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

journal contribution
posted on 16.01.2017, 10:03 by Louise V. Wain, Nick Shrine, María Soler Artigas, A. Mesut Erzurumluoglu, Boris Noyvert, L. Bossini-Castillo, M. Obeidat, A. P. Henry, M. A . Portelli, R. J. Hall, C. K. Billington, E. K. Silverman, I. Sayers, G. Trynka, A. P. Morris, D. P. Strachan, I. P. Hall, Martin D. Tobin, T. L. Rimington, A. G. Fenech, Catherine John, Tineka Blake, Victoria E. Jackson, Richard J. Allen, B. P. Prins, Understanding Society Scientific Group, A. Campbell, D. J. Porteous, M-R. Jarvelin, M. Wielscher, A. L. James, J. Hui, N. J Wareham, J. H. Zhao, J. F. Wilson, P. K. Joshi, B. Stubbe, R. Rawal, H. Schulz, M. Imboden, N. M. Probst-Hensch, S. Karrasch, C. Gieger, I. J. Deary, S. E. Harris, J. Marten, I. Rudan, S. Enroth, U. Gyllensten, S. M. Kerr, O. Polasek, M. Kähönen, I. Surakka, V. Vitart, C. Hayward, T. Lehtimäki, O. Raitakari, D. M. Evans, A. J. Henderson, C. E. Pennell, C. A. Wang, P. D. Sly, E. S. Wan, R. Busch, B. D. Hobbs, A. A. Litonjua, D. W. Sparrow, A. Gulsvik, P. S. Bakke, J. D. Crapo, T. H. Beaty, N. N. Hansel, R. A. Mathias, I. Ruczinski, K. C. Barnes, Y. Bossé, P. Joubert, M. van den Berge, C-A. Brandsma, P. D. Paré, D. D. Sin, D. C. Nickle, K. Hao, O. Gottesman, F. E. Dewey, S. E. Bruse, D. J. Carey, H. L. Kirchner, Geisinger-Regeneron DiscovEHR Collaboration, S. Jonsson, G. Thorleifsson, I. Jonsdottir, T. Gislason, K. Stefansson, C. Schurmann, G. Nadkarni, E. P. Bottinger, R. J. F. Loos, R. G. Walters, Z. Chen, I. Y. Millwood, J. Vaucher, O. P. Kurmi, L. Li, A. L. Hansell, Chris Brightling, E. Zeggini, M. H. Cho
Chronic Obstructive Pulmonary Disease (COPD) is characterised 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 ratios per standard deviation of the risk score (~6 alleles) (95% confidence interval) 1.24 (1.20-1.27), P=5.05x10^-49) and we observed a 3.7 fold difference in COPD risk between highest and lowest genetic risk score deciles in UK Biobank. The 97 signals show enrichment in development, elastic fibres 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.

Funding

This work was funded by a Medical Research Council (MRC) strategic award to M.D. Tobin, I.P. Hall, D. Strachan and L.V. Wain (MC_PC_12010). This research has been conducted using the UK Biobank Resource under Application Number 648. This article presents independent research funded partially by the National Institute for Health Research (NIHR). 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 acknowledgements and funding can be found in the Supplementary Information.

History

Citation

Nature Genetics, 2017

Author affiliation

/Organisation/COLLEGE OF MEDICINE, BIOLOGICAL SCIENCES AND PSYCHOLOGY/School of Medicine/Department of Health Sciences

Version

AM (Accepted Manuscript)

Published in

Nature Genetics

Publisher

Nature Publishing Group

issn

1061-4036

eissn

1546-1718

Acceptance date

13/01/2017

Available date

06/08/2017

Publisher version

http://www.nature.com/ng/journal/vaop/ncurrent/full/ng.3787.html

Notes

The stage 1 (UK BiLEVE) genome-wide association results for FEV1, FVC and FEV1/FVC are available from UK Biobank at http://www.ukbiobank.ac.uk/. The sources of all other data utilised in this study can be found in the Online Methods and Supplementary;The file associated with this record is under embargo until 6 months after publication, in accordance with the publisher's self-archiving policy. The full text may be available through the publisher links provided above.

Language

en

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