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 Maegi, Stuart Meacham, Yukinori Okada, Nicola Pirastu, Rossella Sorice, Alexander Teumer, Katrin Voss, Weihua Zhang, Ramiro Ramirez-SolisJoshua C. Bis, David Ellinghaus, Martin Goegele, Jouke-Jan Hottenga, Claudia Langenberg, Peter Kovacs, Paul F. O'Reilly, So-Youn Shin, Toenu 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, Francois Bastardot, Saonli Basu, Sebastian E. Baumeister, Ginevra Biino, Lorenzo Bomba, Amelie Bonnefond, Francois Cambien, John C. Chambers, Francesco Cucca, Pio D'Adamo, Gail Davies, Rudolf A. de Boer, Eco J. C. de Geus, Angela Doering, 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 Kuehnel, 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 Noethlings, 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 Toenjes, Manuela Uda, Sheila Ulivi, Dirk J. van Veldhuisen, Peter M. Visscher, Uwe Voelker, 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

*Bijbehorende auteur voor dit werk

OnderzoeksoutputAcademicpeer review

290 Citaten (Scopus)

Samenvatting

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.

Originele taal-2English
Pagina's (van-tot)201-208
Aantal pagina's8
TijdschriftNature
Volume480
Nummer van het tijdschrift7376
DOI's
StatusPublished - 8-dec-2011

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