Abstract
Platelets are the second most abundant cell type in blood and are essential for maintaining haemostasis. Their count and volume are tightly controlled within narrow physiological ranges, but there is only limited understanding of the molecular processes controlling both traits. Here we carried out a high-powered meta-analysis of genome-wide association studies (GWAS) in up to 66,867 individuals of European ancestry, followed by extensive biological and functional assessment. We identified 68 genomic loci reliably associated with platelet count and volume mapping to established and putative novel regulators of megakaryopoiesis and platelet formation. These genes show megakaryocyte-specific gene expression patterns and extensive network connectivity. Using gene silencing in Danio rerio and Drosophila melanogaster, we identified 11 of the genes as novel regulators of blood cell formation. Taken together, our findings advance understanding of novel gene functions controlling fate-determining events during megakaryopoiesis and platelet formation, providing a new example of successful translation of GWAS to function.
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Acknowledgements
Reactome is supported by grants from the US National Institutes of Health (P41 HG003751), EU grant LSHG-CT-2005-518254 ‘ENFIN’, and the EBI Industry Programme. A.C. and D.L.S. are supported by the Wellcome Trust grants WT 082597/Z/07/Z and WT 077037/Z/05/Z and WT 077047/Z/05/Z, respectively. J.S.C. and K.V. are supported by the European Union NetSim training fellowship scheme (number 215820). A. Radhakrishnan, A.A., H.L.J., J.J., J.S. and W.H.O. are funded by the National Institute for Health Research, UK. Augusto Rendon is funded by programme grant RG/09/012/28096 from the British Heart Foundation. J.M.P. is supported by an Advanced ERC grant. IntAct is funded by the EC under SLING, grant agreement no. 226073 (Integrating Activity) within Research Infrastructures of the FP7, under PSIMEX, contract no. FP7-HEALTH-2007-223411. C.G. received support by the European Community’s Seventh Framework Programme (FP7/2007-2013), ENGAGE Consortium, grant agreement HEALTH-F4-2007- 201413. N.S. is supported by the Wellcome Trust (Grant Number 098051). Acknowledgements by individual participating studies are provided in Supplementary Information.
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Study design group: C.G., S. Sanna, A.A.H., A. Rendon, M.A.F., W.H.O., N.S.; manuscript writing group: C.G., A. Radhakrishnan, S. Sanna, A.A.H., A. Rendon, M.A.F., W.H.O., N.S.; data preparation, meta-analysis and secondary analysis group: A. Radhakrishnan, B.K., W.T., E.P., G.P., R.M., M.A.F., C.G., N.S.; bioinformatics analyses, pathway analyses and protein–protein interaction network group: S.M., J.-W.N.A., S.J., J.K., Y.M., L.B., A. Rendon, W.H.O.; transcript profiling methods and data group: K.V., A. Rendon, L.W., A.H.G., T.-P.Y., F. Cambien, J.E., C. Hengstenberg, N.J.S., H. Schunkert, P.D., W.H.O.; M. musculus models: R.R.-S.; D. rerio knockdown models: A.C., J.S.-C., D. Stemple, W.H.O.; D. melanogaster knockdown models: U.E., J. Penninger and A.A.H. All other author contributions and roles are listed in Supplementary Information.
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Supplementary Information
The file contains Supplementary Text, Supplementary References, Supplementary Acknowledgements and Author Contributions, Supplementary Tables 2-8 (see separate file for Supplementary Table 1), Supplementary Data and Supplementary Figures 1-6 - see the contents page for more details. This file was replaced online on 02 April 2012 as the Supplementary Tables and supplementary Figures were missing from the original file. (PDF 9853 kb)
Supplementary Table 1
The table shows a summary of population descriptives, trait measurements and details of genotyping and analysis metrics and methods. This file was replaced on line on 13 April 2012 as the file originally posted on line erroneously contained Supplementary Tables 2-8. (XLS 44 kb)
Supplementary Data
The file shows Protein-protein interaction network, containing gene expression levels and other annotation features. This file was removed from our website on 13 April 2012 as the original file posted was corrupted. To download this information please go to the following link - https://haemgen.haem.cam.ac.uk/files/. (ZIP 84 kb)
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Gieger, C., Radhakrishnan, A., Cvejic, A. et al. New gene functions in megakaryopoiesis and platelet formation. Nature 480, 201–208 (2011). https://doi.org/10.1038/nature10659
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DOI: https://doi.org/10.1038/nature10659
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