Abstract
Original language | English |
---|---|
Article number | 5023 |
Journal | Nature communications |
Volume | 14 |
Issue number | 1 |
DOIs | |
Publication status | Published - 1 Dec 2023 |
Access to Document
Other files and links
Cite this
- APA
- Author
- BIBTEX
- Harvard
- Standard
- RIS
- Vancouver
}
In: Nature communications, Vol. 14, No. 1, 5023, 01.12.2023.
Research output: Contribution to journal › Article › Academic › peer-review
TY - JOUR
T1 - A genome-wide association study of blood cell morphology identifies cellular proteins implicated in disease aetiology
AU - Akbari, Parsa
AU - Vuckovic, Dragana
AU - Stefanucci, Luca
AU - Jiang, Tao
AU - Kundu, Kousik
AU - Kreuzhuber, Roman
AU - Bao, Erik L.
AU - Collins, Janine H.
AU - Downes, Kate
AU - Grassi, Luigi
AU - Guerrero, Jose A.
AU - Kaptoge, Stephen
AU - Knight, Julian C.
AU - Meacham, Stuart
AU - Sambrook, Jennifer
AU - Seyres, Denis
AU - Stegle, Oliver
AU - Verboon, Jeffrey M.
AU - Walter, Klaudia
AU - Watkins, Nicholas A.
AU - Danesh, John
AU - Roberts, David J.
AU - di Angelantonio, Emanuele
AU - Sankaran, Vijay G.
AU - Frontini, Mattia
AU - Burgess, Stephen
AU - Kuijpers, Taco
AU - Peters, James E.
AU - Butterworth, Adam S.
AU - Ouwehand, Willem H.
AU - Soranzo, Nicole
AU - Astle, William J.
N1 - Funding Information: The authors are grateful to the participants in the INTERVAL study, whose generosity made this work possible. INTERVAL is a collaboration between the University of Cambridge, the University of Oxford and National Health Service Blood and Transplant (NHSBT; www.nhsbt.nhs.uk). We thank Dr Carmel Moore and the study coordination teams at the University of Cambridge, the University of Oxford and NHSBT. In particular we recognise the contribution of Dr Jennifer Sambrook, whose work made this study possible, and who sadly died before its final publication. We thank Dr Matthew Walker of the Cardiovascular Epidemiology Unit, and the data management team of the NIHR Blood and Transplant Research Unit (BTRU) in Donor Health and Genomics. We thank Dr Jarob Saker and Dr Joachim Linssen of Sysmex Europe and Mr Stephen Garner, lately of the NHSBT Component Development Laboratory, for their invaluable advice on the Sysmex XN-1000 instrument. We thank Joanna Westmoreland of the Medical Research Council (MRC) Laboratory of Molecular Biology for preparing illustrations and artwork. We thank members of the NIHR Cambridge BioResource Scientific Advisory Board and Management Committee for their support of the study. DNA extraction and genotyping were co-funded by the National Institute for Health and Care Research (NIHR), the NIHR BioResource (http://bioresource.nihr.ac.uk) and the NIHR Cambridge Biomedical Research Centre (BRC) (BRC-1215-20014) [*]. The academic coordinating centre for INTERVAL was supported by core funding from: the NIHR BTRU in Donor Health and Genomics (NIHR BTRU-2014-10024), the NIHR BTRU in Donor Health and Behaviour (NIHR203337), the NIHR Cambridge BRC (BRC-1215-20014; NIHR203312), the MRC (MR/L003120/1) and the British Heart Foundation (BHF) (SP/09/002; RG/13/13/30194; RG/18/13/33946) [*]. A complete list of the investigators and contributors to the INTERVAL trial is given in Di Angelantonio et al.103. The academic coordinating centre would like to thank blood donor centre staff for their help and to thank blood donors for participating in the INTERVAL trial. This work was supported by Health Data Research UK (HDR UK), which is funded by the MRC, the Engineering and Physical Sciences Research Council, the Economic and Social Research Council, the Department of Health and Social Care (England), the Chief Scientist Office of the Scottish Government Health and Social Care Directorates, the Health and Social Care Research and Development Division (Welsh Government), the Public Health Agency (Northern Ireland), the BHF and the Wellcome Trust. P.A. and D.V. were funded by the NIHR BTRU in Donor Health and Genomics (NIHR BTRU-2014-10024). T.J. is funded by a Cambridge University MRC Doctoral Training Programme (MR/S502443/1) topped up by Sackler and the NIHR Cambridge BRC [*]. J.H.C. is supported by a MRC Clinical Research Training Fellowship (MR/P02002X/1). K.D. is supported by Health Education England as an HSST trainee. J.C.K. is funded by a Wellcome Trust Investigator Award (204969/Z/16/Z to J.C.K.), Wellcome Trust Grants (074318 to J.C.K., 090532/Z/09/Z and 203141/Z/16/Z to the Wellcome Centre for Human Genetics core facility), NIHR Oxford BRC. S.K. is funded by a BHF Chair award (CH/12/2/29428). J.D. holds a BHF Professorship and a NIHR Senior Investigator Award [*]. V.G.S. is supported by NIH grants R01 DK103794, R01 CA265726, R01 HL146500; a gift from the Lodish Family to Boston Children’s Hospital; the Mathers Foundation; and the New York Stem Cell Foundation (NYSCF). V.G.S. is a NYSCF-Robertson Investigator. M.F. is funded by the BHF (FS/18/53/33863) and is supported by the NIHR Exeter BRC. J.E.P. is supported by a UKRI Innovation Fellowship at HDR UK (MR/S004068/1). Research in the W.H.O. laboratory was funded by the International Society on Thrombosis and Haemostasis, the MRC, NHSBT and the Rosetrees Trust. W.J.A. is funded by NHSBT and the NIHR Cambridge BRC [*]. *The views expressed are those of the authors and not necessarily those of the NIHR, NHSBT or the Department of Health and Social Care. Funding Information: The authors are grateful to the participants in the INTERVAL study, whose generosity made this work possible. INTERVAL is a collaboration between the University of Cambridge, the University of Oxford and National Health Service Blood and Transplant (NHSBT; www.nhsbt.nhs.uk ). We thank Dr Carmel Moore and the study coordination teams at the University of Cambridge, the University of Oxford and NHSBT. In particular we recognise the contribution of Dr Jennifer Sambrook, whose work made this study possible, and who sadly died before its final publication. We thank Dr Matthew Walker of the Cardiovascular Epidemiology Unit, and the data management team of the NIHR Blood and Transplant Research Unit (BTRU) in Donor Health and Genomics. We thank Dr Jarob Saker and Dr Joachim Linssen of Sysmex Europe and Mr Stephen Garner, lately of the NHSBT Component Development Laboratory, for their invaluable advice on the Sysmex XN-1000 instrument. We thank Joanna Westmoreland of the Medical Research Council (MRC) Laboratory of Molecular Biology for preparing illustrations and artwork. We thank members of the NIHR Cambridge BioResource Scientific Advisory Board and Management Committee for their support of the study. DNA extraction and genotyping were co-funded by the National Institute for Health and Care Research (NIHR), the NIHR BioResource ( http://bioresource.nihr.ac.uk ) and the NIHR Cambridge Biomedical Research Centre (BRC) (BRC-1215-20014) [*]. The academic coordinating centre for INTERVAL was supported by core funding from: the NIHR BTRU in Donor Health and Genomics (NIHR BTRU-2014-10024), the NIHR BTRU in Donor Health and Behaviour (NIHR203337), the NIHR Cambridge BRC (BRC-1215-20014; NIHR203312), the MRC (MR/L003120/1) and the British Heart Foundation (BHF) (SP/09/002; RG/13/13/30194; RG/18/13/33946) [*]. A complete list of the investigators and contributors to the INTERVAL trial is given in Di Angelantonio et al.. The academic coordinating centre would like to thank blood donor centre staff for their help and to thank blood donors for participating in the INTERVAL trial. This work was supported by Health Data Research UK (HDR UK), which is funded by the MRC, the Engineering and Physical Sciences Research Council, the Economic and Social Research Council, the Department of Health and Social Care (England), the Chief Scientist Office of the Scottish Government Health and Social Care Directorates, the Health and Social Care Research and Development Division (Welsh Government), the Public Health Agency (Northern Ireland), the BHF and the Wellcome Trust. P.A. and D.V. were funded by the NIHR BTRU in Donor Health and Genomics (NIHR BTRU-2014-10024). T.J. is funded by a Cambridge University MRC Doctoral Training Programme (MR/S502443/1) topped up by Sackler and the NIHR Cambridge BRC [*]. J.H.C. is supported by a MRC Clinical Research Training Fellowship (MR/P02002X/1). K.D. is supported by Health Education England as an HSST trainee. J.C.K. is funded by a Wellcome Trust Investigator Award (204969/Z/16/Z to J.C.K.), Wellcome Trust Grants (074318 to J.C.K., 090532/Z/09/Z and 203141/Z/16/Z to the Wellcome Centre for Human Genetics core facility), NIHR Oxford BRC. S.K. is funded by a BHF Chair award (CH/12/2/29428). J.D. holds a BHF Professorship and a NIHR Senior Investigator Award [*]. V.G.S. is supported by NIH grants R01 DK103794, R01 CA265726, R01 HL146500; a gift from the Lodish Family to Boston Children’s Hospital; the Mathers Foundation; and the New York Stem Cell Foundation (NYSCF). V.G.S. is a NYSCF-Robertson Investigator. M.F. is funded by the BHF (FS/18/53/33863) and is supported by the NIHR Exeter BRC. J.E.P. is supported by a UKRI Innovation Fellowship at HDR UK (MR/S004068/1). Research in the W.H.O. laboratory was funded by the International Society on Thrombosis and Haemostasis, the MRC, NHSBT and the Rosetrees Trust. W.J.A. is funded by NHSBT and the NIHR Cambridge BRC [*]. *The views expressed are those of the authors and not necessarily those of the NIHR, NHSBT or the Department of Health and Social Care. Publisher Copyright: © 2023, Springer Nature Limited.
PY - 2023/12/1
Y1 - 2023/12/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85168375407&partnerID=8YFLogxK
U2 - https://doi.org/10.1038/s41467-023-40679-y
DO - https://doi.org/10.1038/s41467-023-40679-y
M3 - Article
C2 - 37596262
SN - 2041-1723
VL - 14
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 5023
ER -