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

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, Julian C. Knight, Stuart Meacham, Jennifer Sambrook, Denis Seyres, Oliver Stegle, Jeffrey M. Verboon, Klaudia Walter, Nicholas A. Watkins, John Danesh, David J. Roberts, Emanuele Angelantonio, Vijay G. Sankaran, Mattia Frontini, Stephen Burgess, Taco Kuijpers, James E. Peters, Adam S. Butterworth (), Willem H. Ouwehand (), Nicole Soranzo () and William J. Astle ()
Additional contact information
Parsa Akbari: University of Cambridge
Dragana Vuckovic: The Wellcome Sanger Institute, Wellcome Genome Campus
Luca Stefanucci: University of Cambridge, Cambridge Biomedical Campus
Tao Jiang: University of Cambridge
Kousik Kundu: The Wellcome Sanger Institute, Wellcome Genome Campus
Roman Kreuzhuber: University of Cambridge, Cambridge Biomedical Campus
Erik L. Bao: Boston Children’s Hospital, Harvard Medical School
Janine H. Collins: University of Cambridge, Cambridge Biomedical Campus
Kate Downes: University of Cambridge, Cambridge Biomedical Campus
Luigi Grassi: University of Cambridge, Cambridge Biomedical Campus
Jose A. Guerrero: University of Cambridge, Cambridge Biomedical Campus
Stephen Kaptoge: University of Cambridge
Julian C. Knight: University of Oxford
Stuart Meacham: University of Cambridge, Cambridge Biomedical Campus
Jennifer Sambrook: University of Cambridge, Cambridge Biomedical Campus
Denis Seyres: University of Cambridge, Cambridge Biomedical Campus
Oliver Stegle: European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus
Jeffrey M. Verboon: Boston Children’s Hospital, Harvard Medical School
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
David J. Roberts: University of Cambridge
Emanuele Angelantonio: University of Cambridge
Vijay G. Sankaran: Boston Children’s Hospital, Harvard Medical School
Mattia Frontini: University of Cambridge, Cambridge Biomedical Campus
Stephen Burgess: University of Cambridge
Taco Kuijpers: Amsterdam University Medical Center
James E. Peters: Wellcome Genome Campus and University of Cambridge
Adam S. Butterworth: University of Cambridge
Willem H. Ouwehand: University of Cambridge, Cambridge Biomedical Campus
Nicole Soranzo: The Wellcome Sanger Institute, Wellcome Genome Campus
William J. Astle: Medical Research Council Biostatistics Unit, University of Cambridge, East Forvie Building, Cambridge Biomedical Campus, Forvie Site

Nature Communications, 2023, vol. 14, issue 1, 1-19

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-40679-y

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