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

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      Nature Communications
      Nature Publishing Group UK
      Cell biology, Medical genomics, Haematopoiesis, Drug development

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          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.

          Abstract

          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.

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          Most cited references97

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          The Ensembl Variant Effect Predictor

          The Ensembl Variant Effect Predictor is a powerful toolset for the analysis, annotation, and prioritization of genomic variants in coding and non-coding regions. It provides access to an extensive collection of genomic annotation, with a variety of interfaces to suit different requirements, and simple options for configuring and extending analysis. It is open source, free to use, and supports full reproducibility of results. The Ensembl Variant Effect Predictor can simplify and accelerate variant interpretation in a wide range of study designs.
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            LD Score regression distinguishes confounding from polygenicity in genome-wide association studies.

            Both polygenicity (many small genetic effects) and confounding biases, such as cryptic relatedness and population stratification, can yield an inflated distribution of test statistics in genome-wide association studies (GWAS). However, current methods cannot distinguish between inflation from a true polygenic signal and bias. We have developed an approach, LD Score regression, that quantifies the contribution of each by examining the relationship between test statistics and linkage disequilibrium (LD). The LD Score regression intercept can be used to estimate a more powerful and accurate correction factor than genomic control. We find strong evidence that polygenicity accounts for the majority of the inflation in test statistics in many GWAS of large sample size.
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              • Article: not found

              Improved vectors and genome-wide libraries for CRISPR screening.

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                Author and article information

                Contributors
                asb38@medschl.cam.ac.uk
                who1000@cam.ac.uk
                ns6@sanger.ac.uk
                wja24@cam.ac.uk
                Journal
                Nat Commun
                Nat Commun
                Nature Communications
                Nature Publishing Group UK (London )
                2041-1723
                18 August 2023
                18 August 2023
                2023
                : 14
                : 5023
                Affiliations
                [1 ]GRID grid.5335.0, ISNI 0000000121885934, 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
                [2 ]GRID grid.10306.34, ISNI 0000 0004 0606 5382, Department of Human Genetics, , The Wellcome Sanger Institute, Wellcome Genome Campus, ; Hinxton, Cambridge CB10 1HH UK
                [3 ]GRID grid.415038.b, ISNI 0000 0000 9355 1493, Medical Research Council Biostatistics Unit, University of Cambridge, East Forvie Building, Cambridge Biomedical Campus, Forvie Site, ; Robinson Way, Cambridge, CB2 0SR UK
                [4 ]GRID grid.5335.0, ISNI 0000000121885934, 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
                [5 ]GRID grid.7445.2, ISNI 0000 0001 2113 8111, Department of Epidemiology and Biostatistics, School of Public Health, , Imperial College London, ; London, UK
                [6 ]GRID grid.5335.0, ISNI 0000000121885934, Department of Haematology, , University of Cambridge, Cambridge Biomedical Campus, ; Long Road, Cambridge, CB2 0PT UK
                [7 ]GRID grid.436365.1, ISNI 0000 0000 8685 6563, National Health Service Blood and Transplant, Cambridge Centre, Cambridge Biomedical Campus, ; Long Road, Cambridge, CB2 0PT UK
                [8 ]GRID grid.120073.7, ISNI 0000 0004 0622 5016, British Heart Foundation Centre of Research Excellence, , University of Cambridge, Addenbrooke’s Hospital, ; Cambridge Biomedical Campus, Cambridge, CB2 0QQ UK
                [9 ]GRID grid.5335.0, ISNI 0000000121885934, Victor Phillip Dahdaleh Heart and Lung Research Institute, , University of Cambridge, ; Cambridge, CB2 0BB UK
                [10 ]GRID grid.38142.3c, ISNI 000000041936754X, Division of Hematology/Oncology, , Boston Children’s Hospital, Harvard Medical School, ; 1 Blackfan Circle, Boston, MA 02115 USA
                [11 ]GRID grid.38142.3c, ISNI 000000041936754X, Department of Pediatric Oncology, , Dana-Farber Cancer Institute, Harvard Medical School, ; 450 Brookline Ave, Boston, MA 02115 USA
                [12 ]GRID grid.66859.34, ISNI 0000 0004 0546 1623, Broad Institute of MIT and Harvard, ; 415 Main St, Cambridge, MA 02142 USA
                [13 ]GRID grid.38142.3c, ISNI 000000041936754X, Harvard-MIT Health Sciences and Technology, Harvard Medical School, ; 77 Massachusetts Ave, Cambridge, MA 02139 USA
                [14 ]Department of Haematology, Barts Health National Health Service Trust, London, E1 1BB UK
                [15 ]GRID grid.120073.7, ISNI 0000 0004 0622 5016, National Institute for Health and Care Research Cambridge BioResource, Box 229, Addenbrooke’s Hospital, Cambridge Biomedical Campus, ; Cambridge, CB2 0QQ UK
                [16 ]GRID grid.4991.5, ISNI 0000 0004 1936 8948, Wellcome Centre for Human Genetics, , University of Oxford, ; Roosevelt Drive, Oxford, OX3 7BN UK
                [17 ]GRID grid.225360.0, ISNI 0000 0000 9709 7726, European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, ; Hinxton, Cambridge CB10 1SD UK
                [18 ]GRID grid.4709.a, ISNI 0000 0004 0495 846X, European Molecular Biology Laboratory, Genome Biology Unit, ; 69117 Heidelberg, Germany
                [19 ]GRID grid.7497.d, ISNI 0000 0004 0492 0584, Division of Computational Genomics and Systems Genetics, German Cancer Research Center (DKFZ), ; 69120 Heidelberg, Germany
                [20 ]GRID grid.5335.0, ISNI 0000000121885934, Health Data Research UK Cambridge, , Wellcome Genome Campus and University of Cambridge, ; Cambridge, UK
                [21 ]GRID grid.4991.5, ISNI 0000 0004 1936 8948, Nuffield Division of Clinical Laboratory Sciences, Radcliffe Department of Medicine, , University of Oxford, ; Headley Way, Headington, Oxford OX3 9DU UK
                [22 ]GRID grid.8348.7, ISNI 0000 0001 2306 7492, National Institute for Health Research Oxford Biomedical Research Centre—Haematology Theme, John Radcliffe Hospital, ; Headley Way, Headington, Oxford OX3 9DU UK
                [23 ]GRID grid.8348.7, ISNI 0000 0001 2306 7492, National Health Service Blood and Transplant, Oxford Centre, John Radcliffe Hospital, ; Headley Way, Headington, Oxford OX3 9DU UK
                [24 ]GRID grid.510779.d, ISNI 0000 0004 9414 6915, Health Data Science Research Centre, , Fondazione Human Technopole, ; Viale Rita Levi Montalcini 1, Milan, 20157 Italy
                [25 ]GRID grid.8391.3, ISNI 0000 0004 1936 8024, 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
                [26 ]Department of Pediatric Immunology, Rheumatology and Infectious Disease, Emma Children’s Hospital, Amsterdam University Medical Center, Amsterdam, CB2 0PT UK
                [27 ]GRID grid.7177.6, ISNI 0000000084992262, Department of Blood Cell Research, Sanquin Research and Landsteiner Laboratory, Sanquin, , University of Amsterdam, ; Amsterdam, Netherlands
                [28 ]GRID grid.413629.b, ISNI 0000 0001 0705 4923, Department of Immunology and Inflammation, Imperial College London, Commonwealth Building, , The Hammersmith Hospital, ; Du Cane Road, London, W12 0NN UK
                [29 ]GRID grid.439749.4, ISNI 0000 0004 0612 2754, Department of Haematology, , University College London Hospitals, ; WC1E 6AS London, UK
                [30 ]GRID grid.510779.d, ISNI 0000 0004 9414 6915, Genomics Research Centre, , Fondazione Human Technopole, ; Viale Rita Levi Montalcini 1, Milan, 20157 Italy
                Author information
                http://orcid.org/0000-0001-9210-4760
                http://orcid.org/0000-0002-4352-1151
                http://orcid.org/0000-0002-1019-8351
                http://orcid.org/0000-0002-0762-0806
                http://orcid.org/0000-0002-6074-6766
                http://orcid.org/0000-0002-8716-3261
                http://orcid.org/0000-0002-6308-7540
                http://orcid.org/0000-0003-4307-6948
                http://orcid.org/0000-0002-0377-5536
                http://orcid.org/0000-0002-3667-6059
                http://orcid.org/0000-0003-4448-0301
                http://orcid.org/0000-0003-0044-443X
                http://orcid.org/0000-0001-8074-6299
                http://orcid.org/0000-0001-5365-8760
                http://orcid.org/0000-0002-9415-3440
                http://orcid.org/0000-0002-6915-9015
                http://orcid.org/0000-0002-7744-1790
                http://orcid.org/0000-0003-1095-3852
                http://orcid.org/0000-0001-8866-6672
                Article
                40679
                10.1038/s41467-023-40679-y
                10439125
                37596262
                50e072c4-111b-4ff3-95bf-feb960e2c7b7
                © Springer Nature Limited 2023

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 19 July 2021
                : 7 August 2023
                Funding
                Funded by: FundRef https://doi.org/10.13039/501100000272, DH | National Institute for Health Research (NIHR);
                Award ID: NIHR BTRU-2014-10024
                Award Recipient :
                Funded by: FundRef https://doi.org/10.13039/501100000274, British Heart Foundation (BHF);
                Award ID: SP/09/002
                Award ID: RG/13/13/30194
                Award ID: RG/18/13/33946
                Award ID: FS/18/53/33863
                Award Recipient :
                Funded by: FundRef https://doi.org/10.13039/501100000265, RCUK | Medical Research Council (MRC);
                Award ID: MR/L003120/1
                Award Recipient :
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                © Springer Nature Limited 2023

                Uncategorized
                cell biology,medical genomics,haematopoiesis,drug development
                Uncategorized
                cell biology, medical genomics, haematopoiesis, drug development

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