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

Louise V. Wain*, Nick Shrine, María Soler Artigas, A. Mesut Erzurumluoglu, Boris Noyvert, Lara Bossini-Castillo, Ma'En Obeidat, Amanda P. Henry, Michael A. Portelli, Robert J. Hall, Charlotte K. Billington, Tracy L. Rimington, Anthony G. Fenech, Catherine John, Tineka Blake, Victoria E. Jackson, Richard J. Allen, Bram P. Prins, Archie Campbell, David J. PorteousMarjo Riitta Jarvelin, Matthias Wielscher, Alan L. James, Jennie Hui, Nicholas J. Wareham, Jing Hua Zhao, James F. Wilson, Peter K. Joshi, Beate Stubbe, Rajesh Rawal, Holger Schulz, Medea Imboden, Nicole M. Probst-Hensch, Stefan Karrasch, Christian Gieger, Ian J. Deary, Sarah E. Harris, Jonathan Marten, Igor Rudan, Stefan Enroth, Ulf Gyllensten, Shona M. Kerr, Ozren Polasek, Mika Kähönen, Ida Surakka, Veronique Vitart, Caroline Hayward, Terho Lehtimäki, Olli T. Raitakari, David M. Evans, A. John Henderson, Craig E. Pennell, Carol A. Wang, Peter D. Sly, Emily S. Wan, Robert Busch, Brian D. Hobbs, Augusto A. Litonjua, David W. Sparrow, Amund Gulsvik, Per S. Bakke, James D. Crapo, Terri H. Beaty, Nadia N. Hansel, Rasika A. Mathias, Ingo Ruczinski, Kathleen C. Barnes, Yohan Bossé, Philippe Joubert, Maarten Van Den Berge, Corry Anke Brandsma, Peter D. Paré, Don D. Sin, David C. Nickle, Ke Hao, Omri Gottesman, Frederick E. Dewey, Shannon E. Bruse, David J. Carey, H. Lester Kirchner, Stefan Jonsson, Gudmar Thorleifsson, Ingileif Jonsdottir, Thorarinn Gislason, Kari Stefansson, Claudia Schurmann, Girish Nadkarni, Erwin P. Bottinger, Ruth J.F. Loos, Robin G. Walters, Zhengming Chen, Iona Y. Millwood, Julien Vaucher, Om P. Kurmi, Liming Li, Anna L. Hansell, Chris Brightling, Eleftheria Zeggini, Michael H. Cho, Edwin K. Silverman, Ian Sayers, Gosia Trynka, Andrew P. Morris, David P. Strachan, Ian P. Hall, Martin D. Tobin

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

142 Citations (Scopus)

Abstract

Chronic obstructive pulmonary disease (COPD) is characterized 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 ratio per 1 s.d. of the risk score (1/46 alleles) (95% confidence interval) = 1.24 (1.20-1.27), P = 5.05 × 10 49), and we observed a 3.7-fold difference in COPD risk between individuals in the highest and lowest genetic risk score deciles in UK Biobank. The 97 signals show enrichment in genes for development, elastic fibers 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.

Original languageEnglish
Pages (from-to)416-425
Number of pages10
JournalNature Genetics
Volume49
Issue number3
DOIs
Publication statusPublished - 1 Mar 2017
Externally publishedYes

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