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.

The authors identify genetic variation associated with properties of the internal biological structures of blood cells in hundreds of genes and show how such discoveries can be used to improve understanding of cellular mechanisms causing disease.

Details

Title
A genome-wide association study of blood cell morphology identifies cellular proteins implicated in disease aetiology
Author
Akbari, Parsa 1   VIAFID ORCID Logo  ; Vuckovic, Dragana 2 ; Stefanucci, Luca 3   VIAFID ORCID Logo  ; Jiang, Tao 4 ; Kundu, Kousik 5   VIAFID ORCID Logo  ; Kreuzhuber, Roman 6   VIAFID ORCID Logo  ; Bao, Erik L. 7   VIAFID ORCID Logo  ; Collins, Janine H. 8   VIAFID ORCID Logo  ; Downes, Kate 9 ; Grassi, Luigi 10   VIAFID ORCID Logo  ; Guerrero, Jose A. 9   VIAFID ORCID Logo  ; Kaptoge, Stephen 4 ; Knight, Julian C. 11   VIAFID ORCID Logo  ; Meacham, Stuart 12   VIAFID ORCID Logo  ; Sambrook, Jennifer 13 ; Seyres, Denis 10 ; Stegle, Oliver 14 ; Verboon, Jeffrey M. 15 ; Walter, Klaudia 16   VIAFID ORCID Logo  ; Watkins, Nicholas A. 17 ; Danesh, John 18 ; Roberts, David J. 19 ; Di Angelantonio, Emanuele 20 ; Sankaran, Vijay G. 15   VIAFID ORCID Logo  ; Frontini, Mattia 21   VIAFID ORCID Logo  ; Burgess, Stephen 22   VIAFID ORCID Logo  ; Kuijpers, Taco 23 ; Peters, James E. 24   VIAFID ORCID Logo  ; Butterworth, Adam S. 25   VIAFID ORCID Logo  ; Ouwehand, Willem H. 26   VIAFID ORCID Logo  ; Soranzo, Nicole 27   VIAFID ORCID Logo  ; Astle, William J. 28   VIAFID ORCID Logo 

1  University of Cambridge, British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, Strangeways Research Laboratory, Cambridge, UK (GRID:grid.5335.0) (ISNI:0000 0001 2188 5934); The Wellcome Sanger Institute, Wellcome Genome Campus, Department of Human Genetics, Hinxton, UK (GRID:grid.10306.34) (ISNI:0000 0004 0606 5382); Medical Research Council Biostatistics Unit, University of Cambridge, East Forvie Building, Cambridge Biomedical Campus, Forvie Site, Cambridge, UK (GRID:grid.5335.0) (ISNI:0000 0001 2188 5934); University of Cambridge, The National Institute for Health and Care Research Blood and Transplant Unit in Donor Health and Genomics, Strangeways Research Laboratory, Strangeways Research Laboratory, Cambridge, UK (GRID:grid.5335.0) (ISNI:0000 0001 2188 5934) 
2  The Wellcome Sanger Institute, Wellcome Genome Campus, Department of Human Genetics, Hinxton, UK (GRID:grid.10306.34) (ISNI:0000 0004 0606 5382); University of Cambridge, The National Institute for Health and Care Research Blood and Transplant Unit in Donor Health and Genomics, Strangeways Research Laboratory, Strangeways Research Laboratory, Cambridge, UK (GRID:grid.5335.0) (ISNI:0000 0001 2188 5934); Imperial College London, Department of Epidemiology and Biostatistics, School of Public Health, London, UK (GRID:grid.7445.2) (ISNI:0000 0001 2113 8111) 
3  University of Cambridge, Cambridge Biomedical Campus, Department of Haematology, Cambridge, UK (GRID:grid.5335.0) (ISNI:0000 0001 2188 5934); National Health Service Blood and Transplant, Cambridge Centre, Cambridge Biomedical Campus, Cambridge, UK (GRID:grid.436365.1) (ISNI:0000 0000 8685 6563); University of Cambridge, Addenbrooke’s Hospital, British Heart Foundation Centre of Research Excellence, Cambridge, UK (GRID:grid.5335.0) (ISNI:0000000121885934) 
4  University of Cambridge, British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, Strangeways Research Laboratory, Cambridge, UK (GRID:grid.5335.0) (ISNI:0000 0001 2188 5934); University of Cambridge, The National Institute for Health and Care Research Blood and Transplant Unit in Donor Health and Genomics, Strangeways Research Laboratory, Strangeways Research Laboratory, Cambridge, UK (GRID:grid.5335.0) (ISNI:0000 0001 2188 5934); University of Cambridge, Victor Phillip Dahdaleh Heart and Lung Research Institute, Cambridge, UK (GRID:grid.5335.0) (ISNI:0000 0001 2188 5934) 
5  The Wellcome Sanger Institute, Wellcome Genome Campus, Department of Human Genetics, Hinxton, UK (GRID:grid.10306.34) (ISNI:0000 0004 0606 5382); University of Cambridge, Cambridge Biomedical Campus, Department of Haematology, Cambridge, UK (GRID:grid.5335.0) (ISNI:0000 0001 2188 5934) 
6  University of Cambridge, Cambridge Biomedical Campus, Department of Haematology, Cambridge, UK (GRID:grid.5335.0) (ISNI:0000 0001 2188 5934) 
7  Boston Children’s Hospital, Harvard Medical School, Division of Hematology/Oncology, Boston, USA (GRID:grid.38142.3c) (ISNI:000000041936754X); Dana-Farber Cancer Institute, Harvard Medical School, Department of Pediatric Oncology, Boston, USA (GRID:grid.38142.3c) (ISNI:000000041936754X); Broad Institute of MIT and Harvard, Cambridge, USA (GRID:grid.66859.34); Harvard-MIT Health Sciences and Technology, Harvard Medical School, Cambridge, USA (GRID:grid.38142.3c) (ISNI:000000041936754X) 
8  University of Cambridge, Cambridge Biomedical Campus, Department of Haematology, Cambridge, UK (GRID:grid.5335.0) (ISNI:0000 0001 2188 5934); National Health Service Blood and Transplant, Cambridge Centre, Cambridge Biomedical Campus, Cambridge, UK (GRID:grid.436365.1) (ISNI:0000 0000 8685 6563); Department of Haematology, Barts Health National Health Service Trust, London, UK (GRID:grid.436365.1) 
9  University of Cambridge, Cambridge Biomedical Campus, Department of Haematology, Cambridge, UK (GRID:grid.5335.0) (ISNI:0000 0001 2188 5934); National Health Service Blood and Transplant, Cambridge Centre, Cambridge Biomedical Campus, Cambridge, UK (GRID:grid.436365.1) (ISNI:0000 0000 8685 6563) 
10  University of Cambridge, Cambridge Biomedical Campus, Department of Haematology, Cambridge, UK (GRID:grid.5335.0) (ISNI:0000 0001 2188 5934); National Health Service Blood and Transplant, Cambridge Centre, Cambridge Biomedical Campus, Cambridge, UK (GRID:grid.436365.1) (ISNI:0000 0000 8685 6563); National Institute for Health and Care Research Cambridge BioResource, Box 229, Addenbrooke’s Hospital, Cambridge Biomedical Campus, Cambridge, UK (GRID:grid.120073.7) (ISNI:0000 0004 0622 5016) 
11  University of Oxford, Wellcome Centre for Human Genetics, Oxford, UK (GRID:grid.4991.5) (ISNI:0000 0004 1936 8948) 
12  University of Cambridge, Cambridge Biomedical Campus, Department of Haematology, Cambridge, UK (GRID:grid.5335.0) (ISNI:0000 0001 2188 5934); European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, UK (GRID:grid.225360.0) (ISNI:0000 0000 9709 7726) 
13  University of Cambridge, Cambridge Biomedical Campus, Department of Haematology, Cambridge, UK (GRID:grid.5335.0) (ISNI:0000 0001 2188 5934); National Institute for Health and Care Research Cambridge BioResource, Box 229, Addenbrooke’s Hospital, Cambridge Biomedical Campus, Cambridge, UK (GRID:grid.120073.7) (ISNI:0000 0004 0622 5016) 
14  European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, UK (GRID:grid.225360.0) (ISNI:0000 0000 9709 7726); European Molecular Biology Laboratory, Genome Biology Unit, Heidelberg, Germany (GRID:grid.4709.a) (ISNI:0000 0004 0495 846X); Division of Computational Genomics and Systems Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany (GRID:grid.7497.d) (ISNI:0000 0004 0492 0584) 
15  Boston Children’s Hospital, Harvard Medical School, Division of Hematology/Oncology, Boston, USA (GRID:grid.38142.3c) (ISNI:000000041936754X); Dana-Farber Cancer Institute, Harvard Medical School, Department of Pediatric Oncology, Boston, USA (GRID:grid.38142.3c) (ISNI:000000041936754X); Broad Institute of MIT and Harvard, Cambridge, USA (GRID:grid.66859.34) 
16  The Wellcome Sanger Institute, Wellcome Genome Campus, Department of Human Genetics, Hinxton, UK (GRID:grid.10306.34) (ISNI:0000 0004 0606 5382) 
17  National Health Service Blood and Transplant, Cambridge Centre, Cambridge Biomedical Campus, Cambridge, UK (GRID:grid.436365.1) (ISNI:0000 0000 8685 6563) 
18  University of Cambridge, British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, Strangeways Research Laboratory, Cambridge, UK (GRID:grid.5335.0) (ISNI:0000 0001 2188 5934); The Wellcome Sanger Institute, Wellcome Genome Campus, Department of Human Genetics, Hinxton, UK (GRID:grid.10306.34) (ISNI:0000 0004 0606 5382); University of Cambridge, The National Institute for Health and Care Research Blood and Transplant Unit in Donor Health and Genomics, Strangeways Research Laboratory, Strangeways Research Laboratory, Cambridge, UK (GRID:grid.5335.0) (ISNI:0000 0001 2188 5934); University of Cambridge, Addenbrooke’s Hospital, British Heart Foundation Centre of Research Excellence, Cambridge, UK (GRID:grid.5335.0) (ISNI:0000000121885934); University of Cambridge, Victor Phillip Dahdaleh Heart and Lung Research Institute, Cambridge, UK (GRID:grid.5335.0) (ISNI:0000 0001 2188 5934); Wellcome Genome Campus and University of Cambridge, Health Data Research UK Cambridge, Cambridge, UK (GRID:grid.5335.0) (ISNI:0000 0001 2188 5934) 
19  University of Cambridge, The National Institute for Health and Care Research Blood and Transplant Unit in Donor Health and Genomics, Strangeways Research Laboratory, Strangeways Research Laboratory, Cambridge, UK (GRID:grid.5335.0) (ISNI:0000 0001 2188 5934); University of Oxford, Nuffield Division of Clinical Laboratory Sciences, Radcliffe Department of Medicine, Headington, UK (GRID:grid.4991.5) (ISNI:0000 0004 1936 8948); National Institute for Health Research Oxford Biomedical Research Centre—Haematology Theme, John Radcliffe Hospital, Headington, UK (GRID:grid.8348.7) (ISNI:0000 0001 2306 7492); National Health Service Blood and Transplant, Oxford Centre, John Radcliffe Hospital, Headington, UK (GRID:grid.8348.7) (ISNI:0000 0001 2306 7492) 
20  University of Cambridge, British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, Strangeways Research Laboratory, Cambridge, UK (GRID:grid.5335.0) (ISNI:0000 0001 2188 5934); University of Cambridge, The National Institute for Health and Care Research Blood and Transplant Unit in Donor Health and Genomics, Strangeways Research Laboratory, Strangeways Research Laboratory, Cambridge, UK (GRID:grid.5335.0) (ISNI:0000 0001 2188 5934); University of Cambridge, Addenbrooke’s Hospital, British Heart Foundation Centre of Research Excellence, Cambridge, UK (GRID:grid.5335.0) (ISNI:0000000121885934); University of Cambridge, Victor Phillip Dahdaleh Heart and Lung Research Institute, Cambridge, UK (GRID:grid.5335.0) (ISNI:0000 0001 2188 5934); Fondazione Human Technopole, Health Data Science Research Centre, Milan, Italy (GRID:grid.510779.d) (ISNI:0000 0004 9414 6915) 
21  University of Cambridge, Cambridge Biomedical Campus, Department of Haematology, Cambridge, UK (GRID:grid.5335.0) (ISNI:0000 0001 2188 5934); National Health Service Blood and Transplant, Cambridge Centre, Cambridge Biomedical Campus, Cambridge, UK (GRID:grid.436365.1) (ISNI:0000 0000 8685 6563); University of Exeter Medical School, Faculty of Health and Life Sciences, RILD Building, Department of Clinical and Biomedical Sciences, Exeter, UK (GRID:grid.8391.3) (ISNI:0000 0004 1936 8024) 
22  University of Cambridge, British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, Strangeways Research Laboratory, Cambridge, UK (GRID:grid.5335.0) (ISNI:0000 0001 2188 5934); Medical Research Council Biostatistics Unit, University of Cambridge, East Forvie Building, Cambridge Biomedical Campus, Forvie Site, Cambridge, UK (GRID:grid.5335.0) (ISNI:0000 0001 2188 5934); University of Cambridge, Victor Phillip Dahdaleh Heart and Lung Research Institute, Cambridge, UK (GRID:grid.5335.0) (ISNI:0000 0001 2188 5934) 
23  Amsterdam University Medical Center, Department of Pediatric Immunology, Rheumatology and Infectious Disease, Emma Children’s Hospital, Amsterdam, UK (GRID:grid.5335.0); University of Amsterdam, Department of Blood Cell Research, Sanquin Research and Landsteiner Laboratory, Sanquin, Amsterdam, Netherlands (GRID:grid.7177.6) (ISNI:0000000084992262) 
24  Wellcome Genome Campus and University of Cambridge, Health Data Research UK Cambridge, Cambridge, UK (GRID:grid.5335.0) (ISNI:0000 0001 2188 5934); The Hammersmith Hospital, Department of Immunology and Inflammation, Imperial College London, Commonwealth Building, London, UK (GRID:grid.413629.b) (ISNI:0000 0001 0705 4923) 
25  University of Cambridge, British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, Strangeways Research Laboratory, Cambridge, UK (GRID:grid.5335.0) (ISNI:0000 0001 2188 5934); University of Cambridge, The National Institute for Health and Care Research Blood and Transplant Unit in Donor Health and Genomics, Strangeways Research Laboratory, Strangeways Research Laboratory, Cambridge, UK (GRID:grid.5335.0) (ISNI:0000 0001 2188 5934); University of Cambridge, Addenbrooke’s Hospital, British Heart Foundation Centre of Research Excellence, Cambridge, UK (GRID:grid.5335.0) (ISNI:0000000121885934); University of Cambridge, Victor Phillip Dahdaleh Heart and Lung Research Institute, Cambridge, UK (GRID:grid.5335.0) (ISNI:0000 0001 2188 5934); Wellcome Genome Campus and University of Cambridge, Health Data Research UK Cambridge, Cambridge, UK (GRID:grid.5335.0) (ISNI:0000 0001 2188 5934) 
26  University of Cambridge, Cambridge Biomedical Campus, Department of Haematology, Cambridge, UK (GRID:grid.5335.0) (ISNI:0000 0001 2188 5934); National Health Service Blood and Transplant, Cambridge Centre, Cambridge Biomedical Campus, Cambridge, UK (GRID:grid.436365.1) (ISNI:0000 0000 8685 6563); University College London Hospitals, Department of Haematology, London, UK (GRID:grid.439749.4) (ISNI:0000 0004 0612 2754) 
27  The Wellcome Sanger Institute, Wellcome Genome Campus, Department of Human Genetics, Hinxton, UK (GRID:grid.10306.34) (ISNI:0000 0004 0606 5382); University of Cambridge, The National Institute for Health and Care Research Blood and Transplant Unit in Donor Health and Genomics, Strangeways Research Laboratory, Strangeways Research Laboratory, Cambridge, UK (GRID:grid.5335.0) (ISNI:0000 0001 2188 5934); University of Cambridge, Cambridge Biomedical Campus, Department of Haematology, Cambridge, UK (GRID:grid.5335.0) (ISNI:0000 0001 2188 5934); University of Cambridge, Addenbrooke’s Hospital, British Heart Foundation Centre of Research Excellence, Cambridge, UK (GRID:grid.5335.0) (ISNI:0000000121885934); Fondazione Human Technopole, Genomics Research Centre, Milan, Italy (GRID:grid.510779.d) (ISNI:0000 0004 9414 6915) 
28  Medical Research Council Biostatistics Unit, University of Cambridge, East Forvie Building, Cambridge Biomedical Campus, Forvie Site, Cambridge, UK (GRID:grid.5335.0) (ISNI:0000 0001 2188 5934); University of Cambridge, The National Institute for Health and Care Research Blood and Transplant Unit in Donor Health and Genomics, Strangeways Research Laboratory, Strangeways Research Laboratory, Cambridge, UK (GRID:grid.5335.0) (ISNI:0000 0001 2188 5934); National Health Service Blood and Transplant, Cambridge Centre, Cambridge Biomedical Campus, Cambridge, UK (GRID:grid.436365.1) (ISNI:0000 0000 8685 6563) 
Pages
5023
Publication year
2023
Publication date
2023
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41467-023-40679-y
ProQuest document ID
2852874220
Copyright
© The Author(s) 2023. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.