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

An Author Correction to this article was published on 20 May 2019

Abstract

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.

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Fig. 1: Study design.
Fig. 2: Strength and direction of association across four lung function traits for 139 novel signals.
Fig. 3: Association of weighted genetic risk score with COPD and FEV1/FVC.
Fig. 4: Individual PheWAS with 279 variants (traits passing FDR 1% threshold).
Fig. 5: PheWAS with genetic risk score (traits passing FDR 1% threshold).

Data availability

SpiroMeta GWAS summary statistics and UK Biobank GWAS summary statistics are available online via LD-Hub (http://ldsc.broadinstitute.org/ldhub/). Single-variant PheWAS results are available by request to the corresponding authors. The newly derived spirometry variables are available from UK Biobank (http://www.ukbiobank.ac.uk/).

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Acknowledgements

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.

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All authors critically reviewed the manuscript before submission. K.S., U.S.S.G., S.K., S.M.K., T.L., P.S.B., T.H.B., E.R.B., Y.B., Z.C., J.D.C., J.D., D.L.D., C.G., A.G., K.H., J.D.H., J.E.H., P.J., C.L., L.Li, N.L., J.C.M., H.R., I.Sayers, D.D.S., R.T-S., J.C.W., P.G.W., L.M.Y., O.T.R., M.K., O.P., U.G., I.R., I.J.D., N.M.P., H.S., A.L.J., J.F.W., E.Z., M.J., N.W., A.S.B., R.A.S., D.A.M., M.H.C., D.P.S., I.P.H., M.D.T. and L.V.W. contributed to the conception and design of the study. N.S., A.L.G., A.M.E., V.E.J., B.D.H., C.A.M., C.Batini, K.A.F., K.S., P.S., Xingnan Li, R.B., N.F.R., M.O., J.Zhao, M.W., S.W., K.A.K., J.P.C., B.B.S., J.Zhou, J.H., M.I., S.E.H., J.M., S.E., I.Surakka, V.V., T.L., R.J.A., F.D., J.D.H., P.K.J., Xuan Li, A.Mahajan, J.C.M., D.C.N., M.M.P., D.P., D.Q., R.R., H.R., D.S., P.R.H.J.T., M.V., L.M.Y., O.G.T., N.M.P., N.W., E.K.S., C.H., A.P.M., A.S.B., R.A.S., M.H.C., D.P.S., M.D.T. and L.V.W. undertook data analysis. N.S., A.L.G., A.M.E., V.E.J., C.A.M., C.Batini, K.A.F., K.S., P.S., Xingnan Li, N.F.R., M.O., M.W., K.A.K., B.B.S., S.K., M.I., R.J.A., C.Brandsma, J.D., F.D., R.E., C.G., A.G., A.L.H., J.D.H., G.H., P.K.J., C.L., Xuan Li, K.L., L.Lind, J.L., J.C.M., A.Murray, R.P., M.M.P., M.L.P., D.J.P., D.P., D.Q., R.R., H.R., I.Sayers, B.H.S., M.S., L.M.Y., O.G.T., N.M.P., H.S., J.F.W., B.S., M.J., N.W., C.H., A.P.M., A.S.B., R.A.S., R.G.W., M.H.C., D.P.S., I.P.H., M.D.T. and L.V.W. contributed to data acquisition and/or interpretation. N.S., A.L.G., A.M.E., I.P.H., M.D.T. and L.V.W. drafted the manuscript.

Corresponding authors

Correspondence to Martin D. Tobin or Louise V. Wain.

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Competing interests

The following authors report potential conflicts of interest: K.S. is an employee of GlaxoSmithKline (GSK) and may own company stock. Z.C. reports grants from GSK and Merck. J.D. reports personal fees and nonfinancial support from Merck Sharp & Dohme (MSD) and Novartis, and grants from British Heart Foundation, European Research Council, MSD, NIHR, NHS Blood and Transplant, Novartis, Pfizer, UK MRC, Wellcome Trust and AstraZeneca. J.D.H. is an employee of GlaxoSmithKline and may own company stock. N.L. is an employee and shareholder of GSK. J.C.M. was a Merck employee during this study, and is now a Celgene employee. D.C.N. has been a Merck & Co. employee during this study and is now an employee at Biogen Inc. H.R. has been a Merck & Co. employee during this study and is now an employee at Biogen Inc. I.S. has received support from GSK and Boehringer Ingelheim. R.T.-S. is an employee and shareholder of GlaxoSmithKline. M.v.d.B. reports grants paid to the University from Astra Zeneca, TEVA, GSK and Chiesi outside the submitted work. J.C.W. is an employee of GSK and may own company stock. L.M.Y.-A. is an employee of GSK and may own company stock. For H.S., Helmholtz Center Munich is funded by the German Federal Ministry of Education and Research (BMBF) and by the State of Bavaria, Competence Network Asthma and COPD (ASCONET), network COSYCONET (subproject 2, BMBF FKZ 01GI0882), funded by the BMBF. In the past three years, E.K.S. received honoraria from Novartis for Continuing Medical Education Seminars and grant and travel support from GlaxoSmithKline. A.S.B. reports grants from Merck, Pfizer, Novartis, Biogen and AstraZeneca and personal fees from Novartis. R.A.S. is an employee and shareholder in GSK. R.G.W. reports that the China Kadoorie Biobank study has received grant support from GSK. M.H.C. has received grant support from GSK. I.P.H. has funded research collaborations with GSK, Boehringer Ingelheim and Orion. M.D.T. receives funding from GSK for a collaborative research project outside of the submitted work. L.V.W. receives funding from GSK for a collaborative research project outside of the submitted work.

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Supplementary information

Supplementary Text and Figures

Supplementary Note and Supplementary Figures 1–10 and Supplementary Tables 1–3, 14–16, 19–22, 24 and 27

Reporting Summary

Supplementary Tables

Supplementary Tables 4–13, 17, 18, 23, 25, 26, 28 and 29

Supplementary Data 1

Region plots for 139 novel signals of association with lung function

Supplementary Data 2

Region plots for 140 previous signals of association with lung function

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Shrine, N., Guyatt, A.L., Erzurumluoglu, A.M. et al. New genetic signals for lung function highlight pathways and chronic obstructive pulmonary disease associations across multiple ancestries. Nat Genet 51, 481–493 (2019). https://doi.org/10.1038/s41588-018-0321-7

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