Genome-wide association analysis of neutrophil granularity identifies CDK6 as a regulator of primary granules
Summary: Neutrophils are essential immune cells loaded with cytosolic granules that contain potent antimicrobial and immunostimulatory molecules. Alterations of neutrophil granule contents are associated with immunodeficiency and hyperinflammation. Identification of regulators of granule development...
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| Language: | English |
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Elsevier
2025-08-01
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| Series: | iScience |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2589004225013331 |
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| author | Kathryn Fleming Kate Burley Fernando Ponce-Garcia Parsa Akbari Claire Naveh Chris Rice Przemysław Zakrzewski Willem Gibbs Sarah Groves Drinalda Cela Venizelos Papayannopoulos Christopher J. Harbort Andrew Mumford Borko Amulic |
| author_facet | Kathryn Fleming Kate Burley Fernando Ponce-Garcia Parsa Akbari Claire Naveh Chris Rice Przemysław Zakrzewski Willem Gibbs Sarah Groves Drinalda Cela Venizelos Papayannopoulos Christopher J. Harbort Andrew Mumford Borko Amulic |
| author_sort | Kathryn Fleming |
| collection | DOAJ |
| description | Summary: Neutrophils are essential immune cells loaded with cytosolic granules that contain potent antimicrobial and immunostimulatory molecules. Alterations of neutrophil granule contents are associated with immunodeficiency and hyperinflammation. Identification of regulators of granule development can aid in understanding of neutrophil-driven pathologies. Here, we perform a systematic prioritization of genetic variants associated with neutrophil cytometric side scatter (SSC), a proxy for granularity, identified in a genome-wide association study (GWAS) of blood parameters in healthy individuals. We show that triangulation of GWAS data with epigenetic and eQTL data identifies previously unknown factors regulating neutrophil granularity. We validate this approach using cellular and animal models to confirm that cyclin dependent kinase 6 (encoded by CDK6) regulates neutrophil granule development. CDK6 specifically regulates the abundance of primary granules without affecting neutrophil maturation. Our approach demonstrates the utility of cell counter-derived SSC data paired with genomics as a tool to investigate neutrophil development and function. |
| format | Article |
| id | doaj-art-4aa05d4a1ee14d4190a22d996d0bf85e |
| institution | Kabale University |
| issn | 2589-0042 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Elsevier |
| record_format | Article |
| series | iScience |
| spelling | doaj-art-4aa05d4a1ee14d4190a22d996d0bf85e2025-08-20T03:39:36ZengElsevieriScience2589-00422025-08-0128811307210.1016/j.isci.2025.113072Genome-wide association analysis of neutrophil granularity identifies CDK6 as a regulator of primary granulesKathryn Fleming0Kate Burley1Fernando Ponce-Garcia2Parsa Akbari3Claire Naveh4Chris Rice5Przemysław Zakrzewski6Willem Gibbs7Sarah Groves8Drinalda Cela9Venizelos Papayannopoulos10Christopher J. Harbort11Andrew Mumford12Borko Amulic13School of Cellular and Molecular Medicine, University of Bristol, Bristol, UK; Corresponding authorSchool of Cellular and Molecular Medicine, University of Bristol, Bristol, UKSchool of Cellular and Molecular Medicine, University of Bristol, Bristol, UKBritish Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Wort’s Causeway, Cambridge, UK; Department of Human Genetics, The Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, UKSchool of Cellular and Molecular Medicine, University of Bristol, Bristol, UKSchool of Cellular and Molecular Medicine, University of Bristol, Bristol, UKSchool of Cellular and Molecular Medicine, University of Bristol, Bristol, UKSchool of Cellular and Molecular Medicine, University of Bristol, Bristol, UKSchool of Cellular and Molecular Medicine, University of Bristol, Bristol, UKThe Francis Crick Institute, Antimicrobial Defence Laboratory, London, UKThe Francis Crick Institute, Antimicrobial Defence Laboratory, London, UKCellular Microbiology, Max Planck Institute for Infection Biology, Chariteplatz 1, Berlin, GermanySchool of Cellular and Molecular Medicine, University of Bristol, Bristol, UKSchool of Cellular and Molecular Medicine, University of Bristol, Bristol, UK; Corresponding authorSummary: Neutrophils are essential immune cells loaded with cytosolic granules that contain potent antimicrobial and immunostimulatory molecules. Alterations of neutrophil granule contents are associated with immunodeficiency and hyperinflammation. Identification of regulators of granule development can aid in understanding of neutrophil-driven pathologies. Here, we perform a systematic prioritization of genetic variants associated with neutrophil cytometric side scatter (SSC), a proxy for granularity, identified in a genome-wide association study (GWAS) of blood parameters in healthy individuals. We show that triangulation of GWAS data with epigenetic and eQTL data identifies previously unknown factors regulating neutrophil granularity. We validate this approach using cellular and animal models to confirm that cyclin dependent kinase 6 (encoded by CDK6) regulates neutrophil granule development. CDK6 specifically regulates the abundance of primary granules without affecting neutrophil maturation. Our approach demonstrates the utility of cell counter-derived SSC data paired with genomics as a tool to investigate neutrophil development and function.http://www.sciencedirect.com/science/article/pii/S2589004225013331Biological sciencesGeneticsImmunologyNatural sciences |
| spellingShingle | Kathryn Fleming Kate Burley Fernando Ponce-Garcia Parsa Akbari Claire Naveh Chris Rice Przemysław Zakrzewski Willem Gibbs Sarah Groves Drinalda Cela Venizelos Papayannopoulos Christopher J. Harbort Andrew Mumford Borko Amulic Genome-wide association analysis of neutrophil granularity identifies CDK6 as a regulator of primary granules iScience Biological sciences Genetics Immunology Natural sciences |
| title | Genome-wide association analysis of neutrophil granularity identifies CDK6 as a regulator of primary granules |
| title_full | Genome-wide association analysis of neutrophil granularity identifies CDK6 as a regulator of primary granules |
| title_fullStr | Genome-wide association analysis of neutrophil granularity identifies CDK6 as a regulator of primary granules |
| title_full_unstemmed | Genome-wide association analysis of neutrophil granularity identifies CDK6 as a regulator of primary granules |
| title_short | Genome-wide association analysis of neutrophil granularity identifies CDK6 as a regulator of primary granules |
| title_sort | genome wide association analysis of neutrophil granularity identifies cdk6 as a regulator of primary granules |
| topic | Biological sciences Genetics Immunology Natural sciences |
| url | http://www.sciencedirect.com/science/article/pii/S2589004225013331 |
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