University of Oulu

Shrine, N., Guyatt, A. L., Erzurumluoglu, A. M., Jackson, V. E., Hobbs, B. D., … Wain, L. V. (2019). New genetic signals for lung function highlight pathways and chronic obstructive pulmonary disease associations across multiple ancestries. Nature Genetics, 51(3), 481–493. https://doi.org/10.1038/s41588-018-0321-7

New genetic signals for lung function highlight pathways and chronic obstructive pulmonary disease associations across multiple ancestries

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Author: Shrine, Nick1; Guyatt, Anna L.1; Erzurumluoglu, A. Mesut1;
Jackson, Victoria E.1,2,3; Hobbs, Brian D.4,5; Melbourne, Carl A.1; Batini, Chiara1; Fawcett, Katherine A.1; Song, Kijoung6; Sakornsakolpat, Phuwanat4,7; Li, Xingnan8; Boxall, Ruth9,10; Reeve, Nicola F.1; Obeidat, Ma'en11; Zhao, Jing Hua12; Wielscher, Matthias13; Weiss, Stefan14; Kentistou, Katherine A.15,16; Cook, James P.17; Sun, Benjamin B.18; Zhou, Jian19; Hui, Jennie20,21,22,23; Karrasch, Stefan24,25,26; Imboden, Medea27,28,29; Harris, Sarah E.30,31; Marten, Jonathan32; Enroth, Stefan33; Kerr, Shona M.32; Surakka, Ida34,35; Vitart, Veronique32; Lehtimäki, Terho36,37; Allen, Richard J.1; Bakke, Per S.38; Beaty, Terri H.39; Bleecker, Eugene R.8; Bosse, Yohan40,41; Brandsma, Corry-Anke42; Chen, Zhengming9; Crapo, James D.43,44; Danesh, John18,45,46,47; DeMeo, Dawn L.4,5; Dudbridge, Frank1; Ewert, Ralf48; Gieger, Christian49; Gulsvik, Amund38; Hansell, Anna L.50,51,52; Hao, Ke53; Hoffman, Joshua D.6; Hokanson, John E.54; Homuth, Georg14; Joshi, Peter K.15; Joubert, Philippe41,55; Langenberg, Claudia56; Li, Xuan11; Li, Liming57; Lin, Kuang9; Lind, Lars58; Locantore, Nicholas59; Luan, Jian'an56; Mahajan, Anubha60; Maranville, Joseph C.61; Murray, Alison62; Nickle, David C.61,63; Packer, Richard1; Parker, Margaret M.4; Paynton, Megan L.1; Porteous, David J.30,31; Prokopenko, Dmitry4; Qiao, Dandi4; Rawal, Rajesh49,64; Runz, Heiko61; Sayers, Ian65; Sin, Don D.11,66; Smith, Blair H.67,68; Artigas, Maria Soler69,70,71; Sparrow, David72,73; Tal-Singer, Ruth59; Timmers, Paul R. H. J.15; Van den Berge, Maarten74; Whittaker, John C.75; Woodruff, Prescott G.76; Verges-Armstrong, Laura M.6; Troyanskaya, Olga G.77,78; Raitakari, Olli T.79,80; Kähönen, Mika37,81; Polasek, Ozren15,82; Gyllensten, Ulf33; Rudan, Igor15; Deary, Ian J.30,83; Probst-Hensch, Nicole M.27,28,29; Schulz, Holger24,26; James, Alan L.20,84,85; Wilson, James F.15,32; Stubbe, Beate48; Zeggini, Eleftheria86,87; Järvelin, Marjo-Riitta13,88,89,90,91; Wareham, Nick56; Silverman, Edwin K.4,5; Hayward, Caroline32; Morris, Andrew P.17,60; Butterworth, Adam S.18,47; Scott, Robert A.75; Walters, Robin G.9; Meyers, Deborah A.8; Cho, Michael H.4,5; Strachan, David P.92; Hall, Ian P.65; Tobin, Martin D.1,93; Wain, Louise, V1,93
Organizations: 1Univ Leicester, Dept Hlth Sci, Leicester, Leics, England.
2Walter & Eliza Hall Inst Med Res, Populat Hlth & Immun Div, Parkville, Vic, Australia.
3Univ Melbourne, Dept Med Biol, Parkville, Vic, Australia.
4Brigham & Womens Hosp, Channing Div Network Med, 75 Francis St, Boston, MA 02115 USA.
5Brigham & Womens Hosp, Div Pulm & Crit Care Med, 75 Francis St, Boston, MA 02115 USA.
6GlaxoSmithKline, Target Sci, Collegeville, PA USA.
7Mahidol Univ, Fac Med, Dept Med, Siriraj Hosp, Bangkok, Thailand.
8Univ Arizona, Dept Med, Div Genet Genom & Precis Med, Tucson, AZ USA.
9Univ Oxford, Nuffield Dept Populat Hlth, Oxford, England.
10Univ Oxford, Med Res Council, Populat Hlth Res Unit, Oxford, England.
11Univ British Columbia, St Pauls Hosp, Ctr Heart Lung Innovat, Vancouver, BC, Canada.
12Univ Cambridge, Dept Publ Hlth & Primary Care, Cardiovasc Epidemiol Unit, Cambridge, England.
13Imperial Coll London, MRC PHE Ctr Environm & Hlth, Sch Publ Hlth, Dept Epidemiol & Biostat, London, England.
14Univ Med Greifswald, Interfac Inst Genet & Funct Genom, Dept Funct Genom, Greifswald, Germany.
15Univ Edinburgh, Ctr Global Hlth Res, Usher Inst Populat Hlth Sci & Informat, Edinburgh, Midlothian, Scotland.
16Univ Edinburgh, Ctr Cardiovasc Sci, Queens Med Res Inst, Edinburgh, Midlothian, Scotland.
17Univ Liverpool, Dept Biostat, Liverpool, Merseyside, England.
18Univ Cambridge, Dept Publ Hlth & Primary Care, MRC BHF Cardiovasc Epidemiol Unit, Cambridge, England.
19Simons Fdn, Flatiron Inst, New York, NY USA.
20Sir Charles Gairdner Hosp, Busselton Populat Med Res Inst, Nedlands, WA, Australia.
21Univ Western Australia, Sch Populat Hlth, Crawley, WA, Australia.
22Sir Charles Gairdner Hosp, PathWest Lab Med WA, Crawley, WA, Australia.
23Univ Western Australia, Sch Pathol & Lab Med, Crawley, WA, Australia.
24Helmholtz Zentrum Muenchen, Inst Epidemiol, German Res Ctr Environ, Neuherberg, Germany.
25Ludwig Maximilians Univ Munchen, Inst & Outpatient Clin Occupat Social & Environm, Munich, Germany.
26CPC M, Munich, Germany.
27German Ctr Lung Res DZL, Munich, Germany.
28Swiss Trop & Publ Hlth Inst, Basel, Switzerland.
29Univ Basel, Basel, Switzerland.
30Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol, Edinburgh, Midlothian, Scotland.
31Univ Edinburgh, Ctr Genom & Expt Med, Inst Genet & Mol Med, Edinburgh, Midlothian, Scotland.
32Univ Edinburgh, Inst Genet & Mol Med, Med Res Council, Human Genet Unit, Edinburgh, Midlothian, Scotland.
33Uppsala Univ, Dept Immunol Genet & Pathol, Sci Life Lab, Uppsala, Sweden.
34Univ Helsinki, Inst Mol Med Finland FIMM, Helsinki, Finland.
35Natl Inst Hlth & Welf THL, Helsinki, Finland.
36Univ Tampere, Dept Clin Chem, Fimlab Labs, Tampere, Finland.
37Univ Tampere, Finnish Cardiovasc Res Ctr Tampere, Fac Med & Life Sci, Tampere, Finland.
38Univ Bergen, Dept Clin Sci, Bergen, Norway.
39Johns Hopkins Univ, Sch Publ Hlth, Dept Epidemiol, Baltimore, MD 21205 USA.
40Laval Univ, Dept Mol Med, Quebec City, PQ, Canada.
41Laval Univ, Inst Univ Cardiol & Pneumol Quebec, Quebec City, PQ, Canada.
42Univ Groningen, Univ Med Ctr Groningen, GRIAC Res Inst, Dept Pathol & Med Biol, Groningen, Netherlands.
43Natl Jewish Hlth, Denver, CO USA.
44Natl Jewish Hlth, Div Pulm Crit Care & Sleep Med, Denver, CO USA.
45British Heart Fdn Cambridge Ctr Excellence, Addenbrookes Hosp, Div Cardiovasc Med, Cambridge, England.
46Wellcome Trust Sanger Inst, Dept Human Genet, Cambridge, England.
47Univ Cambridge, Dept Publ Hlth & Primary Care, NIHR Blood & Transplant Res Unit Donor Hlth & Gen, Cambridge, England.
48Univ Med Greifswald, Dept Internal Med B Cardiol Intens Care Pulm Med, Greifswald, Germany.
49German Res Ctr Environ, Inst Epidemiol, Res Unit Mol Epidemiol, Helmholtz Zentrum Muenchen, Neuherberg, Germany.
50Univ Leicester, Ctr Environm Hlth & Sustainabil, Leicester, Leics, England.
51Imperial Coll London, MRC PHE Ctr Environm & Hlth, Sch Publ Hlth, UK Small Area Hlth Stat Unit, London, England.
52Imperial Coll Healthcare NHS Trust, St Marys Hosp, London, England.
53Icahn Sch Med Mt Sinai, Dept Genet & Genom Sci, New York, NY 10029 USA.
54Univ Colorado, Dept Epidemiol, Anschutz Med Campus, Aurora, CO USA.
55Laval Univ, Dept Mol Biol Med Biochem & Pathol, Quebec City, PQ, Canada.
56Univ Cambridge, MRC Epidemiol Unit, Sch Clin Med, Cambridge, England.
57Peking Univ, Dept Epidemiol & Biostat, Hlth Sci Ctr, Beijing, Peoples R China.
58Uppsala Univ, Dept Med Sci Cardiovasc Epidemiol, Uppsala, Sweden.
59GlaxoSmithKline Res & Dev Ltd, Collegeville, PA USA.
60Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England.
61Merck & Co Inc, MRL, Kenilworth, NJ USA.
62Univ Aberdeen, Aberdeen Biomed Imaging Ctr, Inst Med Sci, Aberdeen, Scotland.
63Gossamer Bio, San Diego, CA USA.
64Univ Munster, Inst Epidemiol & Social Med, Munster, Germany.
65Univ Nottingham, Div Resp Med & NIHR Nottingham Biomed Res Ctr, Nottingham, England.
66Univ British Columbia, Dept Med, Resp Div, Vancouver, BC, Canada.
67Univ Dundee, Ninewells Hosp, Div Populat Hlth & Genom, Dundee, Scotland.
68Univ Dundee, Med Sch, Dundee, Scotland.
69Univ Autonoma Barcelona, Vail dHebron Res Inst VHIR, Psychiat Genet Unit, Grp Psychiat Mental Hlth & Addict, Barcelona, Spain.
70Hosp Univ Vall Hebron, Dept Psychiat, Barcelona, Spain.
71Inst Salud Carlos III, Biomed Network Res Ctr Mental Hlth CIBERSAM, Barcelona, Spain.
72VA Boston Healthcare Syst, Boston, MA USA.
73Boston Univ, Sch Med, Dept Med, Boston, MA 02118 USA.
74Univ Groningen, Univ Med Ctr Groningen, Dept Pulmonol, GRIAC Res Inst, Groningen, Netherlands.
75Target Sci R&D, GSK Med Res Ctr, Stevenage, Herts, England.
76Univ Calif San Francisco, UCSF Pulm Crit Care Allergy & Sleep Med, San Francisco, CA USA.
77Princeton Univ, Dept Comp Sci, Princeton, NJ 08544 USA.
78Princeton Univ, Lewis Sigler Inst Integrat Genom, Princeton, NJ 08544 USA.
79Turku Univ Hosp, Dept Clin Physiol & Nucl Med, Turku, Finland.
80Univ Turku, Res Ctr Appl & Prevent Cardiovasc Med, Turku, Finland.
81Univ Tampere, Dept Clin Physiol, Tampere Univ Hosp, Fac Med & Life Sci, Tampere, Finland.
82Univ Split Sch Med, Split, Croatia.
83Univ Edinburgh, Dept Psychol, Edinburgh, Midlothian, Scotland.
84Sir Charles Gairdner Hosp, Dept Pulm Physiol & Sleep Med, Nedlands, WA, Australia.
85Univ Western Australia, Sch Med & Pharmacol, Crawley, WA, Australia.
86Wellcome Sanger Inst, Hinxton, England.
87German Res Ctr Environ, Inst Translat Genom, Helmholtz Zentrum Muenchen, Neuherberg, Germany.
88Univ Oulu, Fac Med, Ctr Life Course Hlth Res, Oulu, Finland.
89Univ Oulu, Bioctr Oulu, Oulu, Finland.
90Oulu Univ Hosp, Unit Primary Hlth Care, Oulu, Finland.
91Brunel Univ London, Coll Hlth & Life Sci, Dept Life Sci, Uxbridge, Middx, England.
92St Georges Univ London, Populat Hlth Res Inst, London, England.
93Glenfield Hosp, Leicester Resp Biomed Res Ctr, Natl Inst Hlth Res, Leicester, Leics, England.
Format: article
Version: accepted version
Access: open
Online Access: PDF Full Text (PDF, 4.4 MB)
Persistent link: http://urn.fi/urn:nbn:fi-fe2019091928792
Language: English
Published: Springer Nature, 2019
Publish Date: 2019-09-19
Description:

Abstract

Reduced lung function predicts mortality and is key to the diagnosis of chronic obstructive pulmonary disease (COPD). In a genome-wide association study in 400,102 individuals of European ancestry, we define 279 lung function signals, 139 of which are new. In combination, these variants strongly predict COPD in independent populations. Furthermore, the combined effect of these variants showed generalizability across smokers and never smokers, and across ancestral groups. We highlight biological pathways, known and potential drug targets for COPD and, in phenome-wide association studies, autoimmune-related and other pleiotropic effects of lung function–associated variants. This new genetic evidence has potential to improve future preventive and therapeutic strategies for COPD.

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Series: Nature genetics
ISSN: 1061-4036
ISSN-E: 1546-1718
ISSN-L: 1061-4036
Volume: 51
Issue: 3
Pages: 481 - 493
DOI: 10.1038/s41588-018-0321-7
OADOI: https://oadoi.org/10.1038/s41588-018-0321-7
Type of Publication: A1 Journal article – refereed
Field of Science: 3111 Biomedicine
3121 General medicine, internal medicine and other clinical medicine
Subjects:
Funding: This research has been conducted using the UK Biobank Resource under applications 648, 4892 and 26041. L. Wain holds a GSK/British Lung Foundation Chair in Respiratory Research. M. Tobin is supported by a Wellcome Trust Investigator Award (WT202849/Z/16/Z). M. Tobin and L. Wain have been supported by the Medical Research Council (MRC) (MR/N011317/1). The research was partially supported by the National Institute for Health Research (NIHR) Leicester Biomedical Research Centre; the views expressed are those of the author(s) and not necessarily those of the National Health Service (NHS), the NIHR or the Department of Health. I.H. was partially supported by the NIHR Nottingham Biomedical Research Centre; the views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. This research used the ALICE and SPECTRE High Performance Computing Facilities at the University of Leicester. Additional acknowledgments and funding details for other co-authors and contributing studies (including the SpiroMeta consortium) are in the Supplementary Note.
EU Grant Number: (277849) EURHEALTHAGEING - European ResearcH on DevElopmentAL, BirtH and Genetic Determinants of Ageing
(633595) DYNAHEALTH - Understanding the dynamic determinants of glucose homeostasis and social capability to promote Healthy and active aging
(733206) LIFECYCLE - Early-life stressors and LifeCycle health
Academy of Finland Grant Number: 129269
Detailed Information: 129269 (Academy of Finland Funding decision)
Dataset Reference: Supplementary information:
  https://static-content.springer.com/esm/art%3A10.1038%2Fs41588-018-0321-7/MediaObjects/41588_2018_321_MOESM1_ESM.pdf
https://static-content.springer.com/esm/art%3A10.1038%2Fs41588-018-0321-7/MediaObjects/41588_2018_321_MOESM2_ESM.pdf
https://static-content.springer.com/esm/art%3A10.1038%2Fs41588-018-0321-7/MediaObjects/41588_2018_321_MOESM3_ESM.xlsx
https://static-content.springer.com/esm/art%3A10.1038%2Fs41588-018-0321-7/MediaObjects/41588_2018_321_MOESM4_ESM.pdf
https://static-content.springer.com/esm/art%3A10.1038%2Fs41588-018-0321-7/MediaObjects/41588_2018_321_MOESM5_ESM.pdf
Copyright information: © The Author(s), under exclusive licence to Springer Nature America, Inc. 2019. Published in this repository with the kind permission of the publisher.