New gene functions in megakaryopoiesis and platelet formation

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

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Christian Gieger
van der Schoot et al., 2011

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Nature Research, Nature, 7376(480), p. 201-208, 2011

DOI: 10.1038/nature10659

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@article{van der Schoot2011,
  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.},
  author = {van der Schoot, C. Ellen and Gieger, Christian and van Pelt, L. Joost and Radhakrishnan, Aparna and Cvejic, Ana and Tang, Weihong and Porcu, Eleonora and Serbanovic-Canic, Jovana and Mägi, Reedik and Pistis, Giorgio and Goodall, Alison H. and Magi, Reedik and Elling, Ulrich and Maegi, Reedik and Labrune, Yann and Lopez, Lorna M. and Mägi, Reedik and Meacham, Stuart and Ah, Goodall and Okada, Yukinori and Pirastu, Nicola and Lm, Lopez and Sorice, Rossella and Teumer, Alexander and Voss, Katrin and Ouwehand, Wh and Zhang, Weihua and Ramirez-Solis, Ramiro and Goegele, Martin and Bis, Joshua C. and Gogele, Martin and Ellinghaus, David and Gögele, Martin and Gögele, Martin and Hottenga, Jouke-Jan and Langenberg, Claudia and Kovacs, Peter and O'Reilly, Paul F. and O’reilly, Paul F. and Shin, So-Youn and Esko, Tõnu and Hartiala, Jaana and Kanoni, Stavroula and Jc, Bis and Samani, Nj and Murgia, Federico and Parsa, Afshin and Stephens, Jonathan and van der Harst, Pim and Jj, Hottenga and Ellen van der Schoot, C. and Allayee, Hooman and Attwood, Antony and Pf, OReilly and Balkau, Beverley and Deary, Ij and Bastardot, François and Basu, Saonli and Baumeister, Sebastian E. and Sy, Shin and Biino, Ginevra and Bomba, Lorenzo and Doering, Angela and Bonnefond, Amélie and Cambien, François and Chambers, John C. and D'Adamo, Pio and Cucca, Francesco and D’Adamo, Adamo Pio and Davies, Gail and de Boer, Rudolf A. and de Geus, Eco J. C. and De Boer, Ra and Esko, Tõnu and Döring, Angela and Elliott, Paul and Erdmann, Jeanette and De Geus, Ejc and Evans, David M. and Falchi, Mario and Tang, Weihong H. Wilson and Feng, Wei and Folsom, Aaron R. and Frazer, Ian H. and Kuehnel, Brigitte and Gibson, Quince D. and Glazer, Nicole L. and Hammond, Chris and DAdamo, P. and Hartikainen, Anna-Liisa and Heckbert, Susan R. and Van Der Harst, P. and Hengstenberg, Christian and Hersch, Micha and Illig, Thomas and Se, Baumeister and Loos, Ruth J. F. and Jolley, Jennifer and Noethlings, Ute and Khaw, Kay-Tee and Kühnel, Brigitte and Kyrtsonis, Marie-Christine and Tee Khaw, Kay and Lagou, Vasiliki and Lloyd-Jones, Heather and Lumley, Thomas and Kuhnel, Brigitte and Mangino, Massimo and Maschio, Andrea and Jc, Chambers and Mateo Leach, Irene and Mcknight, Barbara and Memari, Yasin and Leach, Irene Mateo and Mitchell, Braxton D. and Montgomery, Grant W. and Nakamura, Yusuke and Ej, de Geus and Nauck, Matthias and Navis, Gerjan and Nöthlings, Ute and Nolte, Ilja M. and Porteous, David J. and Pouta, Anneli and Pramstaller, Peter Pp and Pullat, Janne and Ring, Susan M. and Rotter, Jerome I. and Dm, Evans and Ruggiero, Daniela and Dj, Van Veldhuisen and Ruokonen, Aimo and Sala, Cinzia and Samani, Nilesh J. and Sambrook, Jennifer and Ar, Folsom and Schlessinger, David and Schreiber, Stefan and Schunkert, Heribert and Ih, Frazer and Scott, James and Smith, Nicholas L. and Starr, John M. and Snieder, Harold and Qd, Gibson and Stumvoll, Michael and Thein, Swee Lay and Takahashi, Atsushi and Wilson Tang, Wh H. and Taylor, Kent and Nl, Glazer and Tenesa, Albert and Lay Thein, Swee and Tönjes, Anke and Toenjes, Anke and Uda, Manuela and Ulivi, Sheila and Erich Wichmann, H. and van Veldhuisen, Dirk J. and Visscher, Peter M. and Völker, Uwe and Al, Hartikainen and Wichmann, H.-Erich and Wiggins, Kerri L. and Smith, Nl and Willemsen, Gonneke and Yang, Tsun-Po and Hua Zhao, Jing and Sr, Heckbert and Zitting, Paavo and Bradley, John R. and Dedoussis, George V. and Zhao, Jing Hua and Gasparini, Paolo and Hazen, Stanley L. and Volker, Uwe and Metspalu, Andres and Pirastu, Mario and Shuldiner, Alan R. and Voelker, Uwe and Joost Van Pelt, L. and Visscher, Pm and Zwaginga, Jaap-Jan and Boomsma, Dorret I. and Deary, Ian J. and Franke, Andre and Rj, Loos and Froguel, Philippe and Ganesh, Santhi K. and Jarvelin, Marjo-Riitta and Nöthlings, U. and Martin, Nicholas G. and Meisinger, Christa and Kýhnel, B. and Porteous, Dj and Spector, Timothy D. and Wareham, Nicholas J. and Mc, Kyrtsonis and Akkerman, Jan-Willem N. and Ciullo, Marina and Deloukas, Panos and Starr, Jm and Greinacher, Andreas and Jupe, Steve and Psaty, Bruce M. and Kamatani, Naoyuki and Khadake, Jyoti and Kooner, Jaspal S. and Wh, Wilson Tang and Penninger, Josef and Prokopenko, Inga and Stemple, Derek and Bd, Mitchell and Toniolo, Daniela and Wernisch, Lorenz and Shuldiner, Ar and Sanna, Serena and Hicks, Andrew Aa and Rendon, Augusto and Gw, Montgomery and Ferreira, Manuel A. and Psaty, Bm and Im, Nolte and Soranzo, Nicole and Ouwehand, Willem H.},
  doi = {10.1038/nature10659},
  journal = {Nature},
  month = {nov},
  pages = {201-208},
  title = {New gene functions in megakaryopoiesis and platelet formation},
  url = {http://www.nature.com/articles/nature10659.pdf},
  volume = {480},
  year = {2011}
}

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New gene functions in megakaryopoiesis and platelet formation

Journal article published in 2011 by C. Ellen van der Schoot, Christian Gieger

, L. Joost van Pelt, Aparna Radhakrishnan, Ana Cvejic, Weihong Tang, Eleonora Porcu, Jovana Serbanovic-Canic, Reedik Mägi

, Giorgio Pistis, Alison H. Goodall, Reedik Magi, Ulrich Elling, Reedik Maegi, Yann Labrune and other authors. C. Ellen van der Schoot, Christian Gieger

, L. Joost van Pelt, Aparna Radhakrishnan, Ana Cvejic, Weihong Tang, Eleonora Porcu, Jovana Serbanovic-Canic, Reedik Mägi

, Giorgio Pistis, Alison H. Goodall, Reedik Magi, Ulrich Elling, Reedik Maegi, Yann Labrune, Lorna M. Lopez, Reedik Mägi, Stuart Meacham, Goodall Ah, Yukinori Okada, Nicola Pirastu, Lopez Lm, Rossella Sorice, Alexander Teumer, Katrin Voss, Wh Ouwehand, Weihua Zhang, Ramiro Ramirez-Solis, Martin Goegele, Joshua C. Bis, Martin Gogele, David Ellinghaus, Martin Gögele, Martin Gögele, Jouke-Jan Hottenga, Claudia Langenberg, Peter Kovacs, Paul F. O'Reilly, Paul F. O’reilly, So-Youn Shin, Tõnu Esko

, Jaana Hartiala, Stavroula Kanoni

, Bis Jc, Nj Samani, Federico Murgia

, Afshin Parsa, Jonathan Stephens, Pim van der Harst, Hottenga Jj, C. Ellen van der Schoot, Hooman Allayee, Antony Attwood, OReilly Pf, Beverley Balkau, Ij Deary, François Bastardot, Saonli Basu, Sebastian E. Baumeister, Shin Sy, Ginevra Biino

, Lorenzo Bomba, Angela Doering, Amélie Bonnefond

, François Cambien, John C. Chambers, Pio D'Adamo, Francesco Cucca, Adamo Pio D’Adamo

, Gail Davies, Rudolf A. de Boer, Eco J. C. de Geus, Ra De Boer, Tõnu Esko, Angela Döring, Paul Elliott, Jeanette Erdmann, Ejc De Geus, David M. Evans, Mario Falchi

, Weihong H. Wilson Tang, Wei Feng, Aaron R. Folsom, Ian H. Frazer, Brigitte Kuehnel, Quince D. Gibson, Nicole L. Glazer, Chris Hammond, P. DAdamo, Anna-Liisa Hartikainen, Susan R. Heckbert, P. Van Der Harst, Christian Hengstenberg, Micha Hersch, Thomas Illig, Baumeister Se, Ruth J. F. Loos, Jennifer Jolley, Ute Noethlings, Kay-Tee Khaw, Brigitte Kühnel, Marie-Christine Kyrtsonis, Kay Tee Khaw, Vasiliki Lagou, Heather Lloyd-Jones, Thomas Lumley, Brigitte Kuhnel, Massimo Mangino, Andrea Maschio, Chambers Jc, Irene Mateo Leach, Barbara Mcknight, Yasin Memari, Irene Mateo Leach, Braxton D. Mitchell, Grant W. Montgomery, Yusuke Nakamura, de Geus Ej, Matthias Nauck, Gerjan Navis, Ute Nöthlings, Ilja M. Nolte, David J. Porteous, Anneli Pouta, Peter Pp Pramstaller

, Janne Pullat, Susan M. Ring, Jerome I. Rotter, Evans Dm, Daniela Ruggiero, Van Veldhuisen Dj, Aimo Ruokonen, Cinzia Sala, Nilesh J. Samani, Jennifer Sambrook, Folsom Ar, David Schlessinger, Stefan Schreiber, Heribert Schunkert, Frazer Ih, James Scott, Nicholas L. Smith, John M. Starr, Harold Snieder, Gibson Qd, Michael Stumvoll, Swee Lay Thein, Atsushi Takahashi, Wh H. Wilson Tang, Kent Taylor, Glazer Nl, Albert Tenesa, Swee Lay Thein, Anke Tönjes, Anke Toenjes, Manuela Uda, Sheila Ulivi, H. Erich Wichmann, Dirk J. van Veldhuisen, Peter M. Visscher, Uwe Völker, Hartikainen Al, H.-Erich Wichmann, Kerri L. Wiggins, Nl Smith, Gonneke Willemsen, Tsun-Po Yang

, Jing Hua Zhao, Heckbert Sr, Paavo Zitting, John R. Bradley

, George V. Dedoussis, Jing Hua Zhao, Paolo Gasparini, Stanley L. Hazen, Uwe Volker, Andres Metspalu, Mario Pirastu, Alan R. Shuldiner, Uwe Voelker, L. Joost Van Pelt, Pm Visscher, Jaap-Jan Zwaginga, Dorret I. Boomsma, Ian J. Deary, Andre Franke, Loos Rj, Philippe Froguel, Santhi K. Ganesh, Marjo-Riitta Jarvelin, U. Nöthlings, Nicholas G. Martin

, Christa Meisinger

, B. Kýhnel, Dj Porteous, Timothy D. Spector, Nicholas J. Wareham, Kyrtsonis Mc, Jan-Willem N. Akkerman, Marina Ciullo, Panos Deloukas

, Jm Starr, Andreas Greinacher, Steve Jupe, Bruce M. Psaty, Naoyuki Kamatani, Jyoti Khadake, Jaspal S. Kooner, Wilson Tang Wh, Josef Penninger, Inga Prokopenko

, Derek Stemple, Mitchell Bd, Daniela Toniolo, Lorenz Wernisch, Ar Shuldiner, Serena Sanna

, Andrew Aa Hicks, Augusto Rendon, Montgomery Gw, Manuel A. Ferreira, Bm Psaty, Nolte Im, Nicole Soranzo, Willem H. Ouwehand

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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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New gene functions in megakaryopoiesis and platelet formation

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