Genome-wide association study identifies five loci associated with lung function (original) (raw)

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Acknowledgements

We thank the many colleagues who contributed to collection and phenotypic characterization of the clinical sampling, genotyping and analysis of the GWAS data. We especially thank those who kindly agreed to participate in the studies.

Major funding for this work is from the following sources (in alphabetical order): Academy of Finland (including project grants 104781, 120315 and 1114194) and Center of Excellence in Complex Disease Genetics; Arthritis Research Campaign; Asthma UK; AstraZeneca; Biocenter Oulu, University of Oulu; Biocentrum Helsinki; Biotechnology and Biological Sciences Research Council project grant; British Heart Foundation (including project grants PG/06/154/22043 and PG/97012 and Senior Research Fellowship FS05/125); British Lung Foundation; Cancer Research United Kingdom; Chief Scientists Office, part of the Scottish Government Health Directorate (including grant CZD/16/6); Department of Health Air Pollution PRP (ref. no. 0020029); ENGAGE project (HEALTH-F4-2007-201413); European Commission (EURO-BLCS, FP-5/QLG1-CT-2000-01643, FP-7/2007-2013, FP-6 LSHB-CT-2006-018996 (GABRIEL), FP-6 LSHG-CT-2006-01947 (EUROSPAN), HEALTH-F2-2008-201865-GEFOS and FP-5 GenomEUtwin project QLG2-CT-2002-01254); Finnish Ministry of Education; German Federal Ministry of Education and Research (BMBF, including grants 01ZZ96030, 01ZZ0701 and 01GI0883 and German Asthma and COPD Network (COSYCONET) grant 01GI0883); German Ministry for Education, Research and Cultural Affairs; German National Genome Research Network (NGFN-2 and NGFN-plus); Healthway, Western Australia; HEFCE Science Research Investment Fund; Helmholtz Zentrum München; German Research Center for Environmental Health, Neuherberg, Germany; International Osteoporosis Foundation; Juvenile Diabetes Research Foundation International; Leicester Biomedical Research Unit in Cardiovascular Science (NIHR); Medical Research Council UK (including grants G0500539, G0501942, G0000943 and G990146); Medical Research Fund of the Tampere University Hospital; Ministry for Social Affairs of the Federal State of Mecklenburg-West Pomerania; MRC Human Genetics Unit; Munich Center of Health Sciences, as part of LMUinnovativ; National Human Genome Research Institute; National Institute for Health Research comprehensive Biomedical Research Centre award to Guy's & St. Thomas' NHS Foundation Trust in partnership with King's College London; National Institute for Health Research Cambridge Biomedical Research Centre; National Institute of Allergy and Infectious Diseases; National Institute of Child Health and Human Development; National Institute of Diabetes and Digestive and Kidney Diseases; National Heart, Lung, and Blood Institute (grant 5R01HL087679-02 through the STAMPEED program (1RL1MH083268-01)); Oulu University Hospital; PHOEBE (FP6, LSHG-CT-2006-518418); Public Population Project in Genomics (Genome Canada and Genome Quebec), Republic of Croatia Ministry of Science, Education and Sports (research grant 108-1080315-0302); Royal Society; Siemens Health Care Sector; Swedish Heart and Lung Foundation (grant 20050561); Swedish Medical Research Council (project no. K2007-66X-20270-01-3); Swedish Research Council for Working Life and Social Research (FAS, grants 2001-0263 and 2003-0139); the Great Wine Estates of the Margaret River region of Western Australia; UBS Wealth Foundation (grant BA29s8Q7-DZZ); UK Department of Health Policy Research Programme; University of Nottingham; University of Bristol; US National Institutes of Health (U01 DK062418); US National Institutes of Health–National Institute of Mental Health (5R01MH63706:02); Wellcome Trust (including grants 068545/Z/02, 076113/B/04/Z, 079895, 077016/Z/05/Z, 075883 and 086160/Z/08/A); and Zentren für Innovationskompetenz (BMBF grant 03ZIK012).

Author information

Author notes

1. Paul Elliott: A full list of members is provided in the Supplementary Note.
2. Emmanouela Repapi, Ian Sayers, Louise V Wain, Paul Elliott, David P Strachan, Ian P Hall and Martin D Tobin: These authors contributed equally to this work.

Authors and 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
   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. Department of Social Medicine, Avon Longitudinal Study of Parents and Children (ALSPAC) Laboratory, 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. Department of Public Health, University of Helsinki, Helsinki, Finland
    Linda Mustelin & Jaakko Kaprio
17. Department of Health Sciences and Finnish Center for Interdisciplinary Gerontology, University of Jyväskylä, Jyväskylä, Finland
    Taina Rantanen
18. Institute for Molecular Medicine Finland FIMM, University of Helsinki, Helsinki, Finland
    Ida Surakka, Leena Peltonen, Samuli Ripatti & Jaakko Kaprio
19. National Institute for Health and Welfare, Helsinki, Finland
    Ida Surakka, Leena Peltonen, Markku Heliövaara, Samuli Ripatti & Jaakko Kaprio
20. Department of Chronic Disease Epidemiology/NICER, Institute of Social and Preventive Medicine, University of Zürich, Zürich, Switzerland
    Medea Imboden & Nicole M Probst-Hensch
21. Institute of Medical Informatics, Biometry and Epidemiology, Ludwig-Maximilians-Universität, Munich, Germany
    H Erich Wichmann
22. Klinikum Grosshadern, Munich, Germany
    H Erich Wichmann
23. Croatian Centre for Global Health, The University of Split Medical School, Split, Croatia
    Ivica Grkovic, Stipan Jankovic & Igor Rudan
24. Andrija Stampar School of Public Health, Faculty of Medicine, University of Zagreb, Zagreb, Croatia
    Lina Zgaga & Ozren Polašek
25. Department of Clinical Sciences, Obstetrics and Gynecology, Institute of Clinical Medicine, University of Oulu, Oulu, Finland
    Anna-Liisa Hartikainen
26. Centre for Population Health Sciences, University of Edinburgh, Edinburgh, Scotland, UK
    Harry Campbell, Sarah H Wild, James F Wilson & Igor Rudan
27. Department of Internal Medicine B–Cardiology, Intensive Care, Pulmonary Medicine and Infectious Diseases, University of Greifswald, Greifswald, Germany,
    Sven Gläser & Beate Koch
28. Interfaculty Institute for Genetics and Functional Genomics, University of Greifswald, Greifswald, Germany
    Georg Homuth
29. Institute for Community Medicine, SHIP/Clinical-Epidemiological Research, University of Greifswald, Greifswald, Germany
    Henry Völzke
30. Gen-Info, Zagreb, Croatia
    Ozren Polašek & Igor Rudan
31. Department of Lifecourse and Services, National Institute for Health and Welfare, Oulu, Finland
    Anneli Pouta & Marjo-Riitta Jarvelin
32. Department of Microbiology and Immunology, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden
    Åsa Torinsson Naluai
33. Occupational and Environmental Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
    Anna-Carin Olin, Kjell Torén & Fredrik Nyberg
34. Centre for Genetic Epidemiology and Biostatistics, University of Western Australia, Perth, Western Australia, Australia
    Matthew N Cooper & Lyle J Palmer
35. Department of Pulmonary Physiology/West Australian Sleep Disorders Research Institute, Western Australia, Australia
    Alan L James
36. Busselton Population Medical Research Foundation, Sir Charles Gairdner Hospital, Western Australia, Australia
    Alan L James, Lyle J Palmer & Jennie Hui
37. Department of Epidemiology and Public Health, University College London, London, UK
    Aroon D Hingorani
38. Department of Primary Care and Population Health, University College London, London, UK
    S Goya Wannamethee & Richard W Morris
39. Department of Social Medicine, MRC Centre for Causal Analyses in Translational Epidemiology, University of Bristol, Bristol, UK
    George Davey Smith, Debbie A Lawlor & David M Evans
40. Department of Epidemiology and Population Health, Non-Communicable Diseases Epidemiology Unit, London School of Hygiene and Tropical Medicine, London, UK
    Shah Ebrahim
41. Division of Epidemiology and Public Health, School of Community Health Sciences, University of Nottingham, Nottingham, UK
    Tricia M McKeever & John R Britton
42. Nottingham Respiratory Biomedical Research Unit, University of Nottingham, Nottingham, UK
    Tricia M McKeever & John R Britton
43. Institute for Lung Health, Glenfield Hospital, University Hospitals of Leicester National Health Service Trust, Leicester, UK
    Ian D Pavord
44. 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
45. Biomedical Research Institute, Ninewells Hospital, University of Dundee, Dundee, UK
    Andrew D Morris
46. MRC Epidemiology Resource Centre, University of Southampton, Southampton General Hospital, Southampton, UK
    Cyrus Cooper & Elaine Dennison
47. National Institute for Health Research (NIHR) Musculoskeletal Biomedical Research Unit, University of Oxford, Oxford, UK
    Cyrus Cooper
48. Institute of Lung Biology and Disease, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
    Stefan Karrasch & Holger Schulz
49. CNRS 8090–Institute of Biology, Pasteur Institute, Lille, France
    Nabila Bouatia-Naji, Jérôme Delplanque & Philippe Froguel
50. Section of Genomic Medicine, Imperial College London, Hammersmith Hospital, London, UK
    Philippe Froguel
51. Human Genetics Division, School of Medicine, University of Southampton, Southampton General Hospital, Southampton, UK
    John W Holloway
52. Inflammation and Immunity Division, Infection, School of Medicine, University of Southampton, Southampton General Hospital, Southampton, UK
    John W Holloway
53. Molecular Genetics, PathWest Laboratory Medicine WA, Nedlands, Western Australia, Australia
    Jennie Hui
54. AstraZeneca Research and Development, Mölndal, Sweden
    Fredrik Nyberg
55. Institute of Health Sciences, University of Oulu, Oulu, Finland
    Marjo-Riitta Jarvelin
56. Biocenter Oulu, University of Oulu, Oulu, Finland
    Marjo-Riitta Jarvelin
57. Bute Medical School, University of St. Andrews, St. Andrews, Fife, UK
    Cathy Jackson
58. Department of Clinical Physiology, University of Tampere and Tampere University Hospital, Tampere, Finland
    Mika Kähönen
59. Institute of Social and Preventive Medicine at Swiss Tropical Institute, University of Basel, Basel, Switzerland
    Jennie Hui & Nicole M Probst-Hensch
60. MRC–Health Protection Agency (HPA) Centre for Environment and Health, Imperial College London, London, UK
    Paul Elliott

Authors

1. Emmanouela Repapi
2. Ian Sayers
3. Louise V Wain
4. Paul R Burton
5. Toby Johnson
6. Ma'en Obeidat
7. Jing Hua Zhao
8. Adaikalavan Ramasamy
9. Guangju Zhai
10. Veronique Vitart
11. Jennifer E Huffman
12. Wilmar Igl
13. Eva Albrecht
14. Panos Deloukas
15. John Henderson
16. Raquel Granell
17. Wendy L McArdle
18. Alicja R Rudnicka
19. Inês Barroso
20. Ruth J F Loos
21. Nicholas J Wareham
22. Linda Mustelin
23. Taina Rantanen
24. Ida Surakka
25. Medea Imboden
26. H Erich Wichmann
27. Ivica Grkovic
28. Stipan Jankovic
29. Lina Zgaga
30. Anna-Liisa Hartikainen
31. Leena Peltonen
32. Ulf Gyllensten
33. Åsa Johansson
34. Ghazal Zaboli
35. Harry Campbell
36. Sarah H Wild
37. James F Wilson
38. Sven Gläser
39. Georg Homuth
40. Henry Völzke
41. Massimo Mangino
42. Nicole Soranzo
43. Tim D Spector
44. Ozren Polašek
45. Igor Rudan
46. Alan F Wright
47. Markku Heliövaara
48. Samuli Ripatti
49. Anneli Pouta
50. Åsa Torinsson Naluai
51. Anna-Carin Olin
52. Kjell Torén
53. Matthew N Cooper
54. Alan L James
55. Lyle J Palmer
56. Aroon D Hingorani
57. S Goya Wannamethee
58. Peter H Whincup
59. George Davey Smith
60. Shah Ebrahim
61. Tricia M McKeever
62. Ian D Pavord
63. Andrew K MacLeod
64. Andrew D Morris
65. David J Porteous
66. Cyrus Cooper
67. Elaine Dennison
68. Seif Shaheen
69. Stefan Karrasch
70. Eva Schnabel
71. Holger Schulz
72. Harald Grallert
73. Nabila Bouatia-Naji
74. Jérôme Delplanque
75. Philippe Froguel
76. John D Blakey
77. John R Britton
78. Richard W Morris
79. John W Holloway
80. Debbie A Lawlor
81. Jennie Hui
82. Fredrik Nyberg
83. Marjo-Riitta Jarvelin
84. Cathy Jackson
85. Mika Kähönen
86. Jaakko Kaprio
87. Nicole M Probst-Hensch
88. Beate Koch
89. Caroline Hayward
90. David M Evans
91. Paul Elliott
92. David P Strachan
93. Ian P Hall
94. Martin D Tobin

Consortia

Wellcome Trust Case Control Consortium

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.

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Correspondence toIan P Hall or Martin D Tobin.

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

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A full list of members is provided in the Supplementary Note.

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Repapi, E., Sayers, I., Wain, L. et al. Genome-wide association study identifies five loci associated with lung function.Nat Genet 42, 36–44 (2010). https://doi.org/10.1038/ng.501

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• Received: 16 July 2009
• Accepted: 10 November 2009
• Published: 13 December 2009
• Issue date: January 2010
• DOI: https://doi.org/10.1038/ng.501