New gene functions in megakaryopoiesis and platelet formation |
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Authors: | Gieger Christian Radhakrishnan Aparna Cvejic Ana Tang Weihong Porcu Eleonora Pistis Giorgio Serbanovic-Canic Jovana Elling Ulrich Goodall Alison H Labrune Yann Lopez Lorna M Mägi Reedik Meacham Stuart Okada Yukinori Pirastu Nicola Sorice Rossella Teumer Alexander Voss Katrin Zhang Weihua Ramirez-Solis Ramiro Bis Joshua C Ellinghaus David Gögele Martin Hottenga Jouke-Jan Langenberg Claudia Kovacs Peter O'Reilly Paul F Shin So-Youn Esko Tõnu Hartiala Jaana Kanoni Stavroula Murgia Federico Parsa Afshin Stephens Jonathan van der Harst Pim Ellen van der Schoot C Allayee Hooman Attwood Antony |
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Affiliation: | Institute of Genetic Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Ingolst?dter Landstr 1, 85764 Neuherberg, Germany. christian.gieger@helmholtz-muenchen.de |
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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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