Article Text

other Versions

Download PDFPDF
Genome-wide association study across five cohorts identifies five novel loci associated with idiopathic pulmonary fibrosis
  1. Richard J Allen1,
  2. Amy Stockwell2,
  3. Justin M Oldham3,
  4. Beatriz Guillen-Guio1,
  5. David A Schwartz4,5,6,
  6. Toby M Maher7,8,9,
  7. Carlos Flores10,11,12,
  8. Imre Noth13,
  9. Brian L Yaspan2,
  10. R Gisli Jenkins7,
  11. Louise V Wain1,14
  12. International IPF Genetics Consortium
    1. 1Department of Health Sciences, University of Leicester, Leicester, UK
    2. 2Genentech Inc, South San Francisco, California, USA
    3. 3Department of Internal Medicine, University of California Davis, Davis, California, USA
    4. 4Center for Genes, Environment and Health, National Jewish Health, Denver, Colorado, USA
    5. 5Department of Medicine, University of Colorado Denver, Denver, Colorado, USA
    6. 6Department of Immunology, University of Colorado Denver, Denver, Colorado, USA
    7. 7National Heart and Lung Institute, Imperial College, London, UK
    8. 8Royal Brompton and Harefield Hospitals, London, UK
    9. 9Division of Pulmonary and Critical Care Medicine, University of Southern California, Los Angeles, California, USA
    10. 10CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain
    11. 11Genomics Division, Instituto Tecnológico y de Energías Renovables SA, Santa Cruz de Tenerife, Spain
    12. 12Research Unit, Hospital Universitario Nuestra Señora de la Candelaria, Santa Cruz de Tenerife, Spain
    13. 13Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, Virginia, USA
    14. 14National Institute for Health Research Leicester Biomedical Research Centre, Leicester, UK
    1. Correspondence to Dr Richard J Allen, Department of Health Sciences, University of Leicester, Leicester LE1 7RH, Leicestershire, UK; rja34{at}leicester.ac.uk

    Abstract

    Idiopathic pulmonary fibrosis (IPF) is a chronic lung condition with poor survival times. We previously published a genome-wide meta-analysis of IPF risk across three studies with independent replication of associated variants in two additional studies. To maximise power and to generate more accurate effect size estimates, we performed a genome-wide meta-analysis across all five studies included in the previous IPF risk genome-wide association studies. We used the distribution of effect sizes across the five studies to assess the replicability of the results and identified five robust novel genetic association signals implicating mTOR (mammalian target of rapamycin) signalling, telomere maintenance and spindle assembly genes in IPF risk.

    • Idiopathic pulmonary fibrosis

    Statistics from Altmetric.com

    Request Permissions

    If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.

    Footnotes

    • Twitter @rjallen513, @LabCflores

    • Collaborators International IPF Genetics Consortium: Ayodeji Adegunsoye (Section of Pulmonary and Critical Care Medicine, University of Chicago, Chicago, Illinois, USA), Richard J Allen (Department of Health Sciences, University of Leicester, Leicester, UK), Helen L Booth (Department of Thoracic Medicine, University College London, London, UK), William A Fahy (Discovery Medicine, GlaxoSmithKline, Stevenage, UK), Tasha E Fingerlin (Center for Genes, Environment and Health, National Jewish Health, Denver, Colorado, USA ; Department of Biostatistics and Informatics, University of Colorado Denver, Denver, Colorado, USA), Carlos Flores (Research Unit, Hospital Universitario Ntra. Sra. de Candelaria, Santa Cruz de Tenerife, Spain ; CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain ; Genomics Division, Instituto Tecnológico y de Energías Renovables (ITER), Santa Cruz de Tenerife, Spain), Beatriz Guillen-Guio (Department of Health Sciences, University of Leicester, Leicester, UK), Ian P Hall (National Institute for Health Research, Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust, Nottingham, UK ; Division of Respiratory Medicine, University of Nottingham, Nottingham, UK), Simon P Hart (Respiratory Research Group, Hull York Medical School, Castle Hill Hospital, Cottingham, UK), Mike R Hill (Clinical Trial Service Unit & Epidemiological Studies Unit (CTSU), Nuffield Department of Population Health, University of Oxford, Oxford, UK), Nik Hirani (Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK), Richard B Hubbard (National Institute for Health Research, Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust, Nottingham, UK; Division of Epidemiology and Public Health, University of Nottingham, Nottingham, UK), R Gisli Jenkins (National Heart and Lung Institute, Imperial College, London, UK), Naftali Kaminski (Section of Pulmonary, Critical Care and Sleep Medicine, Yale School of Medicine, New Haven, Connecticut, USA), Shwu-Fan Ma (Division of Pulmonary & Critical Care Medicine, University of Virginia, Charlottesville, Virginia, USA), Toby M Maher (National Heart and Lung Institute, Imperial College, London, UK; Royal Brompton and Harefield Hospitals, London, UK; Division of Pulmonary and Critical Care Medicine, University of Southern California, Los Angeles, California, USA), Robin J McAnulty (UCL Respiratory Centre for Inflammation and Tissue Repair, University College London, London, UK), Ann B Millar (Academic Respiratory Unit, School of Clinical Sciences, University of Bristol, Bristol, UK), Maria Molina-Molina (CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain; Servei de Pneumologia, Laboratori de Pneumologia Experimental, IDIBELL, Barcelona, Spain; Campus de Bellvitge, Universitat de Barcelona, Barcelona, Spain), Philip L Molyneaux (National Heart and Lung Institute, Imperial College, London, UK; Royal Brompton and Harefield Hospitals, London, UK), Vidya Navaratnam (National Institute for Health Research, Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust, Nottingham, UK; Division of Epidemiology and Public Health, University of Nottingham, Nottingham, UK; Queensland Lung Transplant Service, The Prince Charles Hospital, Brisbane, Queensland, Australia), Margaret Neighbors (Genentech Inc, South San Francisco, California, USA), Imre Noth (Division of Pulmonary & Critical Care Medicine, University of Virginia, Charlottesville, Virginia, USA), Eunice Oballa (Discovery Medicine, GlaxoSmithKline, Stevenage, UK), Justin M Oldham (Department of Internal Medicine, University of California Davis, Davis, California, USA), Helen Parfrey (Cambridge ILD Service, Royal Papworth Hospital, Cambridge, UK), Gauri Saini (Respiratory Medicine, Nottingham University Hospitals Trust, Nottingham, UK), Ian Sayers (National Institute for Health Research, Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust, Nottingham, UK; Division of Respiratory Medicine, University of Nottingham, Nottingham, UK), David A Schwartz (Center for Genes, Environment and Health, National Jewish Health, Denver, Colorado, USA; Department of Medicine, University of Colorado Denver, Denver, Colorado, USA; Department of Immunology, University of Colorado Denver, Denver, Colorado, USA), Xuting Sheng (Genentech Inc, South San Francisco, California, USA), Amy Stockwell (Genentech Inc, South San Francisco, California, USA), Mary E Strek (Section of Pulmonary and Critical Care Medicine, University of Chicago, Chicago, Illinois, USA), Martin D Tobin (Department of Health Sciences, University of Leicester, Leicester, UK), Louise V Wain (Department of Health Sciences, University of Leicester, Leicester, UK; National Institute for Health Research, Leicester Respiratory Biomedical Research Centre, Leicester, UK), Moira K B Whyte (Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK), Brian L Yaspan (Genentech Inc, South San Francisco, California, USA), Yingze Zhang (Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA).

    • Contributors RJA, AS and BG-G performed the analyses. JMO, CF, IN, BLY, RGJ, LVW, HLB, WAF, IPH, SPH, MRH, NH, RBH, TMM, RJM, ABM, PLM, VN, EO, HP, GS, IS, MDT, MKBW, AA, NK, S-FM, MES, YZ, TEF, DAS, MM-M, MN and XS recruited individuals and performed genotyping/sequencing. LVW and RGJ supervised the study. RJA, RGJ, LVW, AS, JMO, BG-G, DAS, TMM, CF, IN and BLY wrote the manuscript. All authors approved the final version.

    • Funding RJA is an Action for Pulmonary Fibrosis Mike Bray Research Fellow. LW holds a GSK/Asthma+Lung UK Chair in Respiratory Research (C17-1). This work was supported by the Medical Research Council Programme (grant number MR/V00235X/1); the National Institute of Health/National Heart, Lung and Blood Institute (grant numbers R56HL158935 and K23HL138190, JMO); Wellcome Trust (grant number 221680/Z/20/Z, BG-G). For the purpose of open access, the author applied a CC BY public copyright licence to any author accepted manuscript version arising from this submission. 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, the NIHR or the Department of Health. The UK and USA, UK and Spain studies selected controls from UK Biobank under application 8389. This research used the SPECTRE High Performance Computing Facility at the University of Leicester.

    • Competing interests AS and BLY are employees of Genentech/Roche and hold stock and stock options in Roche. JMO reports personal fees from Boehringer Ingelheim, Genentech, United Therapeutics, AmMax Bio and Lupin Pharmaceuticals unrelated to the submitted work. RGJ is a trustee of Action for Pulmonary Fibrosis and reports personal fees from Astra Zeneca, Biogen, Boehringer Ingelheim, Bristol Myers Squibb, Chiesi, Daewoong, Galapagos, Galecto, GlaxoSmithKline, Heptares, NuMedii, PatientMPower, Pliant, Promedior, Redx, Resolution Therapeutics, Roche, Veracyte and Vicore. DAS is the founder and chief scientific officer of Eleven P15, a company focused on the early detection and treatment of pulmonary fibrosis. LW reports research funding from GlaxoSmithKline and Orion Pharma, and consultancy for Galapagos (all outside of the submitted work).

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.