New gene functions in megakaryopoiesis and platelet formation

Christian Gieger*, Aparna Radhakrishnan, Ana Cvejic, Weihong Tang, Eleonora Porcu, Giorgio Pistis, Jovana Serbanovic-Canic, Ulrich Elling, Alison H. Goodall, Yann Labrune, Lorna M. Lopez, Reedik Mägi, Stuart Meacham, Yukinori Okada, Nicola Pirastu, Rossella Sorice, Alexander Teumer, Katrin Voss, Weihua Zhang, Ramiro Ramirez-SolisJoshua C. Bis, David Ellinghaus, Martin Gögele, Jouke Jan Hottenga, Claudia Langenberg, Peter Kovacs, Paul F. O'reilly, So Youn Shin, Tõnu Esko, Jaana Hartiala, Stavroula Kanoni, Federico Murgia, Afshin Parsa, Jonathan Stephens, Pim Van Der Harst, C. Ellen Van Der Schoot, Hooman Allayee, Antony Attwood, Beverley Balkau, François Bastardot, Saonli Basu, Sebastian E. Baumeister, Ginevra Biino, Lorenzo Bomba, Amélie Bonnefond, François Cambien, John C. Chambers, Francesco Cucca, Pio Dadamo, Gail Davies, Rudolf A. De Boer, Eco J.C. De Geus, Angela Döring, Paul Elliott, Jeanette Erdmann, David M. Evans, Mario Falchi, Wei Feng, Aaron R. Folsom, Ian H. Frazer, Quince D. Gibson, Nicole L. Glazer, Chris Hammond, Anna Liisa Hartikainen, Susan R. Heckbert, Christian Hengstenberg, Micha Hersch, Thomas Illig, Ruth J.F. Loos, Jennifer Jolley, Kay Tee Khaw, Brigitte Kühnel, Marie Christine Kyrtsonis, Vasiliki Lagou, Heather Lloyd-Jones, Thomas Lumley, Massimo Mangino, Andrea Maschio, Irene Mateo Leach, Barbara Mcknight, Yasin Memari, Braxton D. Mitchell, Grant W. Montgomery, Yusuke Nakamura, Matthias Nauck, Gerjan Navis, Ute Nöthlings, Ilja M. Nolte, David J. Porteous, Anneli Pouta, Peter P. Pramstaller, Janne Pullat, Susan M. Ring, Jerome I. Rotter, Daniela Ruggiero, Aimo Ruokonen, Cinzia Sala, Nilesh J. Samani, Jennifer Sambrook, David Schlessinger, Stefan Schreiber, Heribert Schunkert, James Scott, Nicholas L. Smith, Harold Snieder, John M. Starr, Michael Stumvoll, Atsushi Takahashi, W. H. Wilson Tang, Kent Taylor, Albert Tenesa, Swee Lay Thein, Anke Tönjes, Manuela Uda, Sheila Ulivi, Dirk J. Van Veldhuisen, Peter M. Visscher, Uwe Völker, H. Erich Wichmann, Kerri L. Wiggins, Gonneke Willemsen, Tsun Po Yang, Jing Hua Zhao, Paavo Zitting, John R. Bradley, George V. Dedoussis, Paolo Gasparini, Stanley L. Hazen, Andres Metspalu, Mario Pirastu, Alan R. Shuldiner, L. Joost Van Pelt, Jaap Jan Zwaginga, Dorret I. Boomsma, Ian J. Deary, Andre Franke, Philippe Froguel, Santhi K. Ganesh, Marjo Riitta Jarvelin, Nicholas G. Martin, Christa Meisinger, Bruce M. Psaty, Timothy D. Spector, Nicholas J. Wareham, Jan Willem N. Akkerman, Marina Ciullo, Panos Deloukas, Andreas Greinacher, Steve Jupe, Naoyuki Kamatani, Jyoti Khadake, Jaspal S. Kooner, Josef Penninger, Inga Prokopenko, Derek Stemple, Daniela Toniolo, Lorenz Wernisch, Serena Sanna, Andrew A. Hicks, Augusto Rendon, Manuel A. Ferreira, Willem H. Ouwehand, Nicole Soranzo

*Corresponding author for this work
209 Citations (Scopus)

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.

Original languageEnglish
JournalNature
Volume480
Issue number7376
Pages (from-to)201-208
Number of pages8
ISSN0028-0836
DOIs
Publication statusPublished - 08.12.2011

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