (2004).
  14. Hayes, J.D., Flanagan, J.U. & Jowsey, I.R. Glutathione transferases. Annu. Rev. Pharmacol. Toxicol. 45, 5188 (2005).
  15. Baillat, D. et al. Integrator, a multiprotein mediator of small nuclear RNA processing, associates with the C-terminal repeat of RNA polymerase II. Cell 123, 265276 (2005).
  16. Weigt, C., Gaertner, A., Wegner, A., Korte, H. & Meyer, H.E. Occurrence of an actin-inserting domain in tensin. J. Mol. Biol. 227, 593595 (1992).
  17. Chen, H., Duncan, I.C., Bozorgchami, H. & Lo, S.H. Tensin1 and a previously undocumented family member, tensin2, positively regulate cell migration. Proc. Natl. Acad. Sci. USA 99, 733738 (2002).
  18. Manzke, T. et al. 5–HT4(a) receptors avert opioid-induced breathing depression without loss of analgesia. Science 301, 226229 (2003).
  19. Dupont, L.J. et al. The effects of 5-HT on cholinergic contraction in human airways in vitro. Eur. Respir. J. 14, 642649 (1999).
  20. Bayer, H. et al. Serotoninergic receptors on human airway epithelial cells. Am. J. Respir. Cell Mol. Biol. 36, 8593 (2007).
  21. Mägert, H.J. et al. LEKTI, a novel 15-domain type of human serine proteinase inhibitor. J. Biol. Chem. 274, 2149921502 (1999).
  22. Kipreos, E.T. & Pagano, M. The F-box protein family. Genome Biol. 1, REVIEWS3002 (2000).
  23. Sparvero, L.J. et al. RAGE (Receptor for Advanced Glycation Endproducts), RAGE ligands, and their role in cancer and inflammation. J. Transl. Med. 7, 17 (2009).
  24. Fehrenbach, H. et al. Receptor for advanced glycation endproducts (RAGE) exhibits highly differential cellular and subcellular localisation in rat and human lung. Cell. Mol. Biol. 44, 11471157 (1998).
  25. Konishi, K. et al. Gene expression profiles of acute exacerbations of Idiopathic Pulmonary Fibrosis. Am. J. Respir. Crit. Care Med. 180, 167175 (2009).
  26. Englert, J.M. et al. A role for the receptor for advanced glycation end products in idiopathic pulmonary fibrosis. Am. J. Pathol. 172, 583591 (2008).
  27. Fortini, M.E. Notch signaling: the core pathway and its posttranslational regulation. Dev. Cell 16, 633647 (2009).
  28. Favre, C.J. et al. Expression of genes involved in vascular development and angiogenesis in endothelial cells of adult lung. Am. J. Physiol. Heart Circ. Physiol. 285, H1917H1938 (2003).
  29. Chen, H., Herndon, M.E. & Lawler, J. The cell biology of thrombospondin-1. Matrix Biol. 19, 597614 (2000).
  30. Hancock, D.B. et al. Meta-analyses of genome-wide association studies identify multiple loci associated with pulmonary function. Nat. Genet. advance online publication, doi:10.1038/ng.500 (13 December 2009).
  31. Thorgeirsson, T.E. et al. A variant associated with nicotine dependence, lung cancer and peripheral arterial disease. Nature 452, 638642 (2008).
  32. Uhl, G.R. et al. Molecular genetics of successful smoking cessation: convergent genome-wide association study results. Arch. Gen. Psychiatry 65, 683693 (2008).
  33. Weedon, M.N. et al. Genome-wide association analysis identifies 20 loci that influence adult height. Nat. Genet. 40, 575583 (2008).
  34. Gudbjartsson, D.F. et al. Many sequence variants affecting diversity of adult human height. Nat. Genet. 40, 609615 (2008).
  35. Kohansal, R. et al. The natural history of chronic airflow obstruction revisited: an analysis of the framingham offspring cohort. Am. J. Respir. Crit. Care Med. 180, 310 (2009).
  36. Li, Y. & Abecasis, G.R. Mach 1.0: Rapid haplotype reconstruction and missing genotype inference. Am. J. Hum. Genet. S79, 2290 (2006).
  37. Marchini, J., Howie, B., Myers, S., McVean, G. & Donnelly, P. A new multipoint method for genome-wide association studies by imputation of genotypes. Nat. Genet. 39, 906913 (2007).
  38. Guan, Y. & Stephens, M. Practical issues in imputation-based association mapping. PLoS Genet. 4, e1000279 (2008).
  39. Myers, S., Bottolo, L., Freeman, C., McVean, G. & Donnelly, P. A fine-scale map of recombination rates and hotspots across the human genome. Science 310, 321324 (2005).
  40. Devlin, B. & Roeder, K. Genomic control for association studies. Biometrics 55, 9971004 (1999).
  41. Sayers, I., Swan, C. & Hall, I.P. The effect of beta2-adrenoceptor agonists on phospholipase C (beta1) signalling in human airway smooth muscle cells. Eur. J. Pharmacol. 531, 912 (2006).
  42. Wadsworth, S.J., Nijmeh, H.S. & Hall, I.P. Glucocorticoids increase repair potential in a novel in vitro human airway epithelial wounding model. J. Clin. Immunol. 26, 376387 (2006).

Download references

Author information

  1. These authors contributed equally to this work.

    • Emmanouela Repapi,
    • Ian Sayers,
    • Louise V Wain,
    • Paul Elliott,
    • David P Strachan,
    • Ian P Hall &
    • Martin D Tobin

Affiliations

  1. Departments of Health Sciences and Genetics, Adrian Building, University of Leicester, Leicester, UK.

    • Emmanouela Repapi,
    • Louise V Wain,
    • Paul R Burton &
    • Martin D Tobin
  2. Division of Therapeutics and Molecular Medicine, Nottingham Respiratory Biomedical Research Unit, University Hospital of Nottingham, Nottingham, UK.

    • Ian Sayers,
    • Ma'en Obeidat,
    • John D Blakey &
    • Ian P Hall
  3. Clinical Pharmacology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary, University of London, London, UK.

    • Toby Johnson
  4. Medical Research Council (MRC) Epidemiology Unit, Institute of Metabolic Science, Cambridge, UK.

    • Jing Hua Zhao,
    • Ruth J F Loos &
    • Nicholas J Wareham
  5. Respiratory Epidemiology and Public Health Group, National Heart and Lung Institute, Imperial College London, London, UK.

    • Adaikalavan Ramasamy &
    • Seif Shaheen
  6. Department of Epidemiology and Public Health, Imperial College London, St. Mary's Campus, London, UK.

    • The NSHD Respiratory Study Team,
    • Adaikalavan Ramasamy,
    • Marjo-Riitta Jarvelin &
    • Paul Elliott
  7. Department of Twin Research and Genetic Epidemiology, King's College London, London, UK.

    • Guangju Zhai,
    • Massimo Mangino,
    • Nicole Soranzo &
    • Tim D Spector
  8. MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, Western General Hospital, Edinburgh, Scotland, UK.

    • Veronique Vitart,
    • Jennifer E Huffman,
    • Alan F Wright &
    • Caroline Hayward
  9. Department of Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.

    • Wilmar Igl,
    • Ulf Gyllensten,
    • Åsa Johansson &
    • Ghazal Zaboli
  10. Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.

    • Eva Albrecht,
    • H Erich Wichmann,
    • Eva Schnabel &
    • Harald Grallert
  11. Wellcome Trust Sanger Institute, Cambridge, UK.

    • Panos Deloukas,
    • Inês Barroso,
    • Leena Peltonen &
    • Nicole Soranzo
  12. Department of Community-Based Medicine, University of Bristol, Bristol, UK.

    • John Henderson
  13. Department of Social Medicine, University of Bristol, Bristol, UK.

    • Raquel Granell
  14. Avon Longitudinal Study of Parents and Children (ALSPAC) Laboratory, Department of Social Medicine, University of Bristol, Bristol, UK.

    • Wendy L McArdle
  15. Division of Community Health Sciences, St. George's University of London, London, UK.

    • Alicja R Rudnicka,
    • Peter H Whincup &
    • David P Strachan
  16. A full list of members is provided in the Supplementary Note.

  17. Department of Public Health, University of Helsinki, Helsinki, Finland.

    • Linda Mustelin &
    • Jaakko Kaprio
  18. Department of Health Sciences and Finnish Center for Interdisciplinary Gerontology, University of Jyväskylä, Jyväskylä, Finland.

    • Wellcome Trust Case Control Consortium &
    • Taina Rantanen
  19. Institute for Molecular Medicine Finland FIMM, University of Helsinki, Helsinki, Finland.

    • Ida Surakka,
    • Leena Peltonen,
    • Samuli Ripatti &
    • Jaakko Kaprio
  20. National Institute for Health and Welfare, Helsinki, Finland.

    • Ida Surakka,
    • Leena Peltonen,
    • Markku Heliövaara,
    • Samuli Ripatti &
    • Jaakko Kaprio
  21. Department of Chronic Disease Epidemiology/NICER, Institute of Social and Preventive Medicine, University of Zürich, Zürich, Switzerland.

    • Medea Imboden &
    • Nicole M Probst-Hensch
  22. Institute of Medical Informatics, Biometry and Epidemiology, Ludwig-Maximilians-Universität, Munich, Germany.

    • H Erich Wichmann
  23. Klinikum Grosshadern, Munich, Germany.

    • H Erich Wichmann
  24. Croatian Centre for Global Health, The University of Split Medical School, Split, Croatia.

    • Ivica Grkovic,
    • Stipan Jankovic &
    • Igor Rudan
  25. Andrija Stampar School of Public Health, Faculty of Medicine, University of Zagreb, Zagreb, Croatia.

    • Lina Zgaga &
    • Ozren Polašek
  26. Department of Clinical Sciences, Obstetrics and Gynecology, Institute of Clinical Medicine, University of Oulu, Oulu, Finland.

    • Anna-Liisa Hartikainen
  27. Centre for Population Health Sciences, University of Edinburgh, Edinburgh, Scotland, UK.

    • Harry Campbell,
    • Sarah H Wild,
    • James F Wilson &
    • Igor Rudan
  28. Department of Internal Medicine B–Cardiology, Intensive Care, Pulmonary Medicine and Infectious Diseases, University of Greifswald, Greifswald, Germany.

    • Sven Gläser &
    • Beate Koch
  29. Interfaculty Institute for Genetics and Functional Genomics, University of Greifswald, Greifswald, Germany.

    • Georg Homuth
  30. Institute for Community Medicine, SHIP/Clinical-Epidemiological Research, University of Greifswald, Greifswald, Germany.

    • Henry Völzke
  31. Gen-Info, Zagreb, Croatia.

    • Ozren Polašek &
    • Igor Rudan
  32. Department of Lifecourse and Services, National Institute for Health and Welfare, Oulu, Finland.

    • Anneli Pouta &
    • Marjo-Riitta Jarvelin
  33. Department of Microbiology and Immunology, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden.

    • Åsa Torinsson Naluai
  34. Occupational and Environmental Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.

    • Anna-Carin Olin,
    • Kjell Torén &
    • Fredrik Nyberg
  35. Centre for Genetic Epidemiology and Biostatistics, University of Western Australia, Perth, Western Australia, Australia.

    • Matthew N Cooper &
    • Lyle J Palmer
  36. Department of Pulmonary Physiology/West Australian Sleep Disorders Research Institute, Western Australia, Australia.

    • Alan L James
  37. Busselton Population Medical Research Foundation, Sir Charles Gairdner Hospital, Western Australia, Australia.

    • Alan L James,
    • Lyle J Palmer &
    • Jennie Hui
  38. Department of Epidemiology and Public Health, University College London, London, UK.

    • Aroon D Hingorani
  39. Department of Primary Care and Population Health, University College London, London, UK.

    • S Goya Wannamethee &
    • Richard W Morris
  40. MRC Centre for Causal Analyses in Translational Epidemiology, Department of Social Medicine, University of Bristol, Bristol, UK.

    • George Davey Smith,
    • Debbie A Lawlor &
    • David M Evans
  41. Non-Communicable Diseases Epidemiology Unit, Department of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London, UK.

    • Shah Ebrahim
  42. Division of Epidemiology and Public Health, School of Community Health Sciences, University of Nottingham, Nottingham, UK.

    • Tricia M McKeever &
    • John R Britton
  43. Nottingham Respiratory Biomedical Research Unit, University of Nottingham, Nottingham, UK.

    • Tricia M McKeever &
    • John R Britton
  44. Institute for Lung Health, Glenfield Hospital, University Hospitals of Leicester National Health Service Trust, Leicester, UK.

    • Ian D Pavord
  45. Medical Genetics Section, Centre for Molecular Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, UK.

    • Andrew K MacLeod &
    • David J Porteous
  46. Biomedical Research Institute, Ninewells Hospital, University of Dundee, Dundee, UK.

    • Andrew D Morris
  47. MRC Epidemiology Resource Centre, University of Southampton, Southampton General Hospital, Southampton, UK.

    • Cyrus Cooper &
    • Elaine Dennison
  48. National Institute for Health Research (NIHR) Musculoskeletal Biomedical Research Unit, University of Oxford, Oxford, UK.

    • Cyrus Cooper
  49. Institute of Lung Biology and Disease, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.

    • Stefan Karrasch &
    • Holger Schulz
  50. CNRS 8090–Institute of Biology, Pasteur Institute, Lille, France.

    • Nabila Bouatia-Naji,
    • Jérôme Delplanque &
    • Philippe Froguel
  51. Section of Genomic Medicine, Imperial College London, Hammersmith Hospital, London, UK.

    • Philippe Froguel
  52. A full list of members is provided in the Supplementary Note.

    • The NSHD Respiratory Study Team
  53. MRC National Survey of Health and Development, MRC Unit for Lifelong Health and Ageing, London, UK.

    • The NSHD Respiratory Study Team
  54. Human Genetics Division, School of Medicine, University of Southampton, Southampton General Hospital, Southampton, UK.

    • John W Holloway
  55. Infection, Inflammation and Immunity Division, School of Medicine, University of Southampton, Southampton General Hospital, Southampton, UK.

    • John W Holloway
  56. Molecular Genetics, PathWest Laboratory Medicine WA, Nedlands, Western Australia, Australia.

    • Jennie Hui
  57. AstraZeneca Research and Development, Mölndal, Sweden.

    • Fredrik Nyberg
  58. Institute of Health Sciences, University of Oulu, Oulu, Finland.

    • Marjo-Riitta Jarvelin
  59. Biocenter Oulu, University of Oulu, Oulu, Finland.

    • Marjo-Riitta Jarvelin
  60. Bute Medical School, University of St. Andrews, St. Andrews, Fife, UK.

    • Cathy Jackson
  61. Department of Clinical Physiology, University of Tampere and Tampere University Hospital, Tampere, Finland.

    • Mika Kähönen
  62. Institute of Social and Preventive Medicine at Swiss Tropical Institute, University of Basel, Basel, Switzerland.

    • Nicole M Probst-Hensch
  63. MRC–Health Protection Agency (HPA) Centre for Environment and Health, Imperial College London, London, UK.

    • Paul Elliott

Consortia

  1. Wellcome Trust Case Control Consortium

  2. The NSHD Respiratory Study Team

Contributions

Author contributions are listed in alphabetical order. See Table 1 for definitions of study acronyms.

Project conception, design and management. Stage 1 GWAS, ALSPAC: J. Henderson, R.G. B58C: D.P.S. EPIC: I.B., R.J.F.L., N.J.W., J.H.Z. FTC: J.K., T.R. KORA S3: H.E.W. Korcula: H.C., I.G., S.J., I.R., A.F.W., L.Z. NFBC1966: P.E., M.-R.J., A.P., L.P. NSPHS: U.G. ORCADES: H.C., S.H.W., J.F.W., A.F.W. SHIP: S.G., G.H., B.K., H.V. TwinsUK: T.D.S., G. Zhai. Vis: H.C., C.H., O.P., I.R., A.F.W. Stage 2a follow-up, ADONIX: A.-C.O., K.T. BHS: A.L.J., L.J.P. GS:SFHS: H.C., C.J., A.D.M., D.J.P. HCS: C.C., E.D., J.W.H. KORA F4: S.K, E.S., H.S. NFBC1986: A.-L.H., M.-R.J. Nottingham Smokers: I.P.H., I. Sayers, M.O. NSHD: The NSHD Respiratory Study Team. Stage 2b in silico follow-up, Health 2000: M.H., M.K., L.P.

Phenotype collection and data management. Stage 1 GWAS, ALSPAC: J. Henderson, R.G. B58C: D.P.S., A.R.R. EPIC: N.J.W. FTC: J.K., L.M., T.R. KORA S3: H.E.W. Korcula: I.G., S.J., O.P., I.R., L.Z. NFBC1966: P.E., M.-R.J., A.-L.H., A.P. NSPHS: G. Zaboli. ORCADES: H.C., S.H.W., J.F.W. SHIP: S.G., B.K., H.V. TwinsUK: M.M., T.D.S. Vis: H.C., C.H., O.P., I.R., A.F.W. Stage 2a follow-up, ADONIX: A.-C.O., K.T. BHS: M.N.C., A.L.J., L.J.P. BRHS: R.W.M., S.G.W., P.H.W. BWHHS: G.D.S., S.E., D.A.L., P.H.W. Gedling: J.R.B., T.M.M., I.D.P. GS:SFHS: C.J., D.J.P. HCS: C.C., E.D., S.S. KORA F4: S.K., E.S., H.S. NFBC1986: A.-L.H., M.-R.J. Nottingham Smokers: J.D.B., I.P.H., I. Sayers, M.O. NSHD: The NSHD Respiratory Study Team. Stage 2b in silico follow-up, Health 2000: M.H., M.K.

Genotyping. Stage 1 GWAS, ALSPAC: P.D. B58C: W.L.M., WTCCC. EPIC: I.B., R.J.F.L., N.J.W., J.H.Z. FTC: J.K., I. Surakka. KORA S3: M.I., N.M.P.-H., H.G. NFBC1966: P.E., M.-R.J., L.P. ORCADES: H.C., J.F.W. SHIP: G.H. TwinsUK: N.S. Vis: C.H., I.R., A.F.W. Stage 2a follow-up, ADONIX: A.T.N., F.N. BRHS: A.D.H., R.W.M., P.H.W. GS:SFHS: A.D.M. HCS: C.C., E.D., J.W.H. KORA F4: H.G. NFBC1986: N.B.-N., J.D., P.F., M.-R.J., L.P. Nottingham Smokers: I.P.H. NSHD: D.K., A.W. STAGE 2b in silico follow-up, Health 2000: L.P., S.R., I. Surakka.

Data analysis. Stage 1 GWAS, ALSPAC: D.M.E. B58C: A.R.R. EPIC: R.J.F.L., J.H.Z. FTC: I. Surakka., L.M. KORA S3: E.A., M.I., N.M.P.-H. Korcula: C.H., J.E.H., V.V. NFBC1966: A.R. NSPHS: W.I., A.J. ORCADES: C.H., V.V. SHIP: S.G., G.H., B.K, H.V. TwinsUK: G. Zhai. Vis: C.H., V.V. Stage 2a follow-up, ADONIX: A.T.N., F.N., A.-C.O, K.T. BHS: M.N.C., J. Hui., L.J.P. BRHS: R.W.M. BWHHS: D.A.L. Gedling: M.O., M.D.T. GS:SFHS: A.K.M. HCS: J.W.H., S.S. KORA F4: E.A, H.G. NFBC1986: A.R. Nottingham Smokers: M.O., I. Sayers, M.D.T. NSHD: The NSHD Respiratory Study Team. Stage 2b in silico follow-up, Health 2000: M.K., S.R., I. Surakka.

Meta-analysis group. P.R.B., I.P.H., T.J., E.R., D.P.S., M.D.T., L.V.W.

Bioinformatics and expression profiling groups. I.P.H., M.O., I. Sayers, E.R., M.D.T., L.V.W.

Writing group. P.E., I.P.H., E.R., I. Sayers, D.P.S., M.D.T., L.V.W.

Competing financial interests

I.B. and spouse own stock in GlaxoSmithKline and Incyte.

Corresponding authors

Correspondence to:

Author details

Supplementary information

PDF files

  1. Supplementary Text and Figures (1M)

    Supplementary Figures 1 and 2, Supplementary Tables 1–4 and 6 and Supplementary Note

Excel files

  1. Supplementary Table 5 (360K)

    List of the top 2000 SNPs for association with FEV1 and FEV1/FVC

Additional data