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Genetic landscape of chronic obstructive pulmonary disease identifies heterogeneous cell-type and phenotype associations

Abstract

Chronic obstructive pulmonary disease (COPD) is the leading cause of respiratory mortality worldwide. Genetic risk loci provide new insights into disease pathogenesis. We performed a genome-wide association study in 35,735 cases and 222,076 controls from the UK Biobank and additional studies from the International COPD Genetics Consortium. We identified 82 loci associated with P < 5 × 10−8; 47 of these were previously described in association with either COPD or population-based measures of lung function. Of the remaining 35 new loci, 13 were associated with lung function in 79,055 individuals from the SpiroMeta consortium. Using gene expression and regulation data, we identified functional enrichment of COPD risk loci in lung tissue, smooth muscle, and several lung cell types. We found 14 COPD loci shared with either asthma or pulmonary fibrosis. COPD genetic risk loci clustered into groups based on associations with quantitative imaging features and comorbidities. Our analyses provide further support for the genetic susceptibility and heterogeneity of COPD.

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Fig. 1: Study design.
Fig. 2: Manhattan plot.
Fig. 3: Identification of target genes.
Fig. 4: Effects on COPD-related and other phenotypes.

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Data availability

Genome-wide association summary statistics are available at the database of Genotypes and Phenotypes (dbGaP) under accession phs000179.v5.p2 and via the UK Biobank. Derived phenotypic data for COPD case–control status are also available from UK Biobank.

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Acknowledgements

This work was supported by the Prince Mahidol Award Youth Program Scholarship (P. Sakornsakolpat); NHLBI R01HL084323, R01HL113264, R01HL089856, and P01HL105339 (E.K.S.); K08HL136928 (B.D.H.), the Parker B. Francis Research Opportunity Award (B.D.H.); and R01HL113264, R01HL137927, P01HL105339, and P01HL132825 (M.H.C.). This research was conducted by using the UK Biobank resource under application numbers 20915 (M.H.C.) and 648 (M.D.T.). Please refer to the Supplementary Note for full acknowledgements. Funding bodies had no role in the design of the study, the collection, analysis, or interpretation of the data, or the writing of the manuscript.

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

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Correspondence to Michael H. Cho.

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Competing interests

M.H.C., E.K.S., L.V.W., M.D.T., D.A.L., and I.P.H. have received grant funding from GlaxoSmithKline (GSK). E.K.S. has received honoraria from Novartis for continuing medical education seminars and travel support from GSK. I.P.H. has received grant support from BI. R.T.-S. is an employee and shareholder of GSK. J.V. has received personal fees from GSK, Chiesi Pharmaceuticals, BI, Novartis, and AstraZeneca. D.L.D. has received grants from the National Institutes of Health for research on COPD and personal fees from Novartis. D.A.L. has received honoraria from GSK and chaired the Respiratory Therapy Area Board from 2012 to 2015. Outside the submitted work, L.L. reports expert consultation for Boehringer Ingelheim and Novartis and unrestricted grants from AstraZeneca and Chiesi.

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Sakornsakolpat, P., Prokopenko, D., Lamontagne, M. et al. Genetic landscape of chronic obstructive pulmonary disease identifies heterogeneous cell-type and phenotype associations. Nat Genet 51, 494–505 (2019). https://doi.org/10.1038/s41588-018-0342-2

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