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

Publication type

Journal Article

Published in

Nature Genetics

Authors

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, T. L. Rimington, A. G. Fenech, Catherine John, Tineka Blake, Victoria E. Jackson, Richard J. Allen, B. P. Prins, 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, 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, E. K. Silverman, I. Sayers, G. Trynka, A. P. Morris, D. P. Strachan, I. P. Hall and Martin D. Tobin

Publication date

Summary

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.

Volume and page numbers

49, 416-425

DOI

http://dx.doi.org/10.1038/ng.3787

ISSN

16

Subjects

Medicine, Science And Technology, Health, Biology and Genetics