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Peer-reviewedCC BYEuropean Respiratory Journal

Genome-wide association study of idiopathic pulmonary fibrosis susceptibility using clinically curated European ancestry datasets

  • Daniel Chin1,2,3,4
  • Tamara Hernández-Beeftink1,2,3,4
  • Lauren J. Donoghue5,6
  • Beatriz Guillén‐Guío1,7,8,9,4
  • Olivia C. Leavy1,2,3,4
  • Ayodeji Adegunsoye10,11
  • Helen Booth12,13
  • CleanUP-IPF Investigators of the Pulmonary Trials Cooperative14,15
  • William A. Fahy16,17
  • Tasha E. Fingerlin18,19
  • Bibek Gooptu1,3,20
  • Ian P. Hall21,22
36 more authors
  • Simon Paul Hart23,24
  • Mike R. Hill25,26
  • Nik Hirani27,20
  • Simon R. Johnson28,20
  • Naftali Kaminski29,30
  • Jose Miguel Lorenzo-Salazar31,32
  • Shwu‐Fan Ma33,34
  • Robin J. McAnulty35,36
  • Mark I. McCarthy5,6
  • Amy Stockwell5,6
  • Toby M. Maher37,38,39
  • Ann Millar40
  • Philip L. Molyneaux39
  • María Molina‐Molina7
  • Vidya V. Navaratnam
  • Margaret Neighbors5,6
  • Justin M. Oldham
  • Helen Parfrey
  • Gauri Saini20
  • Ian Sayers21,20
  • X Rebecca Sheng5,6
  • Iain D. Stewart39
  • Mary E. Strek10,11
  • Martin D. Tobin2,4
  • Moira K. B. Whyte27,26
  • Maria Concetta Zarcone38,39
  • Yingze Zhang
  • Fernando J. Martínez14
  • Brian L. Yaspan5,6
  • Carl Reynolds
  • David A. Schwartz
  • Carlos Flores7,31,32
  • Imre Noth33,34
  • Gisli R. Jenkins38,39
  • Richard J. Allen1,2,3,4
  • Louise V. Wain1,2,3,4
40 affiliations
  1. 1Centre for Fibrosis Research, University of Leicester, Leicester, UK
  2. 2Department of Population Health Sciences, University of Leicester, Leicester, UK
  3. 3IHR Leicester Biomedical Research Centre, Leicester, UK
  4. 4University of Leicester
  5. 5Genentech, California, USA
  6. 6Genentech
  7. 7Centro de Investigación Biomédica en Red de Enfermedades Respiratorias (CIBERES), Instituto de Salud Carlos III, Madrid, Spain
  8. 8Division of Public Health and Epidemiology, School of Medical Sciences, University of Leicester, Leicester, UK
  9. 9NIHR Leicester Biomedical Research Centre, Leicester, UK
  10. 10University of Chicago, Chicago, USA
  11. 11University of Chicago
  12. 12University College London Hospitals, London, UK
  13. 13University College London Hospitals
  14. 14Weill Cornell Medicine, New York, USA
  15. 15GlaxoSmithKline
  16. 16GlaxoSmithKline, London, UK
  17. 17National Jewish Health
  18. 18National Jewish Health, Colorado, USA
  19. 19NIHR Leicester Biomedical Research Centre
  20. 20University of Nottingham
  21. 21Centre for Respiratory Research, NIHR Nottingham Biomedical Research Centre, School of Medicine, Biodiscovery Institute, University of Nottingham, Nottingham, UK
  22. 22University of Hull
  23. 23University of Hull, Hull, UK
  24. 24University of Oxford
  25. 25University of Oxford, Oxford, UK
  26. 26University of Edinburgh
  27. 27University of Edinburgh, Edinburgh, UK
  28. 28Centre for Respiratory Research, NIHR Biomedical Research Centre and Biodiscovery Institute, Translational Medical Sciences, School of Medicine, University of Nottingham, Nottingham, UK
  29. 29Yale School of Medicine, Connecticut, USA
  30. 30Yale School of Medicine
  31. 31Genomics Division, Instituto Tecnologico y de Energias Renovables, Santa Cruz de Tenerife, Spain
  32. 32Instituto Tecnologico y de Energias Renovables
  33. 33University of Virginia, Virginia, USA
  34. 34University of Virginia
  35. 35University College London, London, UK
  36. 36University College London
  37. 37Keck Medicine of USC, University of Southern California, Los Angeles, California, 90033, USA
  38. 38NIHR Imperial Biomedical Research Unit, National Heart and Lung Institute, Imperial College London, London, UK
  39. 39Imperial College London
  40. 40University of Bristol, Bristol, UK
Open at sourceDOICite

Abstract

Background Idiopathic pulmonary fibrosis (IPF) is a rare, incurable lung disease with a median survival of 3-5 years after diagnosis. Treatment options are limited. Genetic association studies can identify new genes involved in disease that might represent potential new drug targets, and it has been shown that drug targets with support from genetic studies are more likely to be successful in clinical development. Previous genome-wide association studies (GWAS) of IPF susceptibility have identified more than 20 signals implicating genes involved in multiple mechanisms, including telomere dysfunction, cell-cell adhesion, host defence immunity, various signalling pathways and, more recently, mitotic spindle assembly complex. Aim To leverage new datasets and genotype imputation to discover further genes involved in development of IPF that could yield new pathobiological avenues for exploration and to guide future drug target discovery. Methods We conducted a GWAS of IPF susceptibility including seven IPF case-control studies comprising 5,159 IPF cases and 27,459 controls of European ancestry, where IPF diagnosis was made by a respiratory clinician according to international guidelines. Genotypes were obtained from Whole Genome Sequencing (WGS) or from array-based imputation to the TOPMed WGS reference panel. New signals were replicated in independent biobanks with IPF defined using Electronic Healthcare Records. Bayesian fine-mapping was performed to identify the most likely causal variant(s) and bioinformatic investigation undertaken to map associated variants to putative causal genes. Results We identified three novel genetic signals of association with IPF susceptibility. Genes prioritised by functional evidence at these signals included MUC1 , which encodes a large transmembrane glycoprotein and known biomarker of lung fibrosis, and NTN4 encoding Netrin-4 whose known roles include angiogenesis. The third signal may map to SLC6A6 , a taurine and beta-alanine transporter gene, previously implicated in retinal, cardiac and kidney dysfunction. Conclusion Our study has identified new associations not previously identified by previous large biobank-based studies thereby highlighting the value of utilising clinically-curated IPF case-control studies, and new genotype imputation. We present new evidence for disease-driving roles of MUC1 and of endothelial cell and vascular changes in IPF.

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Cite

BibTeXRIS
BibTeX
@article{chin2026genomewide,
  title = {{Genome-wide association study of idiopathic pulmonary fibrosis susceptibility using clinically curated European ancestry datasets}},
  author = {Daniel Chin and Tamara Hernández-Beeftink and Lauren J. Donoghue and Beatriz Guillén‐Guío and Olivia C. Leavy and Ayodeji Adegunsoye and Helen Booth and CleanUP-IPF Investigators of the Pulmonary Trials Cooperative and William A. Fahy and Tasha E. Fingerlin and Bibek Gooptu and Ian P. Hall and Simon Paul Hart and Mike R. Hill and Nik Hirani and Simon R. Johnson and Naftali Kaminski and Jose Miguel Lorenzo-Salazar and Shwu‐Fan Ma and Robin J. McAnulty and Mark I. McCarthy and Amy Stockwell and Toby M. Maher and Ann Millar and Philip L. Molyneaux and María Molina‐Molina and Vidya V. Navaratnam and Margaret Neighbors and Justin M. Oldham and Helen Parfrey and Gauri Saini and Ian Sayers and X Rebecca Sheng and Iain D. Stewart and Mary E. Strek and Martin D. Tobin and Moira K. B. Whyte and Maria Concetta Zarcone and Yingze Zhang and Fernando J. Martínez and Brian L. Yaspan and Carl Reynolds and David A. Schwartz and Carlos Flores and Imre Noth and Gisli R. Jenkins and Richard J. Allen and Louise V. Wain},
  journal = {European Respiratory Journal},
  year = {2026},
  month = may,
  doi = {10.1183/13993003.00506-2026},
  url = {https://doi.org/10.1183/13993003.00506-2026},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - Genome-wide association study of idiopathic pulmonary fibrosis susceptibility using clinically curated European ancestry datasets
AU  - Daniel Chin
AU  - Tamara Hernández-Beeftink
AU  - Lauren J. Donoghue
AU  - Beatriz Guillén‐Guío
AU  - Olivia C. Leavy
AU  - Ayodeji Adegunsoye
AU  - Helen Booth
AU  - CleanUP-IPF Investigators of the Pulmonary Trials Cooperative
AU  - William A. Fahy
AU  - Tasha E. Fingerlin
AU  - Bibek Gooptu
AU  - Ian P. Hall
AU  - Simon Paul Hart
AU  - Mike R. Hill
AU  - Nik Hirani
AU  - Simon R. Johnson
AU  - Naftali Kaminski
AU  - Jose Miguel Lorenzo-Salazar
AU  - Shwu‐Fan Ma
AU  - Robin J. McAnulty
AU  - Mark I. McCarthy
AU  - Amy Stockwell
AU  - Toby M. Maher
AU  - Ann Millar
AU  - Philip L. Molyneaux
AU  - María Molina‐Molina
AU  - Vidya V. Navaratnam
AU  - Margaret Neighbors
AU  - Justin M. Oldham
AU  - Helen Parfrey
AU  - Gauri Saini
AU  - Ian Sayers
AU  - X Rebecca Sheng
AU  - Iain D. Stewart
AU  - Mary E. Strek
AU  - Martin D. Tobin
AU  - Moira K. B. Whyte
AU  - Maria Concetta Zarcone
AU  - Yingze Zhang
AU  - Fernando J. Martínez
AU  - Brian L. Yaspan
AU  - Carl Reynolds
AU  - David A. Schwartz
AU  - Carlos Flores
AU  - Imre Noth
AU  - Gisli R. Jenkins
AU  - Richard J. Allen
AU  - Louise V. Wain
PY  - 2026
DA  - 2026/05/21
JO  - European Respiratory Journal
DO  - 10.1183/13993003.00506-2026
UR  - https://doi.org/10.1183/13993003.00506-2026
AB  - Background Idiopathic pulmonary fibrosis (IPF) is a rare, incurable lung disease with a median survival of 3-5 years after diagnosis. Treatment options are limited. Genetic association studies can identify new genes involved in disease that might represent potential new drug targets, and it has been shown that drug targets with support from genetic studies are more likely to be successful in clinical development. Previous genome-wide association studies (GWAS) of IPF susceptibility have identified more than 20 signals implicating genes involved in multiple mechanisms, including telomere dysfunction, cell-cell adhesion, host defence immunity, various signalling pathways and, more recently, mitotic spindle assembly complex. Aim To leverage new datasets and genotype imputation to discover further genes involved in development of IPF that could yield new pathobiological avenues for exploration and to guide future drug target discovery. Methods We conducted a GWAS of IPF susceptibility including seven IPF case-control studies comprising 5,159 IPF cases and 27,459 controls of European ancestry, where IPF diagnosis was made by a respiratory clinician according to international guidelines. Genotypes were obtained from Whole Genome Sequencing (WGS) or from array-based imputation to the TOPMed WGS reference panel. New signals were replicated in independent biobanks with IPF defined using Electronic Healthcare Records. Bayesian fine-mapping was performed to identify the most likely causal variant(s) and bioinformatic investigation undertaken to map associated variants to putative causal genes. Results We identified three novel genetic signals of association with IPF susceptibility. Genes prioritised by functional evidence at these signals included MUC1 , which encodes a large transmembrane glycoprotein and known biomarker of lung fibrosis, and NTN4 encoding Netrin-4 whose known roles include angiogenesis. The third signal may map to SLC6A6 , a taurine and beta-alanine transporter gene, previously implicated in retinal, cardiac and kidney dysfunction. Conclusion Our study has identified new associations not previously identified by previous large biobank-based studies thereby highlighting the value of utilising clinically-curated IPF case-control studies, and new genotype imputation. We present new evidence for disease-driving roles of MUC1 and of endothelial cell and vascular changes in IPF.
SN  - 0903-1936
SN  - 1399-3003
ER  -