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

journal contribution
posted on 27.03.2019, 14:57 by N Shrine, AL Guyatt, AM Erzurumluoglu, VE Jackson, BD Hobbs, CA Melbourne, C Batini, KA Fawcett, K Song, P Sakornsakolpat, X Li, NM Probst-Hensch, H Schulz, AL James, JF Wilson, B Stubbe, E Zeggini, M-R Jarvelin, N Wareham, EK Silverman, C Hayward, AP Morris, AS Butterworth, RA Scott, RG Walters, DA Meyers, MH Cho, DP Strachan, IP Hall, MD Tobin, LV Wain, R Boxall, NF Reeve, M Obeidat, JH Zhao, M Wielscher, Understanding Society Scientific Group, S Weiss, KA Kentistou, JP Cook, BB Sun, J Zhou, J Hui, S Karrasch, M Imboden, SE Harris, J Marten, S Enroth, SM Kerr, I Surakka, V Vitart, T Lehtimäki, RJ Allen, PS Bakke, TH Beaty, ER Bleecker, Y Bossé, C-A Brandsma, Z Chen, JD Crapo, J Danesh, DL DeMeo, F Dudbridge, R Ewert, C Gieger, A Gulsvik, AL Hansell, K Hao, JD Hoffman, JE Hokanson, G Homuth, PK Joshi, P Joubert, C Langenberg, L Li, K Lin, L Lind, N Locantore, J Luan, A Mahajan, JC Maranville, A Murray, DC Nickle, R Packer, MM Parker, ML Paynton, DJ Porteous, D Prokopenko, D Qiao, R Rawal, H Runz, I Sayers, DD Sin, BH Smith, M Soler Artigas, D Sparrow, R Tal-Singer, PRHJ Timmers, M Van den Berge, JC Whittaker, PG Woodruff, LM Yerges-Armstrong, OG Troyanskaya, OT Raitakari, M Kähönen, O Polašek, U Gyllensten, I Rudan, IJ Deary
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.

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.

History

Citation

Nature Genetics, 2019, 51 (3), pp. 481-493

Author affiliation

/Organisation/COLLEGE OF LIFE SCIENCES/School of Medicine/Department of Health Sciences

Version

AM (Accepted Manuscript)

Published in

Nature Genetics

Volume

51

Issue

3

Pagination

481-493

Publisher

Nature Research (part of Springer Nature)

eissn

1546-1718

Acceptance date

27/11/2018

Copyright date

2019

Available date

25/08/2019

Notes

In the version of this article initially published, in Supplementary Data 5, the logFC, FC, P value and adjusted P value for advanced AMD versus control (DE 4/1) without age correction did not correspond to the correct gene IDs. The errors have been corrected in the HTML version of the article in the version of record.

Language

en

Publisher version

https://www.nature.com/articles/s41588-019-0351-9

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