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

dc.contributor.authorAkbari, P
dc.contributor.authorVuckovic, D
dc.contributor.authorStefanucci, L
dc.contributor.authorJiang, T
dc.contributor.authorKundu, K
dc.contributor.authorKreuzhuber, R
dc.contributor.authorBao, EL
dc.contributor.authorCollins, JH
dc.contributor.authorDownes, K
dc.contributor.authorGrassi, L
dc.contributor.authorGuerrero, JA
dc.contributor.authorKaptoge, S
dc.contributor.authorKnight, JC
dc.contributor.authorMeacham, S
dc.contributor.authorSambrook, J
dc.contributor.authorSeyres, D
dc.contributor.authorStegle, O
dc.contributor.authorVerboon, JM
dc.contributor.authorWalter, K
dc.contributor.authorWatkins, NA
dc.contributor.authorDanesh, J
dc.contributor.authorRoberts, DJ
dc.contributor.authorDi Angelantonio, E
dc.contributor.authorSankaran, VG
dc.contributor.authorFrontini, M
dc.contributor.authorBurgess, S
dc.contributor.authorKuijpers, T
dc.contributor.authorPeters, JE
dc.contributor.authorButterworth, AS
dc.contributor.authorOuwehand, WH
dc.contributor.authorSoranzo, N
dc.contributor.authorAstle, WJ
dc.date.accessioned2023-11-16T14:22:04Z
dc.date.issued2023-08-18
dc.date.updated2023-11-16T13:15:11Z
dc.description.abstractBlood 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.en_GB
dc.format.extent5023-
dc.format.mediumElectronic
dc.identifier.citationVol. 14, article 5023en_GB
dc.identifier.doihttps://doi.org/10.1038/s41467-023-40679-y
dc.identifier.urihttp://hdl.handle.net/10871/134565
dc.identifierORCID: 0000-0001-8074-6299 (Frontini, Mattia)
dc.identifierScopusID: 57212735122 (Frontini, Mattia)
dc.language.isoenen_GB
dc.publisherNature Researchen_GB
dc.relation.urlhttps://www.ncbi.nlm.nih.gov/pubmed/37596262en_GB
dc.relation.urlhttps://grch37.ensembl.org/info/data/ftp/index.htmlen_GB
dc.relation.urlhttps://github.com/caleblareau/singlecell_bloodtraits/en_GB
dc.relation.urlhttps://github.com/ParsaAkbari/UKBB500K-Conditional-Analysisen_GB
dc.rights© The Author(s) 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/en_GB
dc.titleA genome-wide association study of blood cell morphology identifies cellular proteins implicated in disease aetiologyen_GB
dc.typeArticleen_GB
dc.date.available2023-11-16T14:22:04Z
dc.identifier.issn2041-1723
exeter.article-number5023
exeter.place-of-publicationEngland
dc.descriptionThis is the final version. Available on open access from Nature Research via the DOI in this recorden_GB
dc.descriptionData availability; For ethical and legal reasons access to INTERVAL data are subject to controls. Bona fide scientists can seek access to relevant de-identified individual participant data—including genetic, haematology analyser and proteomic data—and a copy of the trial’s data dictionary by applying to the INTERVAL Data Access Committee using the email address helpdesk@intervalstudy.org.uk. The INTERVAL Data Access Committee (supplemented, when required, by expertise from additional external scientists) meets several times a year to review applications according to the usual academic criteria of scientific validity and feasibility. Following approval by the INTERVAL Data Access Committee, a material transfer or research collaboration agreement will be agreed and signed with the applicants. Applicants might be requested to provide reimbursement of data management or preparation costs, as the INTERVAL trial is no longer in receipt of funding. Applicants will be required to provide updates to the INTERVAL Data Access Committee on their use of the INTERVAL trial data, including provision of copies of any publications. Applicants will be required to adhere in publications with the INTERVAL trial’s policy for acknowledgment of the trial’s funders, stakeholders, and scientific or technical contributors. The GRCh37 genome reference build is available for download from https://grch37.ensembl.org/info/data/ftp/index.html. Genomewide summary statistics may be downloaded by anonymous ftp from ftp://ftp.sanger.ac.uk/pub/project/humgen/summary_statistics/sysmex_blood_cell_genetics. The data from Ulirsch et al.29 are available from https://github.com/caleblareau/singlecell_bloodtraits/, from the Gene Expression Omnibus (GEO) under accession GSE119453 and from the Sequence Read Archive (SRA) under accession PRJNA491478. Other MK epigenetic data were generated by the BLUEPRINT project and are available in the EGA dataset EGAD00001001871.en_GB
dc.descriptionCode availability: The R code used for the association analysis is available in the git repository: https://github.com/ParsaAkbari/UKBB500K-Conditional-Analysis.en_GB
dc.identifier.eissn2041-1723
dc.identifier.journalNature Communicationsen_GB
dc.relation.ispartofNat Commun, 14(1)
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/en_GB
dcterms.dateAccepted2023-08-07
dc.rights.licenseCC BY
rioxxterms.versionVoRen_GB
rioxxterms.licenseref.startdate2023-08-18
rioxxterms.typeJournal Article/Reviewen_GB
refterms.dateFCD2023-11-16T14:20:12Z
refterms.versionFCDVoR
refterms.dateFOA2023-11-16T14:22:21Z
refterms.panelAen_GB
refterms.dateFirstOnline2023-08-18


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© The Author(s) 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/
Except where otherwise noted, this item's licence is described as © The Author(s) 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/