Genome-wide association analyses for lung function and chronic obstructive pulmonary disease identify new loci and potential druggable targets.
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.
Department of Health Sciences, University of Leicester, Leicester, UK.|National Institute for Health Research, Leicester Respiratory Biomedical Research Unit, Glenfield Hospital, Leicester, UK.
Louise V
http://orcid.org/0000-0003-4951-1867
LV
Wain
Department of Health Sciences, University of Leicester, Leicester, UK.
Nick
N
Shrine
Department of Health Sciences, University of Leicester, Leicester, UK.
María Soler
MS
Artigas
Department of Health Sciences, University of Leicester, Leicester, UK.
A Mesut
http://orcid.org/0000-0003-1322-8138
AM
Erzurumluoglu
Department of Health Sciences, University of Leicester, Leicester, UK.
Boris
B
Noyvert
Wellcome Trust Sanger Institute, Hinxton, UK.
Lara
L
Bossini-Castillo
University of British Columbia Centre for Heart Lung Innovation, St Paul's Hospital, Vancouver, British Columbia, Canada.
Ma'en
http://orcid.org/0000-0002-5443-2752
M
Obeidat
Division of Respiratory Medicine, University of Nottingham, Nottingham, UK.
Amanda P
AP
Henry
Division of Respiratory Medicine, University of Nottingham, Nottingham, UK.
Michael A
MA
Portelli
Division of Respiratory Medicine, University of Nottingham, Nottingham, UK.
Robert J
RJ
Hall
Division of Respiratory Medicine, University of Nottingham, Nottingham, UK.
Charlotte K
CK
Billington
Division of Respiratory Medicine, University of Nottingham, Nottingham, UK.
Tracy L
TL
Rimington
Department of Clinical Pharmacology and Therapeutics, University of Malta, Msida, Malta.
Anthony G
http://orcid.org/0000-0002-7654-8828
AG
Fenech
Department of Health Sciences, University of Leicester, Leicester, UK.
Catherine
C
John
Department of Health Sciences, University of Leicester, Leicester, UK.
Tineka
T
Blake
Department of Health Sciences, University of Leicester, Leicester, UK.
Victoria E
VE
Jackson
Department of Health Sciences, University of Leicester, Leicester, UK.
Richard J
RJ
Allen
Department of Human Genetics, Wellcome Trust Sanger Institute, Hinxton, UK.
Bram P
BP
Prins
Medical Genetics Section, Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.|Generation Scotland, Centre for Genomic and Experimental Medicine, University of Edinburgh, Edinburgh, UK.
Archie
http://orcid.org/0000-0003-0198-5078
A
Campbell
Medical Genetics Section, Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.|Generation Scotland, Centre for Genomic and Experimental Medicine, University of Edinburgh, Edinburgh, UK.
David J
DJ
Porteous
Department of Epidemiology and Biostatistics, MRC-PHE Centre for Environment and Health, School of Public Health, Imperial College London, London, UK.|Faculty of Medicine, Center for Life Course Health Research, University of Oulu, Oulu, Finland.|Biocenter Oulu, University of Oulu, Oulu, Finland.|Unit of Primary Care, Oulu University Hospital, Oulu, Finland.
Marjo-Riitta
MR
Jarvelin
Department of Epidemiology and Biostatistics, MRC-PHE Centre for Environment and Health, School of Public Health, Imperial College London, London, UK.
Matthias
M
Wielscher
Busselton Population Medical Research Institute, Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia.|Department of Pulmonary Physiology and Sleep Medicine, Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia.|School of Medicine and Pharmacology, University of Western Australia, Crawley, Western Australia, Australia.
Alan L
AL
James
Busselton Population Medical Research Institute, Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia.|School of Population Health, University of Western Australia, Crawley, Western Australia, Australia.|PathWest Laboratory Medicine of Western Australia, Sir Charles Gairdner Hospital, Crawley, Western Australia, Australia.|School of Pathology and Laboratory Medicine, University of Western Australia, Crawley, Western Australia, Australia.
Jennie
J
Hui
MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Institute of Metabolic Science, Cambridge Biomedical Campus, Cambridge, UK.
Nicholas J
NJ
Wareham
MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Institute of Metabolic Science, Cambridge Biomedical Campus, Cambridge, UK.
Jing Hua
JH
Zhao
Centre for Global Health Research, Usher Institute for Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, UK.|Medical Research Council Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.
James F
http://orcid.org/0000-0001-5751-9178
JF
Wilson
Centre for Global Health Research, Usher Institute for Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, UK.
Peter K
http://orcid.org/0000-0002-6361-5059
PK
Joshi
Department of Internal Medicine B-Cardiology, Intensive Care, Pulmonary Medicine and Infectious Diseases, University Medicine Greifswald, Greifswald, Germany.
Beate
B
Stubbe
Research Unit of Molecular Epidemiology, Institute of Epidemiology II, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
Rajesh
R
Rawal
Institute of Epidemiology I, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.|Comprehensive Pneumology Center Munich (CPC-M), Member of the German Center for Lung Research, Neuherberg, Germany.
Holger
H
Schulz
Swiss Tropical and Public Health Institute, Basel, Switzerland.|University of Basel, Basel, Switzerland.
Medea
M
Imboden
Swiss Tropical and Public Health Institute, Basel, Switzerland.|University of Basel, Basel, Switzerland.
Nicole M
NM
Probst-Hensch
Institute of Epidemiology I, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.|Institute and Outpatient Clinic for Occupational, Social and Environmental Medicine, Ludwig-Maximilians-Universität, Munich, Germany.
Stefan
S
Karrasch
Research Unit of Molecular Epidemiology, Institute of Epidemiology II, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
Christian
C
Gieger
Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK.|Department of Psychology, University of Edinburgh, Edinburgh, UK.
Ian J
IJ
Deary
Medical Genetics Section, Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.|Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK.
Sarah E
SE
Harris
Medical Research Council Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.
Jonathan
J
Marten
Centre for Global Health Research, Usher Institute for Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, UK.
Igor
http://orcid.org/0000-0001-6993-6884
I
Rudan
Department of Immunology, Genetics and Pathology, Uppsala Universitet, Science for Life Laboratory, Uppsala, Sweden.
Stefan
http://orcid.org/0000-0002-5056-9137
S
Enroth
Department of Immunology, Genetics and Pathology, Uppsala Universitet, Science for Life Laboratory, Uppsala, Sweden.
Ulf
U
Gyllensten
Medical Research Council Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.
Shona M
SM
Kerr
Centre for Global Health Research, Usher Institute for Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, UK.|University of Split School of Medicine, Split, Croatia.
Ozren
O
Polasek
Department of Clinical Physiology, University of Tampere and Tampere University Hospital, Tampere, Finland.
Mika
M
Kähönen
Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.|National Institute for Health and Welfare (THL), Helsinki, Finland.
Ida
I
Surakka
Medical Research Council Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.
Veronique
V
Vitart
Medical Research Council Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.
Caroline
C
Hayward
Department of Clinical Chemistry, Fimlab Laboratories and School of Medicine University of Tampere, Tampere, Finland.|Department of Clinical Chemistry, University of Tampere School of Medicine, Tampere, Finland.
Terho
T
Lehtimäki
Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku, Finland.|Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland.
Olli T
OT
Raitakari
University of Queensland Diamantina Institute, Translational Research Institute, University of Queensland, Brisbane, Queensland, Australia.|MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK.
David M
DM
Evans
School of Social and Community Medicine, University of Bristol, Bristol, UK.
A John
AJ
Henderson
School of Women's and Infants' Health, University of Western Australia, Perth, Western Australia, Australia.
Craig E
CE
Pennell
School of Women's and Infants' Health, University of Western Australia, Perth, Western Australia, Australia.
Carol A
CA
Wang
Child Health Research Centre, Faculty of Medicine, University of Queensland, Brisbane, Queensland, Australia.
Peter D
http://orcid.org/0000-0001-6305-2201
PD
Sly
Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.|Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.
Emily S
ES
Wan
Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.|Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.
Robert
http://orcid.org/0000-0003-0820-7164
R
Busch
Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.|Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.
Brian D
http://orcid.org/0000-0001-9564-0745
BD
Hobbs
Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.|Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.
Augusto A
AA
Litonjua
VA Boston Healthcare System, Boston, Massachusetts, USA.|Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, USA.
David W
DW
Sparrow
Department of Clinical Science, University of Bergen, Bergen, Norway.
Amund
A
Gulsvik
Department of Clinical Science, University of Bergen, Bergen, Norway.
Per S
PS
Bakke
National Jewish Health, Denver, Colorado, USA.|Division of Pulmonary, Critical Care and Sleep Medicine, National Jewish Health, Denver, Colorado, USA.
James D
JD
Crapo
Department of Epidemiology, Johns Hopkins University School of Public Health, Baltimore, Maryland, USA.
Terri H
TH
Beaty
Pulmonary and Critical Care Medicine, School of Medicine, Johns Hopkins University, Baltimore, Maryland, USA.
Nadia N
NN
Hansel
Division of Allergy and Clinical Immunology, School of Medicine, Johns Hopkins University, Baltimore, Maryland, USA.
Rasika A
RA
Mathias
Department of Biostatistics, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, USA.
Ingo
I
Ruczinski
Division of Biomedical Informatics and Personalized Medicine, Department of Medicine, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, Colorado, USA.
Kathleen C
KC
Barnes
Department of Molecular Medicine, Laval University, Quebec City, Quebec, Canada.|Institut Universitaire de Cardiologie et de Pneumologie de Québec, Laval University, Quebec City, Quebec, Canada.
Yohan
http://orcid.org/0000-0002-3067-3711
Y
Bossé
Institut Universitaire de Cardiologie et de Pneumologie de Québec, Laval University, Quebec City, Quebec, Canada.|Department of Molecular Biology, Medical Biochemistry and Pathology, Laval University, Quebec City, Quebec, Canada.
Philippe
P
Joubert
University of Groningen, University Medical Center Groningen, Department of Pulmonology, GRIAC Research Institute, Groningen, the Netherlands.
Maarten
M
van den Berge
University of Groningen, University Medical Center Groningen, Department of Pathology and Medical Biology, GRIAC Research Institute, Groningen, the Netherlands.
Corry-Anke
CA
Brandsma
University of British Columbia Centre for Heart Lung Innovation, St Paul's Hospital, Vancouver, British Columbia, Canada.|Respiratory Division, Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
Peter D
PD
Paré
University of British Columbia Centre for Heart Lung Innovation, St Paul's Hospital, Vancouver, British Columbia, Canada.|Respiratory Division, Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
Don D
DD
Sin
Merck Research Laboratories, Genetics and Pharmacogenomics, Boston, Massachusetts, USA.
David C
DC
Nickle
Icahn Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
Ke
K
Hao
Regeneron Genetics Center, Regeneron Pharmaceuticals, Tarrytown, New York, USA.
Omri
O
Gottesman
Regeneron Genetics Center, Regeneron Pharmaceuticals, Tarrytown, New York, USA.
Frederick E
FE
Dewey
Regeneron Genetics Center, Regeneron Pharmaceuticals, Tarrytown, New York, USA.
Shannon E
http://orcid.org/0000-0002-3037-6266
SE
Bruse
Geisinger Health System, Danville, Pennsylvania, USA.
David J
DJ
Carey
Geisinger Health System, Danville, Pennsylvania, USA.
H Lester
HL
Kirchner
deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.
Stefan
S
Jonsson
deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.
Gudmar
G
Thorleifsson
deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.|Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland.
Ingileif
http://orcid.org/0000-0001-8339-150X
I
Jonsdottir
Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland.|Department of Respiratory Medicine and Sleep, Landspitali University Hospital Reykjavik, Reykjavik, Iceland.
Thorarinn
T
Gislason
deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.|Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland.
Kari
K
Stefansson
Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA.|Genetics of Obesity and Related Metabolic Traits Program, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
Claudia
http://orcid.org/0000-0003-4158-9192
C
Schurmann
Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
Girish
G
Nadkarni
Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
Erwin P
EP
Bottinger
Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA.|Genetics of Obesity and Related Metabolic Traits Program, Icahn School of Medicine at Mount Sinai, New York, New York, USA.|Mindich Child Health Development Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
Ruth J F
RJ
Loos
Clinical Trial Service Unit and Epidemiological Studies Unit (CTSU), Nuffield Department of Population Health, University of Oxford, Oxford, UK.
Robin G
http://orcid.org/0000-0002-9179-0321
RG
Walters
Clinical Trial Service Unit and Epidemiological Studies Unit (CTSU), Nuffield Department of Population Health, University of Oxford, Oxford, UK.
Zhengming
Z
Chen
Clinical Trial Service Unit and Epidemiological Studies Unit (CTSU), Nuffield Department of Population Health, University of Oxford, Oxford, UK.|Medical Research Council Population Health Research Unit at the University of Oxford, Oxford, UK.
Iona Y
IY
Millwood
Clinical Trial Service Unit and Epidemiological Studies Unit (CTSU), Nuffield Department of Population Health, University of Oxford, Oxford, UK.
Julien
http://orcid.org/0000-0002-3230-3693
J
Vaucher
Clinical Trial Service Unit and Epidemiological Studies Unit (CTSU), Nuffield Department of Population Health, University of Oxford, Oxford, UK.
Om P
OP
Kurmi
Chinese Academy of Medical Sciences, Beijing, China.|Department of Epidemiology and Biostatistics, Peking University Health Science Centre, Peking University, Beijing, China.
Liming
L
Li
UK Small Area Health Statistics Unit, MRC-PHE Centre for Environment and Health, School of Public Health, Imperial College London, London, UK.|Imperial College Healthcare NHS Trust, St Mary's Hospital, Paddington, London, UK.
Anna L
AL
Hansell
National Institute for Health Research, Leicester Respiratory Biomedical Research Unit, Glenfield Hospital, Leicester, UK.|Department of Infection, Inflammation and Immunity, Institute for Lung Health, University of Leicester, Leicester, UK.
Chris
C
Brightling
Department of Human Genetics, Wellcome Trust Sanger Institute, Hinxton, UK.
Eleftheria
http://orcid.org/0000-0003-4238-659X
E
Zeggini
Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.|Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.
Michael H
http://orcid.org/0000-0002-4907-1657
MH
Cho
Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.|Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.
Edwin K
EK
Silverman
Division of Respiratory Medicine, University of Nottingham, Nottingham, UK.
Ian
http://orcid.org/0000-0001-5601-5410
I
Sayers
Wellcome Trust Sanger Institute, Hinxton, UK.
Gosia
http://orcid.org/0000-0002-6955-9529
G
Trynka
Department of Biostatistics, University of Liverpool, Liverpool, UK.
Andrew P
AP
Morris
Population Health Research Institute, St George's, University of London, London, UK.
David P
http://orcid.org/0000-0001-7854-1366
DP
Strachan
Division of Respiratory Medicine, University of Nottingham, Nottingham, UK.
Ian P
IP
Hall
Department of Health Sciences, University of Leicester, Leicester, UK.|National Institute for Health Research, Leicester Respiratory Biomedical Research Unit, Glenfield Hospital, Leicester, UK.
Martin D
http://orcid.org/0000-0002-3596-7874
MD
Tobin
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D001249:Asthma / Q000235:genetics; D044127:Epigenesis, Genetic / Q000235:genetics; D005260:Female; D056426:Genetic Loci / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D055106:Genome-Wide Association Study / Q000379:methods; D006801:Humans; D008168:Lung / Q000503:physiopathology*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D029424:Pulmonary Disease, Chronic Obstructive / Q000235:genetics*; D012307:Risk Factors