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

Genome-Wide Association Study Proteomics Microscopy Transcription Factors Causality

Journal

Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555

Informations de publication

Date de publication:
18 08 2023
Historique:
received: 19 07 2021
accepted: 07 08 2023
medline: 21 8 2023
pubmed: 19 8 2023
entrez: 18 8 2023
Statut: epublish

Résumé

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.

Identifiants

DOI: 10.1038/s41467-023-40679-y PMID: 37596262 PMC: PMC10439125
pubmed: 37596262
doi: 10.1038/s41467-023-40679-y
pii: 10.1038/s41467-023-40679-y
pmc: PMC10439125
doi:

Substances chimiques

Transcription Factors 0

Types de publication

Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

5023

Subventions

Organisme : Medical Research Council
ID : MR/L003120/1
Pays : United Kingdom
Organisme : British Heart Foundation
Pays : United Kingdom

Informations de copyright

© 2023. Springer Nature Limited.

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Auteurs

Parsa Akbari (P)

British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, Strangeways Research Laboratory, University of Cambridge, Wort's Causeway, Cambridge, CB1 8RN, UK.
Department of Human Genetics, The Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, CB10 1HH, UK.
Medical Research Council Biostatistics Unit, University of Cambridge, East Forvie Building, Cambridge Biomedical Campus, Forvie Site, Robinson Way, Cambridge, CB2 0SR, UK.
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, Wort's Causeway, Cambridge, CB1 8RN, UK.
ORCID: 0000-0001-9210-4760

Dragana Vuckovic (D)

Department of Human Genetics, The Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, CB10 1HH, UK.
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, Wort's Causeway, Cambridge, CB1 8RN, UK.
Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK.

Luca Stefanucci (L)

Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Long Road, Cambridge, CB2 0PT, UK.
National Health Service Blood and Transplant, Cambridge Centre, Cambridge Biomedical Campus, Long Road, Cambridge, CB2 0PT, UK.
British Heart Foundation Centre of Research Excellence, University of Cambridge, Addenbrooke's Hospital, Cambridge Biomedical Campus, Cambridge, CB2 0QQ, UK.
ORCID: 0000-0002-4352-1151

Tao Jiang (T)

British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, Strangeways Research Laboratory, University of Cambridge, Wort's Causeway, Cambridge, CB1 8RN, UK.
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, Wort's Causeway, Cambridge, CB1 8RN, UK.
Victor Phillip Dahdaleh Heart and Lung Research Institute, University of Cambridge, Cambridge, CB2 0BB, UK.

Kousik Kundu (K)

Department of Human Genetics, The Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, CB10 1HH, UK.
Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Long Road, Cambridge, CB2 0PT, UK.
ORCID: 0000-0002-1019-8351

Roman Kreuzhuber (R)

Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Long Road, Cambridge, CB2 0PT, UK.
ORCID: 0000-0002-0762-0806

Erik L Bao (EL)

Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, 1 Blackfan Circle, Boston, MA, 02115, USA.
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, 450 Brookline Ave, Boston, MA, 02115, USA.
Broad Institute of MIT and Harvard, 415 Main St, Cambridge, MA, 02142, USA.
Harvard-MIT Health Sciences and Technology, Harvard Medical School, 77 Massachusetts Ave, Cambridge, MA, 02139, USA.
ORCID: 0000-0002-6074-6766

Janine H Collins (JH)

Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Long Road, Cambridge, CB2 0PT, UK.
National Health Service Blood and Transplant, Cambridge Centre, Cambridge Biomedical Campus, Long Road, Cambridge, CB2 0PT, UK.
Department of Haematology, Barts Health National Health Service Trust, London, E1 1BB, UK.
ORCID: 0000-0002-8716-3261

Kate Downes (K)

Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Long Road, Cambridge, CB2 0PT, UK.
National Health Service Blood and Transplant, Cambridge Centre, Cambridge Biomedical Campus, Long Road, Cambridge, CB2 0PT, UK.

Luigi Grassi (L)

Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Long Road, Cambridge, CB2 0PT, UK.
National Health Service Blood and Transplant, Cambridge Centre, Cambridge Biomedical Campus, Long Road, Cambridge, CB2 0PT, UK.
National Institute for Health and Care Research Cambridge BioResource, Box 229, Addenbrooke's Hospital, Cambridge Biomedical Campus, Cambridge, CB2 0QQ, UK.
ORCID: 0000-0002-6308-7540

Jose A Guerrero (JA)

Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Long Road, Cambridge, CB2 0PT, UK.
National Health Service Blood and Transplant, Cambridge Centre, Cambridge Biomedical Campus, Long Road, Cambridge, CB2 0PT, UK.
ORCID: 0000-0003-4307-6948

Stephen Kaptoge (S)

British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, Strangeways Research Laboratory, University of Cambridge, Wort's Causeway, Cambridge, CB1 8RN, UK.
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, Wort's Causeway, Cambridge, CB1 8RN, UK.
Victor Phillip Dahdaleh Heart and Lung Research Institute, University of Cambridge, Cambridge, CB2 0BB, UK.

Julian C Knight (JC)

Wellcome Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford, OX3 7BN, UK.
ORCID: 0000-0002-0377-5536

Stuart Meacham (S)

Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Long Road, Cambridge, CB2 0PT, UK.
European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SD, UK.
ORCID: 0000-0002-3667-6059

Jennifer Sambrook (J)

Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Long Road, Cambridge, CB2 0PT, UK.
National Institute for Health and Care Research Cambridge BioResource, Box 229, Addenbrooke's Hospital, Cambridge Biomedical Campus, Cambridge, CB2 0QQ, UK.

Denis Seyres (D)

Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Long Road, Cambridge, CB2 0PT, UK.
National Health Service Blood and Transplant, Cambridge Centre, Cambridge Biomedical Campus, Long Road, Cambridge, CB2 0PT, UK.
National Institute for Health and Care Research Cambridge BioResource, Box 229, Addenbrooke's Hospital, Cambridge Biomedical Campus, Cambridge, CB2 0QQ, UK.

Oliver Stegle (O)

European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SD, UK.
European Molecular Biology Laboratory, Genome Biology Unit, 69117, Heidelberg, Germany.
Division of Computational Genomics and Systems Genetics, German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany.

Jeffrey M Verboon (JM)

Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, 1 Blackfan Circle, Boston, MA, 02115, USA.
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, 450 Brookline Ave, Boston, MA, 02115, USA.
Broad Institute of MIT and Harvard, 415 Main St, Cambridge, MA, 02142, USA.

Klaudia Walter (K)

Department of Human Genetics, The Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, CB10 1HH, UK.
ORCID: 0000-0003-4448-0301

Nicholas A Watkins (NA)

National Health Service Blood and Transplant, Cambridge Centre, Cambridge Biomedical Campus, Long Road, Cambridge, CB2 0PT, UK.

John Danesh (J)

British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, Strangeways Research Laboratory, University of Cambridge, Wort's Causeway, Cambridge, CB1 8RN, UK.
Department of Human Genetics, The Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, CB10 1HH, UK.
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, Wort's Causeway, Cambridge, CB1 8RN, UK.
British Heart Foundation Centre of Research Excellence, University of Cambridge, Addenbrooke's Hospital, Cambridge Biomedical Campus, Cambridge, CB2 0QQ, UK.
Victor Phillip Dahdaleh Heart and Lung Research Institute, University of Cambridge, Cambridge, CB2 0BB, UK.
Health Data Research UK Cambridge, Wellcome Genome Campus and University of Cambridge, Cambridge, UK.

David J Roberts (DJ)

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, Wort's Causeway, Cambridge, CB1 8RN, UK.
Nuffield Division of Clinical Laboratory Sciences, Radcliffe Department of Medicine, University of Oxford, Headley Way, Headington, Oxford, OX3 9DU, UK.
National Institute for Health Research Oxford Biomedical Research Centre-Haematology Theme, John Radcliffe Hospital, Headley Way, Headington, Oxford, OX3 9DU, UK.
National Health Service Blood and Transplant, Oxford Centre, John Radcliffe Hospital, Headley Way, Headington, Oxford, OX3 9DU, UK.

Emanuele Di Angelantonio (E)

British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, Strangeways Research Laboratory, University of Cambridge, Wort's Causeway, Cambridge, CB1 8RN, UK.
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, Wort's Causeway, Cambridge, CB1 8RN, UK.
British Heart Foundation Centre of Research Excellence, University of Cambridge, Addenbrooke's Hospital, Cambridge Biomedical Campus, Cambridge, CB2 0QQ, UK.
Victor Phillip Dahdaleh Heart and Lung Research Institute, University of Cambridge, Cambridge, CB2 0BB, UK.
Health Data Science Research Centre, Fondazione Human Technopole, Viale Rita Levi Montalcini 1, Milan, 20157, Italy.

Vijay G Sankaran (VG)

Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, 1 Blackfan Circle, Boston, MA, 02115, USA.
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, 450 Brookline Ave, Boston, MA, 02115, USA.
Broad Institute of MIT and Harvard, 415 Main St, Cambridge, MA, 02142, USA.
ORCID: 0000-0003-0044-443X

Mattia Frontini (M)

Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Long Road, Cambridge, CB2 0PT, UK.
National Health Service Blood and Transplant, Cambridge Centre, Cambridge Biomedical Campus, Long Road, Cambridge, CB2 0PT, UK.
Department of Clinical and Biomedical Sciences, University of Exeter Medical School, Faculty of Health and Life Sciences, RILD Building, Barrack Road, Exeter, EX2 5DW, UK.
ORCID: 0000-0001-8074-6299

Stephen Burgess (S)

British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, Strangeways Research Laboratory, University of Cambridge, Wort's Causeway, Cambridge, CB1 8RN, UK.
Medical Research Council Biostatistics Unit, University of Cambridge, East Forvie Building, Cambridge Biomedical Campus, Forvie Site, Robinson Way, Cambridge, CB2 0SR, UK.
Victor Phillip Dahdaleh Heart and Lung Research Institute, University of Cambridge, Cambridge, CB2 0BB, UK.
ORCID: 0000-0001-5365-8760

Taco Kuijpers (T)

Department of Pediatric Immunology, Rheumatology and Infectious Disease, Emma Children's Hospital, Amsterdam University Medical Center, Amsterdam, CB2 0PT, UK.
Department of Blood Cell Research, Sanquin Research and Landsteiner Laboratory, Sanquin, University of Amsterdam, Amsterdam, Netherlands.

James E Peters (JE)

Health Data Research UK Cambridge, Wellcome Genome Campus and University of Cambridge, Cambridge, UK.
Department of Immunology and Inflammation, Imperial College London, Commonwealth Building, The Hammersmith Hospital, Du Cane Road, London, W12 0NN, UK.
ORCID: 0000-0002-9415-3440

Adam S Butterworth (AS)

British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, Strangeways Research Laboratory, University of Cambridge, Wort's Causeway, Cambridge, CB1 8RN, UK. asb38@medschl.cam.ac.uk.
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, Wort's Causeway, Cambridge, CB1 8RN, UK. asb38@medschl.cam.ac.uk.
British Heart Foundation Centre of Research Excellence, University of Cambridge, Addenbrooke's Hospital, Cambridge Biomedical Campus, Cambridge, CB2 0QQ, UK. asb38@medschl.cam.ac.uk.
Victor Phillip Dahdaleh Heart and Lung Research Institute, University of Cambridge, Cambridge, CB2 0BB, UK. asb38@medschl.cam.ac.uk.
Health Data Research UK Cambridge, Wellcome Genome Campus and University of Cambridge, Cambridge, UK. asb38@medschl.cam.ac.uk.
ORCID: 0000-0002-6915-9015

Willem H Ouwehand (WH)

Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Long Road, Cambridge, CB2 0PT, UK. who1000@cam.ac.uk.
National Health Service Blood and Transplant, Cambridge Centre, Cambridge Biomedical Campus, Long Road, Cambridge, CB2 0PT, UK. who1000@cam.ac.uk.
Department of Haematology, University College London Hospitals, WC1E 6AS, London, UK. who1000@cam.ac.uk.
ORCID: 0000-0002-7744-1790

Nicole Soranzo (N)

Department of Human Genetics, The Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, CB10 1HH, UK. ns6@sanger.ac.uk.
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, Wort's Causeway, Cambridge, CB1 8RN, UK. ns6@sanger.ac.uk.
Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Long Road, Cambridge, CB2 0PT, UK. ns6@sanger.ac.uk.
British Heart Foundation Centre of Research Excellence, University of Cambridge, Addenbrooke's Hospital, Cambridge Biomedical Campus, Cambridge, CB2 0QQ, UK. ns6@sanger.ac.uk.
Genomics Research Centre, Fondazione Human Technopole, Viale Rita Levi Montalcini 1, Milan, 20157, Italy. ns6@sanger.ac.uk.
ORCID: 0000-0003-1095-3852

William J Astle (WJ)

Medical Research Council Biostatistics Unit, University of Cambridge, East Forvie Building, Cambridge Biomedical Campus, Forvie Site, Robinson Way, Cambridge, CB2 0SR, UK. wja24@cam.ac.uk.
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, Wort's Causeway, Cambridge, CB1 8RN, UK. wja24@cam.ac.uk.
National Health Service Blood and Transplant, Cambridge Centre, Cambridge Biomedical Campus, Long Road, Cambridge, CB2 0PT, UK. wja24@cam.ac.uk.
ORCID: 0000-0001-8866-6672

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Classifications MeSH

questionsmedicales.fr › Environnement et santé publique › Santé publique › Méthodes épidémiologiques › Épidémiologie moléculaire › Étude d'association pangénomique › A genome-wide association study of blood cell...
questionsmedicales.fr › Disciplines des sciences naturelles › Chimie › Biochimie › Protéomique › A genome-wide association study of blood cell...
questionsmedicales.fr › Disciplines des sciences naturelles › Physique › Microscopie › A genome-wide association study of blood cell...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Facteurs de transcription › A genome-wide association study of blood cell...
questionsmedicales.fr › Environnement et santé publique › Santé publique › Facteurs épidémiologiques › Causalité › A genome-wide association study of blood cell...