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Genetic loci associated with chronic obstructive pulmonary disease overlap with loci for lung function and pulmonary fibrosis

Abstract

Chronic obstructive pulmonary disease (COPD) is a leading cause of mortality worldwide1. We performed a genetic association study in 15,256 cases and 47,936 controls, with replication of select top results (P < 5 × 10−6) in 9,498 cases and 9,748 controls. In the combined meta-analysis, we identified 22 loci associated at genome-wide significance, including 13 new associations with COPD. Nine of these 13 loci have been associated with lung function in general population samples2,3,4,5,6,7, while 4 (EEFSEC, DSP, MTCL1, and SFTPD) are new. We noted two loci shared with pulmonary fibrosis8,9 (FAM13A and DSP) but that had opposite risk alleles for COPD. None of our loci overlapped with genome-wide associations for asthma, although one locus has been implicated in joint susceptibility to asthma and obesity10. We also identified genetic correlation between COPD and asthma. Our findings highlight new loci associated with COPD, demonstrate the importance of specific loci associated with lung function to COPD, and identify potential regions of genetic overlap between COPD and other respiratory diseases.

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Figure 1: Study design showing the cohorts used in each stage of the analysis.
Figure 2: Manhattan plot.
Figure 3: Regional association plots for newly associated loci.
Figure 4: Genetic correlation (from LD score regression) between COPD and other traits.

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Acknowledgements

Please refer to the Supplementary Note for full acknowledgments.

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Contributions

B.D.H. and M.H.C. contributed to the study concept and design, data analysis, statistical support, and manuscript writing. K.d.J., A.B.W., S.J.L., and D.P.S. contributed to the study concept and design and to data analysis. N.S. and M.S.A. contributed to the data analysis and statistical support. T.H.B. and J.E.H. contributed to the study concept and design and to statistical support. L.L. contributed to the data collection, data analysis, and statistical support. K.E.N. contributed to data collection and data analysis. J.D.C., B.M.P., N.L., R.T.-S., G.T.O., Y.T., R.G.B., S.I.R., P.B., A.G., P.G.W., D.A.M., D.A.S., and E.K.S. contributed to the study concept and design and to data collection. D.Q., T.A.F., M.L., Y.B., N.S., N.F., P.J.C., R.P.C., T.M.B., S.A.G., J.C.L., J.D., J.B.W., M.K.L., S.L., A.M., X.-Q.W., and E.J.A. contributed to the data analysis. L.V.W., I.P.H., P.D.P., D.S.P., W.M., M.D.T., and H.M.B. contributed to the study concept and design. S.R.H., M.O., J.V., P.A.D., W.J.K., Y.-M.O., S.S.R., D.S., A.A.L., G.G.B., B.H.S., A.G.U., E.R.B., D.A.L., J.-J.Y., D.K.K., I.H., P.S., and M.H. contributed to the data collection. All authors, including those whose initials are not listed above, contributed to the critical review and editing of the manuscript and approved the final version of the manuscript.

Corresponding author

Correspondence to Michael H Cho.

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Competing interests

I.P.H. has received grant support from Pfizer. P.J.C. has received research funding from GlaxoSmithKline. B.P. serves on the data and safety monitoring board (DSMB) of a clinical trial funded by the manufacturer and on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson. N.L. and R.T.-S. are shareholders and employees of GlaxoSmithKline. S.I.R. is a current employee and shareholder at AstraZeneca. He has served as a consultant, participated on advisory boards, and received honoraria for speaking or grant support from the American Board of Internal Medicine, Advantage Healthcare, Almirall, the American Thoracic Society, AstraZeneca, Baxter, Boehringer Ingelheim, Chiesi, ClearView Healthcare, the Cleveland Clinic, Complete Medical Group, CSL, Dailchi Sankyo, Decision Resources, Forest, Gerson Lehman, Grifols, GroupH, Guidepoint Global, Haymarket, Huron Consulting, Inthought, Johnson & Johnson, Methodist Health System–Dallas, NCI Consulting, Novartis, Pearl, Penn Technology, Pfizer, PlanningShop, PSL FirstWord, Qwessential, Takeda, Theron, and WebMD. W.T. reports fees to the Department, all outside the submitted work, from Pfizer, GSK, Chiesi, Roche Diagnostics/Ventana, Biotest, Merck Sharp Dohme, Novartis, Lilly Oncology, Boehringer Ingelheim, and grants from Dutch Asthma Fund. J.C.L. is currently an employee of GNS Healthcare. J.B.W. was employed by Pfizer during the time this research was performed. P.B. has received consulting and lecture fees from AstraZeneca, Boehringer Ingelheim, Chiesi, Novartis, and Teva. L.L. has performed consultancy for Boehringer Ingelheim and has received an AstraZeneca Scientific Award and travel support from Novartis, the European Respiratory Society, and the Belgian Respiratory Society. P.G.W. has consulted for Amgen, Sanofi, Novartis, Genentech/Roche, Boehringer Ingelheim, and Neostem and has had research grants from Pfizer and Genentech. D.L. received grant support, honoraria, and consultancy fees from GlaxoSmithKline for work on the ICGN and ECLIPSE studies and was a member of and chaired the GSK Respiratory Therapy Area Board (2009–2015). M.H. is a current employee of AstraZeneca. D.A.S. is serving on the scientific advisory boards of Apellis Pharmaceuticals and Pliant Therapeutics, and is the founder and owner of Eleven P15. The University of Groningen has received money for D.S.P. with regard to a grant for research from AstraZeneca, Chiesi, Genentec, GlaxoSmithKline, and Roche. Fees for consultancies were given to the University of Groningen by AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Takeda, and TEVA. E.K.S. has received honoraria and consulting fees from Merck, grant support and consulting fees from GlaxoSmithKline, and honoraria and travel support from Novartis. M.H.C. has received grant support from GlaxoSmithKline.

Additional information

A list of members and affiliations appears in the Supplementary Note.

A list of members and affiliations appears in the Supplementary Note.

A list of members and affiliations appears in the Supplementary Note.

A list of members and affiliations appears in the Supplementary Note.

A list of members and affiliations appears in the Supplementary Note.

A list of members and affiliations appears in the Supplementary Note.

A list of members and affiliations appears in the Supplementary Note.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–6, Supplementary Tables 1, 2, 4–7, 9–13 and 15–20, and Supplementary Note (PDF 8454 kb)

Supplementary Table 3

Full results table for all 79 variants submitted for testing in UK BiLEVE stage 2 analysis. (XLSX 63 kb)

Supplementary Table 8

Full results (P < 0.05 in meta-analysis) for lung expression quantitative trait locus (eQTL) analysis. (XLSX 24 kb)

Supplementary Table 14

Lookup of NHGRI-EBI GWAS Catalog asthma-associated trait genome-wide significant GWAS loci in our COPD association stage 1 meta-analysis results. (XLSX 13 kb)

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Hobbs, B., de Jong, K., Lamontagne, M. et al. Genetic loci associated with chronic obstructive pulmonary disease overlap with loci for lung function and pulmonary fibrosis. Nat Genet 49, 426–432 (2017). https://doi.org/10.1038/ng.3752

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