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Nat Genet. 2017 Mar;49(3):416-425. doi: 10.1038/ng.3787. Epub 2017 Feb 6.

Genome-wide association analyses for lung function and chronic obstructive pulmonary disease identify new loci and potential druggable targets.

Wain LV1,2, Shrine N1, Artigas MS1, Erzurumluoglu AM1, Noyvert B1, Bossini-Castillo L3, Obeidat M4, Henry AP5, Portelli MA5, Hall RJ5, Billington CK5, Rimington TL5, Fenech AG6, John C1, Blake T1, Jackson VE1, Allen RJ1, Prins BP7; Understanding Society Scientific Group, Campbell A8,9, Porteous DJ8,9, Jarvelin MR10,11,12,13, Wielscher M10, James AL14,15,16, Hui J14,17,18,19, Wareham NJ20, Zhao JH20, Wilson JF21,22, Joshi PK21, Stubbe B23, Rawal R24, Schulz H25,26, Imboden M27,28, Probst-Hensch NM27,28, Karrasch S25,29, Gieger C24, Deary IJ30,31, Harris SE8,30, Marten J22, Rudan I21, Enroth S32, Gyllensten U32, Kerr SM22, Polasek O21,33, Kähönen M34, Surakka I35,36, Vitart V22, Hayward C22, Lehtimäki T37,38, Raitakari OT39,40, Evans DM41,42, Henderson AJ43, Pennell CE44, Wang CA44, Sly PD45, Wan ES46,47, Busch R46,47, Hobbs BD46,47, Litonjua AA46,47, Sparrow DW48,49, Gulsvik A50, Bakke PS50, Crapo JD51,52, Beaty TH53, Hansel NN54, Mathias RA55, Ruczinski I56, Barnes KC57, Bossé Y58,59, Joubert P59,60, van den Berge M61, Brandsma CA62, Paré PD4,63, Sin DD4,63, Nickle DC64, Hao K65, Gottesman O66, Dewey FE66, Bruse SE66, Carey DJ67, Kirchner HL67; Geisinger-Regeneron DiscovEHR Collaboration, Jonsson S68, Thorleifsson G68, Jonsdottir I68,69, Gislason T69,70, Stefansson K68,69, Schurmann C71,72, Nadkarni G71, Bottinger EP71, Loos RJ71,72,73, Walters RG74, Chen Z74, Millwood IY74,75, Vaucher J74, Kurmi OP74, Li L76,77, Hansell AL78,79, Brightling C2,80, Zeggini E7, Cho MH46,47, Silverman EK46,47, Sayers I5, Trynka G3, Morris AP81, Strachan DP82, Hall IP5, Tobin MD1,2.

Author information

1
Department of Health Sciences, University of Leicester, Leicester, UK.
2
National Institute for Health Research, Leicester Respiratory Biomedical Research Unit, Glenfield Hospital, Leicester, UK.
3
Wellcome Trust Sanger Institute, Hinxton, UK.
4
University of British Columbia Centre for Heart Lung Innovation, St Paul's Hospital, Vancouver, British Columbia, Canada.
5
Division of Respiratory Medicine, University of Nottingham, Nottingham, UK.
6
Department of Clinical Pharmacology and Therapeutics, University of Malta, Msida, Malta.
7
Department of Human Genetics, Wellcome Trust Sanger Institute, Hinxton, UK.
8
Medical Genetics Section, Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.
9
Generation Scotland, Centre for Genomic and Experimental Medicine, University of Edinburgh, Edinburgh, UK.
10
Department of Epidemiology and Biostatistics, MRC-PHE Centre for Environment and Health, School of Public Health, Imperial College London, London, UK.
11
Faculty of Medicine, Center for Life Course Health Research, University of Oulu, Oulu, Finland.
12
Biocenter Oulu, University of Oulu, Oulu, Finland.
13
Unit of Primary Care, Oulu University Hospital, Oulu, Finland.
14
Busselton Population Medical Research Institute, Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia.
15
Department of Pulmonary Physiology and Sleep Medicine, Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia.
16
School of Medicine and Pharmacology, University of Western Australia, Crawley, Western Australia, Australia.
17
School of Population Health, University of Western Australia, Crawley, Western Australia, Australia.
18
PathWest Laboratory Medicine of Western Australia, Sir Charles Gairdner Hospital, Crawley, Western Australia, Australia.
19
School of Pathology and Laboratory Medicine, University of Western Australia, Crawley, Western Australia, Australia.
20
MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Institute of Metabolic Science, Cambridge Biomedical Campus, Cambridge, UK.
21
Centre for Global Health Research, Usher Institute for Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, UK.
22
Medical Research Council Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.
23
Department of Internal Medicine B-Cardiology, Intensive Care, Pulmonary Medicine and Infectious Diseases, University Medicine Greifswald, Greifswald, Germany.
24
Research Unit of Molecular Epidemiology, Institute of Epidemiology II, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
25
Institute of Epidemiology I, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
26
Comprehensive Pneumology Center Munich (CPC-M), Member of the German Center for Lung Research, Neuherberg, Germany.
27
Swiss Tropical and Public Health Institute, Basel, Switzerland.
28
University of Basel, Basel, Switzerland.
29
Institute and Outpatient Clinic for Occupational, Social and Environmental Medicine, Ludwig-Maximilians-Universität, Munich, Germany.
30
Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK.
31
Department of Psychology, University of Edinburgh, Edinburgh, UK.
32
Department of Immunology, Genetics and Pathology, Uppsala Universitet, Science for Life Laboratory, Uppsala, Sweden.
33
University of Split School of Medicine, Split, Croatia.
34
Department of Clinical Physiology, University of Tampere and Tampere University Hospital, Tampere, Finland.
35
Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
36
National Institute for Health and Welfare (THL), Helsinki, Finland.
37
Department of Clinical Chemistry, Fimlab Laboratories and School of Medicine University of Tampere, Tampere, Finland.
38
Department of Clinical Chemistry, University of Tampere School of Medicine, Tampere, Finland.
39
Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku, Finland.
40
Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland.
41
University of Queensland Diamantina Institute, Translational Research Institute, University of Queensland, Brisbane, Queensland, Australia.
42
MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK.
43
School of Social and Community Medicine, University of Bristol, Bristol, UK.
44
School of Women's and Infants' Health, University of Western Australia, Perth, Western Australia, Australia.
45
Child Health Research Centre, Faculty of Medicine, University of Queensland, Brisbane, Queensland, Australia.
46
Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.
47
Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.
48
VA Boston Healthcare System, Boston, Massachusetts, USA.
49
Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, USA.
50
Department of Clinical Science, University of Bergen, Bergen, Norway.
51
National Jewish Health, Denver, Colorado, USA.
52
Division of Pulmonary, Critical Care and Sleep Medicine, National Jewish Health, Denver, Colorado, USA.
53
Department of Epidemiology, Johns Hopkins University School of Public Health, Baltimore, Maryland, USA.
54
Pulmonary and Critical Care Medicine, School of Medicine, Johns Hopkins University, Baltimore, Maryland, USA.
55
Division of Allergy and Clinical Immunology, School of Medicine, Johns Hopkins University, Baltimore, Maryland, USA.
56
Department of Biostatistics, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, USA.
57
Division of Biomedical Informatics and Personalized Medicine, Department of Medicine, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, Colorado, USA.
58
Department of Molecular Medicine, Laval University, Quebec City, Quebec, Canada.
59
Institut Universitaire de Cardiologie et de Pneumologie de Québec, Laval University, Quebec City, Quebec, Canada.
60
Department of Molecular Biology, Medical Biochemistry and Pathology, Laval University, Quebec City, Quebec, Canada.
61
University of Groningen, University Medical Center Groningen, Department of Pulmonology, GRIAC Research Institute, Groningen, the Netherlands.
62
University of Groningen, University Medical Center Groningen, Department of Pathology and Medical Biology, GRIAC Research Institute, Groningen, the Netherlands.
63
Respiratory Division, Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
64
Merck Research Laboratories, Genetics and Pharmacogenomics, Boston, Massachusetts, USA.
65
Icahn Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
66
Regeneron Genetics Center, Regeneron Pharmaceuticals, Tarrytown, New York, USA.
67
Geisinger Health System, Danville, Pennsylvania, USA.
68
deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.
69
Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland.
70
Department of Respiratory Medicine and Sleep, Landspitali University Hospital Reykjavik, Reykjavik, Iceland.
71
Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
72
Genetics of Obesity and Related Metabolic Traits Program, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
73
Mindich Child Health Development Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
74
Clinical Trial Service Unit and Epidemiological Studies Unit (CTSU), Nuffield Department of Population Health, University of Oxford, Oxford, UK.
75
Medical Research Council Population Health Research Unit at the University of Oxford, Oxford, UK.
76
Chinese Academy of Medical Sciences, Beijing, China.
77
Department of Epidemiology and Biostatistics, Peking University Health Science Centre, Peking University, Beijing, China.
78
UK Small Area Health Statistics Unit, MRC-PHE Centre for Environment and Health, School of Public Health, Imperial College London, London, UK.
79
Imperial College Healthcare NHS Trust, St Mary's Hospital, Paddington, London, UK.
80
Department of Infection, Inflammation and Immunity, Institute for Lung Health, University of Leicester, Leicester, UK.
81
Department of Biostatistics, University of Liverpool, Liverpool, UK.
82
Population Health Research Institute, St George's, University of London, London, UK.

Abstract

Chronic obstructive pulmonary disease (COPD) is characterized by reduced lung function and is the third leading cause of death globally. Through genome-wide association discovery in 48,943 individuals, selected from extremes of the lung function distribution in UK Biobank, and follow-up in 95,375 individuals, we increased the yield of independent signals for lung function from 54 to 97. A genetic risk score was associated with COPD susceptibility (odds ratio per 1 s.d. of the risk score (∼6 alleles) (95% confidence interval) = 1.24 (1.20-1.27), P = 5.05 × 10-49), and we observed a 3.7-fold difference in COPD risk between individuals in the highest and lowest genetic risk score deciles in UK Biobank. The 97 signals show enrichment in genes for development, elastic fibers and epigenetic regulation pathways. We highlight targets for drugs and compounds in development for COPD and asthma (genes in the inositol phosphate metabolism pathway and CHRM3) and describe targets for potential drug repositioning from other clinical indications.

PMID:
28166213
PMCID:
PMC5326681
DOI:
10.1038/ng.3787
[Indexed for MEDLINE]
Free PMC Article

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