Nature Communications (Aug 2023)
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 Di Angelantonio,
- Vijay G. Sankaran,
- Mattia Frontini,
- Stephen Burgess,
- Taco Kuijpers,
- James E. Peters,
- Adam S. Butterworth,
- Willem H. Ouwehand,
- Nicole Soranzo,
- William J. Astle
Affiliations
- Parsa Akbari
- British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, Strangeways Research Laboratory, University of Cambridge
- Dragana Vuckovic
- Department of Human Genetics, The Wellcome Sanger Institute, Wellcome Genome Campus
- Luca Stefanucci
- Department of Haematology, University of Cambridge, Cambridge Biomedical Campus
- Tao Jiang
- British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, Strangeways Research Laboratory, University of Cambridge
- Kousik Kundu
- Department of Human Genetics, The Wellcome Sanger Institute, Wellcome Genome Campus
- Roman Kreuzhuber
- Department of Haematology, University of Cambridge, Cambridge Biomedical Campus
- Erik L. Bao
- Division of Hematology/Oncology, Boston Children’s Hospital, Harvard Medical School
- Janine H. Collins
- Department of Haematology, University of Cambridge, Cambridge Biomedical Campus
- Kate Downes
- Department of Haematology, University of Cambridge, Cambridge Biomedical Campus
- Luigi Grassi
- Department of Haematology, University of Cambridge, Cambridge Biomedical Campus
- Jose A. Guerrero
- Department of Haematology, University of Cambridge, Cambridge Biomedical Campus
- Stephen Kaptoge
- British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, Strangeways Research Laboratory, University of Cambridge
- Julian C. Knight
- Wellcome Centre for Human Genetics, University of Oxford
- Stuart Meacham
- Department of Haematology, University of Cambridge, Cambridge Biomedical Campus
- Jennifer Sambrook
- Department of Haematology, University of Cambridge, Cambridge Biomedical Campus
- Denis Seyres
- Department of Haematology, University of Cambridge, Cambridge Biomedical Campus
- Oliver Stegle
- European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus
- Jeffrey M. Verboon
- Division of Hematology/Oncology, Boston Children’s Hospital, Harvard Medical School
- Klaudia Walter
- Department of Human Genetics, The Wellcome Sanger Institute, Wellcome Genome Campus
- Nicholas A. Watkins
- National Health Service Blood and Transplant, Cambridge Centre, Cambridge Biomedical Campus
- John Danesh
- British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, Strangeways Research Laboratory, University of Cambridge
- David J. Roberts
- The National Institute for Health and Care Research Blood and Transplant Unit in Donor Health and Genomics, Strangeways Research Laboratory, Strangeways Research Laboratory, University of Cambridge
- Emanuele Di Angelantonio
- British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, Strangeways Research Laboratory, University of Cambridge
- Vijay G. Sankaran
- Division of Hematology/Oncology, Boston Children’s Hospital, Harvard Medical School
- Mattia Frontini
- Department of Haematology, University of Cambridge, Cambridge Biomedical Campus
- Stephen Burgess
- British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, Strangeways Research Laboratory, University of Cambridge
- Taco Kuijpers
- Department of Pediatric Immunology, Rheumatology and Infectious Disease, Emma Children’s Hospital, Amsterdam University Medical Center
- James E. Peters
- Health Data Research UK Cambridge, Wellcome Genome Campus and University of Cambridge
- Adam S. Butterworth
- British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, Strangeways Research Laboratory, University of Cambridge
- Willem H. Ouwehand
- Department of Haematology, University of Cambridge, Cambridge Biomedical Campus
- Nicole Soranzo
- Department of Human Genetics, 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
- DOI
- https://doi.org/10.1038/s41467-023-40679-y
- Journal volume & issue
-
Vol. 14,
no. 1
pp. 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.
