IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v14y2023i1d10.1038_s41467-023-40679-y.html
   My bibliography  Save this article

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

Author

Listed:
  • Parsa Akbari

    (University of Cambridge
    The Wellcome Sanger Institute, Wellcome Genome Campus
    Medical Research Council Biostatistics Unit, University of Cambridge, East Forvie Building, Cambridge Biomedical Campus, Forvie Site
    University of Cambridge)

  • Dragana Vuckovic

    (The Wellcome Sanger Institute, Wellcome Genome Campus
    University of Cambridge
    Imperial College London)

  • Luca Stefanucci

    (University of Cambridge, Cambridge Biomedical Campus
    National Health Service Blood and Transplant, Cambridge Centre, Cambridge Biomedical Campus
    University of Cambridge, Addenbrooke’s Hospital)

  • Tao Jiang

    (University of Cambridge
    University of Cambridge
    University of Cambridge)

  • Kousik Kundu

    (The Wellcome Sanger Institute, Wellcome Genome Campus
    University of Cambridge, Cambridge Biomedical Campus)

  • Roman Kreuzhuber

    (University of Cambridge, Cambridge Biomedical Campus)

  • Erik L. Bao

    (Boston Children’s Hospital, Harvard Medical School
    Dana-Farber Cancer Institute, Harvard Medical School
    Broad Institute of MIT and Harvard
    Harvard-MIT Health Sciences and Technology, Harvard Medical School)

  • Janine H. Collins

    (University of Cambridge, Cambridge Biomedical Campus
    National Health Service Blood and Transplant, Cambridge Centre, Cambridge Biomedical Campus
    Department of Haematology, Barts Health National Health Service Trust)

  • Kate Downes

    (University of Cambridge, Cambridge Biomedical Campus
    National Health Service Blood and Transplant, Cambridge Centre, Cambridge Biomedical Campus)

  • Luigi Grassi

    (University of Cambridge, Cambridge Biomedical Campus
    National Health Service Blood and Transplant, Cambridge Centre, Cambridge Biomedical Campus
    National Institute for Health and Care Research Cambridge BioResource, Box 229, Addenbrooke’s Hospital, Cambridge Biomedical Campus)

  • Jose A. Guerrero

    (University of Cambridge, Cambridge Biomedical Campus
    National Health Service Blood and Transplant, Cambridge Centre, Cambridge Biomedical Campus)

  • Stephen Kaptoge

    (University of Cambridge
    University of Cambridge
    University of Cambridge)

  • Julian C. Knight

    (University of Oxford)

  • Stuart Meacham

    (University of Cambridge, Cambridge Biomedical Campus
    European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus)

  • Jennifer Sambrook

    (University of Cambridge, Cambridge Biomedical Campus
    National Institute for Health and Care Research Cambridge BioResource, Box 229, Addenbrooke’s Hospital, Cambridge Biomedical Campus)

  • Denis Seyres

    (University of Cambridge, Cambridge Biomedical Campus
    National Health Service Blood and Transplant, Cambridge Centre, Cambridge Biomedical Campus
    National Institute for Health and Care Research Cambridge BioResource, Box 229, Addenbrooke’s Hospital, Cambridge Biomedical Campus)

  • Oliver Stegle

    (European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus
    European Molecular Biology Laboratory, Genome Biology Unit
    Division of Computational Genomics and Systems Genetics, German Cancer Research Center (DKFZ))

  • Jeffrey M. Verboon

    (Boston Children’s Hospital, Harvard Medical School
    Dana-Farber Cancer Institute, Harvard Medical School
    Broad Institute of MIT and Harvard)

  • Klaudia Walter

    (The Wellcome Sanger Institute, Wellcome Genome Campus)

  • Nicholas A. Watkins

    (National Health Service Blood and Transplant, Cambridge Centre, Cambridge Biomedical Campus)

  • John Danesh

    (University of Cambridge
    The Wellcome Sanger Institute, Wellcome Genome Campus
    University of Cambridge
    University of Cambridge, Addenbrooke’s Hospital)

  • David J. Roberts

    (University of Cambridge
    University of Oxford
    National Institute for Health Research Oxford Biomedical Research Centre—Haematology Theme, John Radcliffe Hospital
    National Health Service Blood and Transplant, Oxford Centre, John Radcliffe Hospital)

  • Emanuele Angelantonio

    (University of Cambridge
    University of Cambridge
    University of Cambridge, Addenbrooke’s Hospital
    University of Cambridge)

  • Vijay G. Sankaran

    (Boston Children’s Hospital, Harvard Medical School
    Dana-Farber Cancer Institute, Harvard Medical School
    Broad Institute of MIT and Harvard)

  • Mattia Frontini

    (University of Cambridge, Cambridge Biomedical Campus
    National Health Service Blood and Transplant, Cambridge Centre, Cambridge Biomedical Campus
    University of Exeter Medical School, Faculty of Health and Life Sciences, RILD Building)

  • Stephen Burgess

    (University of Cambridge
    Medical Research Council Biostatistics Unit, University of Cambridge, East Forvie Building, Cambridge Biomedical Campus, Forvie Site
    University of Cambridge)

  • Taco Kuijpers

    (Amsterdam University Medical Center
    University of Amsterdam)

  • James E. Peters

    (Wellcome Genome Campus and University of Cambridge
    The Hammersmith Hospital)

  • Adam S. Butterworth

    (University of Cambridge
    University of Cambridge
    University of Cambridge, Addenbrooke’s Hospital
    University of Cambridge)

  • Willem H. Ouwehand

    (University of Cambridge, Cambridge Biomedical Campus
    National Health Service Blood and Transplant, Cambridge Centre, Cambridge Biomedical Campus
    University College London Hospitals)

  • Nicole Soranzo

    (The Wellcome Sanger Institute, Wellcome Genome Campus
    University of Cambridge
    University of Cambridge, Cambridge Biomedical Campus
    University of Cambridge, Addenbrooke’s Hospital)

  • William J. Astle

    (Medical Research Council Biostatistics Unit, University of Cambridge, East Forvie Building, Cambridge Biomedical Campus, Forvie Site
    University of Cambridge
    National Health Service Blood and Transplant, Cambridge Centre, Cambridge Biomedical Campus)

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.

Suggested Citation

  • Parsa Akbari & Dragana Vuckovic & Luca Stefanucci & Tao Jiang & Kousik Kundu & Roman Kreuzhuber & Erik L. Bao & Janine H. Collins & Kate Downes & Luigi Grassi & Jose A. Guerrero & Stephen Kaptoge & Ju, 2023. "A genome-wide association study of blood cell morphology identifies cellular proteins implicated in disease aetiology," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-40679-y
    DOI: 10.1038/s41467-023-40679-y
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-023-40679-y
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-023-40679-y?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Thomas Moreau & Amanda L. Evans & Louella Vasquez & Marloes R. Tijssen & Ying Yan & Matthew W. Trotter & Daniel Howard & Maria Colzani & Meera Arumugam & Wing Han Wu & Amanda Dalby & Riina Lampela & G, 2016. "Large-scale production of megakaryocytes from human pluripotent stem cells by chemically defined forward programming," Nature Communications, Nature, vol. 7(1), pages 1-16, September.
    2. B. Devlin & Kathryn Roeder, 1999. "Genomic Control for Association Studies," Biometrics, The International Biometric Society, vol. 55(4), pages 997-1004, December.
    3. Benjamin B. Sun & Joseph C. Maranville & James E. Peters & David Stacey & James R. Staley & James Blackshaw & Stephen Burgess & Tao Jiang & Ellie Paige & Praveen Surendran & Clare Oliver-Williams & Mi, 2018. "Genomic atlas of the human plasma proteome," Nature, Nature, vol. 558(7708), pages 73-79, June.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Lei Zhang & Yu-Fang Pei & Jian Li & Christopher J Papasian & Hong-Wen Deng, 2009. "Univariate/Multivariate Genome-Wide Association Scans Using Data from Families and Unrelated Samples," PLOS ONE, Public Library of Science, vol. 4(8), pages 1-12, August.
    2. Dominic Holland & Oleksandr Frei & Rahul Desikan & Chun-Chieh Fan & Alexey A Shadrin & Olav B Smeland & V S Sundar & Paul Thompson & Ole A Andreassen & Anders M Dale, 2020. "Beyond SNP heritability: Polygenicity and discoverability of phenotypes estimated with a univariate Gaussian mixture model," PLOS Genetics, Public Library of Science, vol. 16(5), pages 1-30, May.
    3. Yihao Lu & Meritxell Oliva & Brandon L. Pierce & Jin Liu & Lin S. Chen, 2024. "Integrative cross-omics and cross-context analysis elucidates molecular links underlying genetic effects on complex traits," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    4. Vincent Michaud & Eulalie Lasseaux & David J. Green & Dave T. Gerrard & Claudio Plaisant & Tomas Fitzgerald & Ewan Birney & Benoît Arveiler & Graeme C. Black & Panagiotis I. Sergouniotis, 2022. "The contribution of common regulatory and protein-coding TYR variants to the genetic architecture of albinism," Nature Communications, Nature, vol. 13(1), pages 1-8, December.
    5. Gang Zheng & Zhaohai Li & Mitchell H. Gail & Joseph L. Gastwirth, 2010. "Impact of Population Substructure on Trend Tests for Genetic Case–Control Association Studies," Biometrics, The International Biometric Society, vol. 66(1), pages 196-204, March.
    6. Sandosh Padmanabhan & Olle Melander & Toby Johnson & Anna Maria Di Blasio & Wai K Lee & Davide Gentilini & Claire E Hastie & Cristina Menni & Maria Cristina Monti & Christian Delles & Stewart Laing & , 2010. "Genome-Wide Association Study of Blood Pressure Extremes Identifies Variant near UMOD Associated with Hypertension," PLOS Genetics, Public Library of Science, vol. 6(10), pages 1-11, October.
    7. Jakris Eu-ahsunthornwattana & E Nancy Miller & Michaela Fakiola & Wellcome Trust Case Control Consortium 2 & Selma M B Jeronimo & Jenefer M Blackwell & Heather J Cordell, 2014. "Comparison of Methods to Account for Relatedness in Genome-Wide Association Studies with Family-Based Data," PLOS Genetics, Public Library of Science, vol. 10(7), pages 1-20, July.
    8. Elena V. Feofanova & Michael R. Brown & Taryn Alkis & Astrid M. Manuel & Xihao Li & Usman A. Tahir & Zilin Li & Kevin M. Mendez & Rachel S. Kelly & Qibin Qi & Han Chen & Martin G. Larson & Rozenn N. L, 2023. "Whole-Genome Sequencing Analysis of Human Metabolome in Multi-Ethnic Populations," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    9. Jianzhong Ma & Christopher I Amos, 2010. "Theoretical Formulation of Principal Components Analysis to Detect and Correct for Population Stratification," PLOS ONE, Public Library of Science, vol. 5(9), pages 1-14, September.
    10. Claire L Simpson & Robert Wojciechowski & Konrad Oexle & Federico Murgia & Laura Portas & Xiaohui Li & Virginie J M Verhoeven & Veronique Vitart & Maria Schache & S Mohsen Hosseini & Pirro G Hysi & Le, 2014. "Genome-Wide Meta-Analysis of Myopia and Hyperopia Provides Evidence for Replication of 11 Loci," PLOS ONE, Public Library of Science, vol. 9(9), pages 1-19, September.
    11. Danni A. Gadd & Robert F. Hillary & Daniel L. McCartney & Liu Shi & Aleks Stolicyn & Neil A. Robertson & Rosie M. Walker & Robert I. McGeachan & Archie Campbell & Shen Xueyi & Miruna C. Barbu & Claire, 2022. "Integrated methylome and phenome study of the circulating proteome reveals markers pertinent to brain health," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    12. Matthieu Bouaziz & Christophe Ambroise & Mickael Guedj, 2011. "Accounting for Population Stratification in Practice: A Comparison of the Main Strategies Dedicated to Genome-Wide Association Studies," PLOS ONE, Public Library of Science, vol. 6(12), pages 1-13, December.
    13. Aditi Shendre & Howard W Wiener & Marguerite R Irvin & Bradley E Aouizerat & Edgar T Overton & Jason Lazar & Chenglong Liu & Howard N Hodis & Nita A Limdi & Kathleen M Weber & Stephen J Gange & Degui , 2017. "Genome-wide admixture and association study of subclinical atherosclerosis in the Women’s Interagency HIV Study (WIHS)," PLOS ONE, Public Library of Science, vol. 12(12), pages 1-23, December.
    14. Li Shaoyu & Lu Qing & Fu Wenjiang & Romero Roberto & Cui Yuehua, 2009. "A Regularized Regression Approach for Dissecting Genetic Conflicts that Increase Disease Risk in Pregnancy," Statistical Applications in Genetics and Molecular Biology, De Gruyter, vol. 8(1), pages 1-28, October.
    15. Warrington Nicole M. & Tilling Kate & Howe Laura D. & Paternoster Lavinia & Pennell Craig E. & Wu Yan Yan & Briollais Laurent, 2014. "Robustness of the linear mixed effects model to error distribution assumptions and the consequences for genome-wide association studies," Statistical Applications in Genetics and Molecular Biology, De Gruyter, vol. 13(5), pages 1-21, October.
    16. Wang, Linglu & Li, Qizhai & Li, Zhaohai & Zheng, Gang, 2011. "Bayes factors in the presence of population stratification," Statistics & Probability Letters, Elsevier, vol. 81(7), pages 836-841, July.
    17. Boitard Simon & Mangin Brigitte & Azaïs Jean-Marc, 2010. "Asymptotic Distribution of the "Orthogonal" Quantitative Transmission Disequilibrium Test in a Structured Population: Exact Formula," Statistical Applications in Genetics and Molecular Biology, De Gruyter, vol. 9(1), pages 1-25, January.
    18. Magdalena Zimoń & Yunfeng Huang & Anthi Trasta & Aliaksandr Halavatyi & Jimmy Z. Liu & Chia-Yen Chen & Peter Blattmann & Bernd Klaus & Christopher D. Whelan & David Sexton & Sally John & Wolfgang Hube, 2021. "Pairwise effects between lipid GWAS genes modulate lipid plasma levels and cellular uptake," Nature Communications, Nature, vol. 12(1), pages 1-16, December.
    19. Ilja M Nolte & Chris Wallace & Stephen J Newhouse & Daryl Waggott & Jingyuan Fu & Nicole Soranzo & Rhian Gwilliam & Panos Deloukas & Irina Savelieva & Dongling Zheng & Chrysoula Dalageorgou & Martin F, 2009. "Common Genetic Variation Near the Phospholamban Gene Is Associated with Cardiac Repolarisation: Meta-Analysis of Three Genome-Wide Association Studies," PLOS ONE, Public Library of Science, vol. 4(7), pages 1-10, July.
    20. Grace Png & Andrei Barysenka & Linda Repetto & Pau Navarro & Xia Shen & Maik Pietzner & Eleanor Wheeler & Nicholas J. Wareham & Claudia Langenberg & Emmanouil Tsafantakis & Maria Karaleftheri & George, 2021. "Mapping the serum proteome to neurological diseases using whole genome sequencing," Nature Communications, Nature, vol. 12(1), pages 1-12, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-40679-y. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.