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, Be...

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.

Citation

Shrine, N., Guyatt, A. L., Erzurumluoglu, A. M., Jackson, V. E., Hobbs, B. D., Melbourne, C. A., Batini, C., Fawcett, K. A., Song, K., Hao, K., Hoffman, J. D., Hokanson, J. E., Homuth, G., Joshi, P. K., Joubert, P., Langenberg, C., Li, X., Li, L., Lin, K., Lind, L., …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

• Journal Article Type: Article
• Acceptance Date: Nov 27, 2018
• Online Publication Date: Feb 25, 2019
• Publication Date: Feb 25, 2019
• Deposit Date: Dec 17, 2018
• Publicly Available Date: Aug 26, 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
• DOI: https://doi.org/10.1038/s41588-018-0321-7
• Keywords: Genetics
• Public URL: https://nottingham-repository.worktribe.com/output/1418673
• 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.
• Contract Date: Dec 17, 2018