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Genome-wide association study identifies multiple susceptibility loci for pulmonary fibrosis

Nature Genetics volume 45, pages 613–620 (2013)Cite this article

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A Corrigendum to this article was published on 29 October 2013

This article has been updated

Abstract

We performed a genome-wide association study of non-Hispanic, white individuals with fibrotic idiopathic interstitial pneumonias (IIPs; n = 1,616) and controls (n = 4,683), with follow-up replication analyses in 876 cases and 1,890 controls. We confirmed association with TERT at 5p15, MUC5B at 11p15 and the 3q26 region near TERC, and we identified seven newly associated loci (Pmeta = 2.4 × 10−8 to 1.1 × 10−19), including FAM13A (4q22), DSP (6p24), OBFC1 (10q24), ATP11A (13q34), DPP9 (19p13) and chromosomal regions 7q22 and 15q14-15. Our results suggest that genes involved in host defense, cell-cell adhesion and DNA repair contribute to risk of fibrotic IIPs.

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Figure 1: GWAS results at 439,828 SNPs with 1,616 cases and 4,683 controls under an additive model.
Figure 2: Locus-specific plots corresponding to discovery GWAS results for all loci reaching genome-wide significance in the GWAS discovery analysis and meta-analysis of the discovery and replication results.
Figure 3: Locus-specific plots corresponding to discovery GWAS results for four additional loci reaching genome-wide significance after the meta-analysis of the discovery and replication results.
Figure 4: Relative expression of DSP in lung tissue from 100 cases and 94 controls.

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Change history

  • 01 October 2013

    In the version of this article initially published, the minor alleles for two SNPs (rs2076295 and rs7934606) were listed incorrectly in Table 1. The correct minor allele for rs2076295 is G, and the correct minor allele for rs7934606 is T. As a result, there were two incorrect statements in the text regarding the relationship between the disease risk allele of rs2076295 and DSP expression. The text should have stated that the allele of rs2076295 associated with increased risk of pulmonary fibrosis is associated with decreased DSP expression rather than increased DSP expression. These errors have been corrected in the HTML and PDF versions of the article.

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Acknowledgements

We gratefully acknowledge the individuals who participated in the studies that contributed to this work. This research was supported by the National Heart, Lung, and Blood Institute (R01-HL095393, R01-HL097163, P01-HL092870, RC2-HL101715, U01-HL089897, U01-HL089856, U01-HL108642 and P50-HL0894932), the Veterans Administration (1I01BX001534), the Dorothy P. and Richard P. Simmons Center and InterMune.

Author information

Author notes

  1. Elissa Murphy and Weiming Zhang: These authors contributed equally to this work.

Authors and Affiliations

  1. University of Colorado Denver, School of Public Health, Denver, Colorado, USA

    Tasha E Fingerlin, Weiming Zhang & Anna L Peljto

  2. Department of Medicine, University of Colorado Denver, School of Medicine, Denver, Colorado, USA

    Elissa Murphy, Kevin K Brown, Gregory P Cosgrove, James D Crapo, Barry J Make, Keith Smith, David McKean, Brent S Pedersen, Marvin I Schwarz & David A Schwartz

  3. Department of Medicine, National Jewish Health, Denver, Colorado, USA

    Kevin K Brown, Gregory P Cosgrove, David Lynch, Steve Groshong, James D Crapo, Barry J Make, Elizabeth A Regan, Janet Talbert, Marvin I Schwarz & David A Schwartz

  4. Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, USA

    Mark P Steele, James E Loyd, Lisa H Lancaster, Joy D Cogan, Wendi R Mason & Cheryl R Markin

  5. Department of Medicine, University of California, San Francisco, San Francisco, California, USA

    Harold R Collard & Paul J Wolters

  6. InterMune, Brisbane, California, USA

    Williamson Z Bradford, Karl Kossen & Scott D Seiwert

  7. National Heart and Lung Institute, Imperial College London, London, UK

    Roland M du Bois, Toby M Maher, Philip L Molyneaux, Athol U Wells & Miriam F Moffatt

  8. Royal Brompton Hospital, London, UK

    Roland M du Bois, Toby M Maher, Philip L Molyneaux, Athol U Wells & Miriam F Moffatt

  9. Department of Medicine, University of Texas Southwestern, Dallas, Texas, USA

    Christine Kim Garcia & Megan S Devine

  10. Department of Medicine, Landspitali University Hospital, Reykjavik, Iceland

    Gunnar Gudmundsson & Helgi J Isaksson

  11. Department of Pathology, Landspitali University Hospital, Reykjavik, Iceland

    Gunnar Gudmundsson & Helgi J Isaksson

  12. Department of Medicine, University of Iceland Faculty of Medicine, Reykjavik, Iceland

    Gunnar Gudmundsson & Helgi J Isaksson

  13. Department of Pathology, University of Iceland Faculty of Medicine, Reykjavik, Iceland

    Gunnar Gudmundsson & Helgi J Isaksson

  14. Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA

    Naftali Kaminski, Yingze Zhang & Kevin F Gibson

  15. Instituto Nacional de Enfermedades Respiratorias, Mexico City, Mexico

    Moises Selman

  16. Facultad de Ciencias, Universidad Nacional Autonoma de Mexico, Mexico City, Mexico

    Annie Pardo

  17. Department of Pulmonary, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea

    Dong Soon Kim

  18. Biomedical Genomics Center, University of Minnesota, Minneapolis, Minnesota, USA

    Dinesha S Walek, Jerry J Daniel & Kenneth B Beckman

  19. Fondation Jean Dausset, Centre d′Étude du Polymorphisme Humain, Paris, France

    Yoichiro Kamatani & Mark Lathrop

  20. Commissariat à l′Energie Atomique, Institut Génomique, Centre National de Génotypage, Evry, France

    Diana Zelenika & Mark Lathrop

  21. Quintiles, Parsippany, New Jersey, USA

    Raven N Kidd

  22. Department of Immunology, University of Colorado Denver, Denver, Colorado, USA

    David A Schwartz

Authors
  1. Tasha E Fingerlin
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  2. Elissa Murphy
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  50. David A Schwartz
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Contributions

T.E.F. and D.A.S. designed the study. K.K.B., M.P.S., J.E.L., G.P.C., D.L., S.G., H.R.C., P.J.W., R.M.d.B., C.K.G., M.S.D., G.G., H.J.I., N.K., Y.Z., K.F.G., L.H.L., W.R.M., T.M.M., P.L.M., A.U.W., J.D. Crapo, B.J.M., E.A.R. and M.I.S. performed clinical, radiological and pathological phenotyping of study subjects. W.Z.B., K.K. and S.D.S. provided data and samples from the InterMune subjects. J.T., R.N.K. and C.R.M. coordinated the clinical evaluations. E.M. supervised and coordinated the laboratory work. E.M., J.D. Cogan, D.S.W., J.J.D., D.Z. and K.S. performed the laboratory work. D.M. organized the database. K.B.B. supervised the replication genotyping. M.L. supervised the genome-wide genotyping. M.F.M., M.S., A.P., D.S.K. and M.I.S. provided advice on design and relevance to pulmonary fibrosis. T.E.F., W.Z., A.L.P., B.S.P. and Y.K. analyzed the data. T.E.F., M.L. and D.A.S. developed the conceptual approaches to data analysis. T.E.F. and D.A.S. wrote the manuscript.

Corresponding authors

Correspondence to Tasha E Fingerlin or David A Schwartz.

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The authors have filed applications with the US Patent Office entitled 'Methods and Compositions for Risk Prediction, Diagnosis, Prognosis, and Treatment of Pulmonary Disorders' (application serial number 61/298473; D.A.S. and T.E.F.) and 'Use of MUC5B Gene Expression in Therapeutics' (application serial number 61/693861; D.A.S.).

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Fingerlin, T., Murphy, E., Zhang, W. et al. Genome-wide association study identifies multiple susceptibility loci for pulmonary fibrosis. Nat Genet 45, 613–620 (2013). https://doi.org/10.1038/ng.2609

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