Journal
NATURE
Volume 480, Issue 7376, Pages 201-208Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nature10659
Keywords
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Categories
Funding
- US National Institutes of Health [P41 HG003751]
- EU [LSHG-CT-2005-518254 'ENFIN', 215820]
- EBI Industry Programme
- Wellcome Trust [WT 082597/Z/07/Z, WT 077037/Z/05/Z, WT 077047/Z/05/Z, 098051]
- National Institute for Health Research, UK
- British Heart Foundation [RG/09/012/28096]
- ERC
- EC under SLING [226073, FP7-HEALTH-2007-223411]
- European Community
- ENGAGE Consortium [HEALTH-F4-2007-201413]
- Wellcome Trust [082597/Z/07/Z] Funding Source: Wellcome Trust
- Austrian Science Fund (FWF) [I 434] Funding Source: researchfish
- Biotechnology and Biological Sciences Research Council [BB/F019394/1] Funding Source: researchfish
- British Heart Foundation [RG/09/012/28096] Funding Source: researchfish
- Chief Scientist Office [ETM/55, CZB/4/505] Funding Source: researchfish
- Medical Research Council [G0801056, G0000111, G0401527, G0700704, G0701863, G0601966, G0801056B, MC_U106188470, MC_U106179471, G0700704B, G0700931, MC_U105260799, G1000143, G0701120] Funding Source: researchfish
- BBSRC [BB/F019394/1] Funding Source: UKRI
- MRC [G0601966, MC_U105260799, G0801056, G0700931, G0701863, G0700704, G0000111, MC_U106188470] Funding Source: UKRI
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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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