{
  "abstract": "Background Pulmonary fibrosis (PF) is a rare lung disease with diverse pathogenesis and biological mechanisms. Mosaic loss of chromosome Y (mLOY) has been reported to be associated with increased risk of fibrotic diseases. However, the exact role of mLOY in the development of PF remains to be elucidated.Methods Copy number on chromosome Y was used to estimate mLOY comparing patients in PROFILE and gnomAD cohorts and between cases and control patients from the GE100KGP cohort. Correlation of mLOY with demographic and clinical variables was tested using patients from the PROFILE cohort. Lung single-cell transcriptomic data were analysed to assess the cell types implicated in mLOY. Mendelian randomisation was performed to examine the causal relationship between mLOY, idiopathic pulmonary fibrosis (IPF) and telomere length.Results The genetic analysis suggests that mLOY is found in PF from both case cohorts but when compared with an age matched population the effect is minimal (p=0.00316, median: 0.288 vs 0.291). mLOY is related to age (p=0.000214) and shorter telomere length (p=0.00815) rather than PF severity or progression. Single-cell analysis indicates that mLOY appears to be found primarily in immune cells. Mendelian randomisation demonstrates that mLOY is not on the causal pathway for IPF, but partial evidence supports that telomere shortening is on the causal pathway for mLOY.Conclusions Our study confirms the existence of mLOY in PF patients, suggests that mLOY is not a major driver of IPF, and might support a triangulation model where telomere shortening leads to both IPF and mLOY.",
  "authors": [
    {
      "affiliations": [
        "National Heart and Lung Institute, Imperial College London, London, UK",
        "Shandong Key Laboratory of Intelligent Oil & Gas Industrial Software, Qingdao Institute of Software, College of Computer Science and Technology, China University of Petroleum (East China), Qingdao, China"
      ],
      "name": "Dapeng Wang"
    },
    {
      "affiliations": [
        "Translational Genomics Research Institute, Phoenix, Arizona, USA"
      ],
      "name": "Niran Hadad"
    },
    {
      "affiliations": [
        "National Heart and Lung Institute, Imperial College London, London, UK"
      ],
      "name": "Samuel Moss"
    },
    {
      "affiliations": [
        "National Heart and Lung Institute, Imperial College London, London, UK"
      ],
      "name": "Elena Lopez-Jimenez"
    },
    {
      "affiliations": [
        "Centre for Respiratory Research, NIHR Biomedical Research Centre and Biodiscovery Institute, Translational Medical Sciences, University of Nottingham, Nottingham, UK"
      ],
      "name": "Simon R Johnson"
    },
    {
      "affiliations": [
        "National Heart and Lung Institute, Imperial College London, London, UK",
        "Keck Medicine of University of Southern California, Los Angeles, California, USA"
      ],
      "name": "Toby M Maher"
    },
    {
      "affiliations": [
        "National Heart and Lung Institute, Imperial College London, London, UK"
      ],
      "name": "Philip L Molyneaux"
    },
    {
      "affiliations": [
        "MRC Epidemiology Unit, Wellcome-MRC Institute of Metabolic Science, University of Cambridge School of Clinical Medicine, Cambridge, UK"
      ],
      "name": "Yajie Zhao"
    },
    {
      "affiliations": [
        "MRC Epidemiology Unit, Wellcome-MRC Institute of Metabolic Science, University of Cambridge School of Clinical Medicine, Cambridge, UK"
      ],
      "name": "John R B Perry"
    },
    {
      "affiliations": [
        "Department of Medicine, University of California, San Francisco, California, USA"
      ],
      "name": "Paul J Wolters"
    },
    {
      "affiliations": [
        "Division of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA",
        "Department of Cell and Developmental Biology, Vanderbilt University, Nashville, Tennessee, USA",
        "Department of Veterans Affairs Medical Center, Nashville, Tennessee, USA"
      ],
      "name": "Jonathan A Kropski"
    },
    {
      "affiliations": [
        "National Heart and Lung Institute, Imperial College London, London, UK"
      ],
      "name": "R Gisli Jenkins"
    },
    {
      "affiliations": [
        "Translational Genomics Research Institute, Phoenix, Arizona, USA"
      ],
      "name": "Nicholas E Banovich"
    },
    {
      "affiliations": [
        "National Heart and Lung Institute, Imperial College London, London, UK"
      ],
      "name": "Iain Stewart"
    }
  ],
  "title": "Assessment of mosaic loss of chromosome Y in pulmonary fibrosis reveals limited association with susceptibility or disease severity",
  "uid": "ddd09aff-dc7c-572b-86a5-740d5264a16c"
}