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

Autor:	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., 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., 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., 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., 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., Kreuzhuber R; Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Long Road, Cambridge, CB2 0PT, UK., 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., 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., 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., 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., 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., 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., Knight JC; Wellcome Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford, OX3 7BN, UK., 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., 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., 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., 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., 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., Walter K; Department of Human Genetics, The Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, CB10 1HH, UK., Watkins NA; National Health Service Blood and Transplant, Cambridge Centre, Cambridge Biomedical Campus, Long Road, Cambridge, CB2 0PT, UK., 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., 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., 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., 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., 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., 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., 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., 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., 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., 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., 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., 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.
Jazyk:	angličtina
Zdroj:	Nature communications [Nat Commun] 2023 Aug 18; Vol. 14 (1), pp. 5023. Date of Electronic Publication: 2023 Aug 18.
DOI:	10.1038/s41467-023-40679-y
Abstrakt:	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. (© 2023. Springer Nature Limited.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu Full text from SpringerLink