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

Shrine, Nick; Guyatt, Anna L.; Erzurumluoglu, A Mesut; Jackson, Victoria E.; Hobbs, Brian D.; Melbourne, Carl A.; Batini, Chiara; Fawcett, Katherine A.; Song, Kijoung; Hao, Ke; Hoffman, Joshua D.; Hokanson, John E.; Homuth, Georg; Joshi, Peter K.; Joubert, Philippe; Langenberg, Claudia; Li, Xuan; Li, Liming; Lin, Kuang; Lind, Lars; Locantore, Nicholas; Luan, Jian'an; Mahajan, Anubha; Maranville, Joseph C.; Murray, Alison; Nickle, David C; Packer, Richard; Parker, Margaret M.; Paynton, Megan L; Porteous, David J.; Prokopenko, Dmitry; Qiao, Dandi; Rawal, Rajesh; Runz, Heiko; Sayers, Ian; Sin, Don D.; Smith, Blair H.; Artigas, Maria Soler; Sparrow, David; Tal-Singer, Ruth; Timmers, Paul R.H.J.; Van den Berge, Maarten; Whittaker, John C.; Woodruff, Prescott G.; Yerges-Armstrong, Laura M.; Troyanskaya, Olga G.; Raitakari, Olli T.; Kahonen, Mika; Polasek, Ozren; Gyllensten, Ulf; Rudan, Igor; Deary, Ian J.; Probst-Hensch, Nicole M.; Schulz, Holger; James, Alan L.; Wilson, James F.; Stubbe, Beate; Zeggini, Eleftheria; Jarvelin, Marjo-Riitta; Wareham, Nick; Silverman, Edwin K.; Hayward, Caroline; Morris, Andrew P.; Butterworth, Adam S.; Scott, Robert A.; Hayward, Caroline; Walters, Robin G.; Meyers, Deborah A.; Cho, Michael H.; Strachan, David P.; Wareham, Nick; Hall, Ian P.; Tobin, Martin D.; Wain, Louise V.

Authors

Nick Shrine

Anna L. Guyatt

A Mesut Erzurumluoglu

Victoria E. Jackson

Brian D. Hobbs

Carl A. Melbourne

Chiara Batini

Katherine A. Fawcett

Kijoung Song

Ke Hao

Joshua D. Hoffman

John E. Hokanson

Georg Homuth

Peter K. Joshi

Philippe Joubert

Claudia Langenberg

Xuan Li

Liming Li

Kuang Lin

Lars Lind

Nicholas Locantore

Jian'an Luan

Anubha Mahajan

Joseph C. Maranville

Alison Murray

David C Nickle

Richard Packer

Margaret M. Parker

Megan L Paynton

David J. Porteous

Dmitry Prokopenko

Dandi Qiao

Rajesh Rawal

Heiko Runz

Don D. Sin

Blair H. Smith

Maria Soler Artigas

David Sparrow

Ruth Tal-Singer

Paul R.H.J. Timmers

Maarten Van den Berge

John C. Whittaker

Prescott G. Woodruff

Laura M. Yerges-Armstrong

Olga G. Troyanskaya

Olli T. Raitakari

Mika Kahonen

Ozren Polasek

Ulf Gyllensten

Igor Rudan

Ian J. Deary

Nicole M. Probst-Hensch

Holger Schulz

Alan L. James

James F. Wilson

Beate Stubbe

Eleftheria Zeggini

Marjo-Riitta Jarvelin

Nick Wareham

Edwin K. Silverman

Caroline Hayward

Andrew P. Morris

Adam S. Butterworth

ROBERT SCOTT Rob.Scott@nottingham.ac.uk
Clinical Assistant Professor

Caroline Hayward

Robin G. Walters

Deborah A. Meyers

Michael H. Cho

David P. Strachan

Nick Wareham

IAN HALL ian.hall@nottingham.ac.uk
Professor of Molecular Medicine

Martin D. Tobin

Louise V. Wain



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.

Journal Article Type Article
Publication Date Feb 25, 2019
Journal Nature Genetics
Print ISSN 1061-4036
Electronic ISSN 1546-1718
Publisher Nature Publishing Group
Peer Reviewed Peer Reviewed
Volume 51
Issue 3
Pages 481-493
APA6 Citation Shrine, N., Guyatt, A. L., Erzurumluoglu, A. M., Jackson, V. E., Hobbs, B. D., Melbourne, C. A., …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
DOI https://doi.org/10.1038/s41588-018-0321-7
Keywords Genetics
Publisher URL https://www.nature.com/articles/s41588-018-0321-7
Additional Information Received: 8 June 2018; Accepted: 27 November 2018; First Online: 25 February 2019; : The following authors report potential conflicts of interest: K.S. is an employee of GlaxoSmithKline (GSK) and may own company stock. Z.C. reports grants from GSK and Merck. J.D. reports personal fees and nonfinancial support from Merck Sharp & Dohme (MSD) and Novartis, and grants from British Heart Foundation, European Research Council, MSD, NIHR, NHS Blood and Transplant, Novartis, Pfizer, UK MRC, Wellcome Trust and AstraZeneca. J.D.H. is an employee of GlaxoSmithKline and may own company stock. N.L. is an employee and shareholder of GSK. J.C.M. was a Merck employee during this study, and is now a Celgene employee. D.C.N. has been a Merck & Co. employee during this study and is now an employee at Biogen Inc. H.R. has been a Merck & Co. employee during this study and is now an employee at Biogen Inc. I.S. has received support from GSK and Boehringer Ingelheim. R.T.-S. is an employee and shareholder of GlaxoSmithKline. M.v.d.B. reports grants paid to the University from Astra Zeneca, TEVA, GSK and Chiesi outside the submitted work. J.C.W. is an employee of GSK and may own company stock. L.M.Y.-A. is an employee of GSK and may own company stock. For H.S., Helmholtz Center Munich is funded by the German Federal Ministry of Education and Research (BMBF) and by the State of Bavaria, Competence Network Asthma and COPD (ASCONET), network COSYCONET (subproject 2, BMBF FKZ 01GI0882), funded by the BMBF. In the past three years, E.K.S. received honoraria from Novartis for Continuing Medical Education Seminars and grant and travel support from GlaxoSmithKline. A.S.B. reports grants from Merck, Pfizer, Novartis, Biogen and AstraZeneca and personal fees from Novartis. R.A.S. is an employee and shareholder in GSK. R.G.W. reports that the China Kadoorie Biobank study has received grant support from GSK. M.H.C. has received grant support from GSK. I.P.H. has funded research collaborations with GSK, Boehringer Ingelheim and Orion. M.D.T. receives funding from GSK for a collaborative research project outside of the submitted work. L.V.W. receives funding from GSK for a collaborative research project outside of the submitted work.

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