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A genome-wide association study of blood cell morphology identifies cellular proteins implicated in disease aetiology

Author

Listed:
  • Parsa Akbari

    (University of Cambridge
    The Wellcome Sanger Institute, Wellcome Genome Campus
    Medical Research Council Biostatistics Unit, University of Cambridge, East Forvie Building, Cambridge Biomedical Campus, Forvie Site
    University of Cambridge)

  • Dragana Vuckovic

    (The Wellcome Sanger Institute, Wellcome Genome Campus
    University of Cambridge
    Imperial College London)

  • Luca Stefanucci

    (University of Cambridge, Cambridge Biomedical Campus
    National Health Service Blood and Transplant, Cambridge Centre, Cambridge Biomedical Campus
    University of Cambridge, Addenbrooke’s Hospital)

  • Tao Jiang

    (University of Cambridge
    University of Cambridge
    University of Cambridge)

  • Kousik Kundu

    (The Wellcome Sanger Institute, Wellcome Genome Campus
    University of Cambridge, Cambridge Biomedical Campus)

  • Roman Kreuzhuber

    (University of Cambridge, Cambridge Biomedical Campus)

  • Erik L. Bao

    (Boston Children’s Hospital, Harvard Medical School
    Dana-Farber Cancer Institute, Harvard Medical School
    Broad Institute of MIT and Harvard
    Harvard-MIT Health Sciences and Technology, Harvard Medical School)

  • Janine H. Collins

    (University of Cambridge, Cambridge Biomedical Campus
    National Health Service Blood and Transplant, Cambridge Centre, Cambridge Biomedical Campus
    Department of Haematology, Barts Health National Health Service Trust)

  • Kate Downes

    (University of Cambridge, Cambridge Biomedical Campus
    National Health Service Blood and Transplant, Cambridge Centre, Cambridge Biomedical Campus)

  • Luigi Grassi

    (University of Cambridge, Cambridge Biomedical Campus
    National Health Service Blood and Transplant, Cambridge Centre, Cambridge Biomedical Campus
    National Institute for Health and Care Research Cambridge BioResource, Box 229, Addenbrooke’s Hospital, Cambridge Biomedical Campus)

  • Jose A. Guerrero

    (University of Cambridge, Cambridge Biomedical Campus
    National Health Service Blood and Transplant, Cambridge Centre, Cambridge Biomedical Campus)

  • Stephen Kaptoge

    (University of Cambridge
    University of Cambridge
    University of Cambridge)

  • Julian C. Knight

    (University of Oxford)

  • Stuart Meacham

    (University of Cambridge, Cambridge Biomedical Campus
    European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus)

  • Jennifer Sambrook

    (University of Cambridge, Cambridge Biomedical Campus
    National Institute for Health and Care Research Cambridge BioResource, Box 229, Addenbrooke’s Hospital, Cambridge Biomedical Campus)

  • Denis Seyres

    (University of Cambridge, Cambridge Biomedical Campus
    National Health Service Blood and Transplant, Cambridge Centre, Cambridge Biomedical Campus
    National Institute for Health and Care Research Cambridge BioResource, Box 229, Addenbrooke’s Hospital, Cambridge Biomedical Campus)

  • Oliver Stegle

    (European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus
    European Molecular Biology Laboratory, Genome Biology Unit
    Division of Computational Genomics and Systems Genetics, German Cancer Research Center (DKFZ))

  • Jeffrey M. Verboon

    (Boston Children’s Hospital, Harvard Medical School
    Dana-Farber Cancer Institute, Harvard Medical School
    Broad Institute of MIT and Harvard)

  • Klaudia Walter

    (The Wellcome Sanger Institute, Wellcome Genome Campus)

  • Nicholas A. Watkins

    (National Health Service Blood and Transplant, Cambridge Centre, Cambridge Biomedical Campus)

  • John Danesh

    (University of Cambridge
    The Wellcome Sanger Institute, Wellcome Genome Campus
    University of Cambridge
    University of Cambridge, Addenbrooke’s Hospital)

  • David J. Roberts

    (University of Cambridge
    University of Oxford
    National Institute for Health Research Oxford Biomedical Research Centre—Haematology Theme, John Radcliffe Hospital
    National Health Service Blood and Transplant, Oxford Centre, John Radcliffe Hospital)

  • Emanuele Angelantonio

    (University of Cambridge
    University of Cambridge
    University of Cambridge, Addenbrooke’s Hospital
    University of Cambridge)

  • Vijay G. Sankaran

    (Boston Children’s Hospital, Harvard Medical School
    Dana-Farber Cancer Institute, Harvard Medical School
    Broad Institute of MIT and Harvard)

  • Mattia Frontini

    (University of Cambridge, Cambridge Biomedical Campus
    National Health Service Blood and Transplant, Cambridge Centre, Cambridge Biomedical Campus
    University of Exeter Medical School, Faculty of Health and Life Sciences, RILD Building)

  • Stephen Burgess

    (University of Cambridge
    Medical Research Council Biostatistics Unit, University of Cambridge, East Forvie Building, Cambridge Biomedical Campus, Forvie Site
    University of Cambridge)

  • Taco Kuijpers

    (Amsterdam University Medical Center
    University of Amsterdam)

  • James E. Peters

    (Wellcome Genome Campus and University of Cambridge
    The Hammersmith Hospital)

  • Adam S. Butterworth

    (University of Cambridge
    University of Cambridge
    University of Cambridge, Addenbrooke’s Hospital
    University of Cambridge)

  • Willem H. Ouwehand

    (University of Cambridge, Cambridge Biomedical Campus
    National Health Service Blood and Transplant, Cambridge Centre, Cambridge Biomedical Campus
    University College London Hospitals)

  • Nicole Soranzo

    (The Wellcome Sanger Institute, Wellcome Genome Campus
    University of Cambridge
    University of Cambridge, Cambridge Biomedical Campus
    University of Cambridge, Addenbrooke’s Hospital)

  • William J. Astle

    (Medical Research Council Biostatistics Unit, University of Cambridge, East Forvie Building, Cambridge Biomedical Campus, Forvie Site
    University of Cambridge
    National Health Service Blood and Transplant, Cambridge Centre, Cambridge Biomedical Campus)

Abstract

Blood cells contain functionally important intracellular structures, such as granules, critical to immunity and thrombosis. Quantitative variation in these structures has not been subjected previously to large-scale genetic analysis. We perform genome-wide association studies of 63 flow-cytometry derived cellular phenotypes—including cell-type specific measures of granularity, nucleic acid content and reactivity—in 41,515 participants in the INTERVAL study. We identify 2172 distinct variant-trait associations, including associations near genes coding for proteins in organelles implicated in inflammatory and thrombotic diseases. By integrating with epigenetic data we show that many intracellular structures are likely to be determined in immature precursor cells. By integrating with proteomic data we identify the transcription factor FOG2 as an early regulator of platelet formation and α-granularity. Finally, we show that colocalisation of our associations with disease risk signals can suggest aetiological cell-types—variants in IL2RA and ITGA4 respectively mirror the known effects of daclizumab in multiple sclerosis and vedolizumab in inflammatory bowel disease.

Suggested Citation

  • Parsa Akbari & Dragana Vuckovic & Luca Stefanucci & Tao Jiang & Kousik Kundu & Roman Kreuzhuber & Erik L. Bao & Janine H. Collins & Kate Downes & Luigi Grassi & Jose A. Guerrero & Stephen Kaptoge & Ju, 2023. "A genome-wide association study of blood cell morphology identifies cellular proteins implicated in disease aetiology," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-40679-y
    DOI: 10.1038/s41467-023-40679-y
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    References listed on IDEAS

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    1. Thomas Moreau & Amanda L. Evans & Louella Vasquez & Marloes R. Tijssen & Ying Yan & Matthew W. Trotter & Daniel Howard & Maria Colzani & Meera Arumugam & Wing Han Wu & Amanda Dalby & Riina Lampela & G, 2016. "Large-scale production of megakaryocytes from human pluripotent stem cells by chemically defined forward programming," Nature Communications, Nature, vol. 7(1), pages 1-16, September.
    2. B. Devlin & Kathryn Roeder, 1999. "Genomic Control for Association Studies," Biometrics, The International Biometric Society, vol. 55(4), pages 997-1004, December.
    3. Benjamin B. Sun & Joseph C. Maranville & James E. Peters & David Stacey & James R. Staley & James Blackshaw & Stephen Burgess & Tao Jiang & Ellie Paige & Praveen Surendran & Clare Oliver-Williams & Mi, 2018. "Genomic atlas of the human plasma proteome," Nature, Nature, vol. 558(7708), pages 73-79, June.
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    Cited by:

    1. Hannah Poisner & Annika Faucon & Nancy Cox & Alexander G. Bick, 2024. "Genetic determinants and phenotypic consequences of blood T-cell proportions in 207,000 diverse individuals," Nature Communications, Nature, vol. 15(1), pages 1-12, December.

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