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-Solis; Joshua 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

doi:10.1038/nature10659

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

Research output: Contribution to journal › Article › peer-review

339 Scopus citations

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 language	English (US)
Pages (from-to)	201-208
Number of pages	8
Journal	Nature
Volume	480
Issue number	7376
DOIs	https://doi.org/10.1038/nature10659
State	Published - Dec 8 2011

Bibliographical note

Funding Information:
Acknowledgements Reactome is supported by grants from the US National Institutes of Health (P41 HG003751), EU grant LSHG-CT-2005-518254 ‘ENFIN’, and the EBI Industry Programme. A.C. and D.L.S. are supported by the Wellcome Trust grants WT 082597/Z/07/Z and WT 077037/Z/05/Z and WT 077047/Z/05/Z, respectively. J.S.C. and K.V. are supported by the European Union NetSim training fellowship scheme (number 215820). A. Radhakrishnan, A.A., H.L.J., J.J., J.S. and W.H.O. are funded by the National Institute for Health Research, UK. Augusto Rendon is funded by programme grant RG/09/012/28096 from the British Heart Foundation. J.M.P. is supported by an Advanced ERC grant. IntAct is funded by the EC under SLING, grant agreement no. 226073 (Integrating Activity) within Research Infrastructures of the FP7, under PSIMEX, contract no. FP7-HEALTH-2007-223411. C.G. received support by the European Community’s Seventh Framework Programme (FP7/2007-2013), ENGAGE Consortium, grant agreement HEALTH-F4-2007-201413. N.S. is supported by the Wellcome Trust (Grant Number 098051). Acknowledgements by individual participating studies are provided in Supplementary Information.

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Gieger, C., Radhakrishnan, A., Cvejic, A., Tang, W., Porcu, E., Pistis, G., Serbanovic-Canic, J., Elling, U., Goodall, A. H., Labrune, Y., Lopez, L. M., Mägi, R., Meacham, S., Okada, Y., Pirastu, N., Sorice, R., Teumer, A., Voss, K., Zhang, W., ... Soranzo, N. (2011). New gene functions in megakaryopoiesis and platelet formation. Nature, 480(7376), 201-208. https://doi.org/10.1038/nature10659

Gieger, C, Radhakrishnan, A, Cvejic, A, Tang, W, Porcu, E, Pistis, G, Serbanovic-Canic, J, Elling, U, Goodall, AH, Labrune, Y, Lopez, LM, Mägi, R, Meacham, S, Okada, Y, Pirastu, N, Sorice, R, Teumer, A, Voss, K, Zhang, W, Ramirez-Solis, R, Bis, JC, Ellinghaus, D, Gögele, M, Hottenga, JJ, Langenberg, C, Kovacs, P, O'reilly, PF, Shin, SY, Esko, T, Hartiala, J, Kanoni, S, Murgia, F, Parsa, A, Stephens, J, Van Der Harst, P, Ellen Van Der Schoot, C, Allayee, H, Attwood, A, Balkau, B, Bastardot, F, Basu, S, Baumeister, SE, Biino, G, Bomba, L, Bonnefond, A, Cambien, F, Chambers, JC, Cucca, F, Dadamo, P, Davies, G, De Boer, RA, De Geus, EJC, Döring, A, Elliott, P, Erdmann, J, Evans, DM, Falchi, M, Feng, W, Folsom, AR, Frazer, IH, Gibson, QD, Glazer, NL, Hammond, C, Hartikainen, AL, Heckbert, SR, Hengstenberg, C, Hersch, M, Illig, T, Loos, RJF, Jolley, J, Tee Khaw, K, Kühnel, B, Kyrtsonis, MC, Lagou, V, Lloyd-Jones, H, Lumley, T, Mangino, M, Maschio, A, Mateo Leach, I, Mcknight, B, Memari, Y, Mitchell, BD, Montgomery, GW, Nakamura, Y, Nauck, M, Navis, G, Nöthlings, U, Nolte, IM, Porteous, DJ, Pouta, A, Pramstaller, PP, Pullat, J, Ring, SM, Rotter, JI, Ruggiero, D, Ruokonen, A, Sala, C, Samani, NJ, Sambrook, J, Schlessinger, D, Schreiber, S, Schunkert, H, Scott, J, Smith, NL, Snieder, H, Starr, JM, Stumvoll, M, Takahashi, A, Wilson Tang, WH, Taylor, K, Tenesa, A, Lay Thein, S, Tönjes, A, Uda, M, Ulivi, S, Van Veldhuisen, DJ, Visscher, PM, Völker, U, Wichmann, HE, Wiggins, KL, Willemsen, G, Yang, TP, Hua Zhao, J, Zitting, P, Bradley, JR, Dedoussis, GV, Gasparini, P, Hazen, SL, Metspalu, A, Pirastu, M, Shuldiner, AR, Joost Van Pelt, L, Zwaginga, JJ, Boomsma, DI, Deary, IJ, Franke, A, Froguel, P, Ganesh, SK, Jarvelin, MR, Martin, NG, Meisinger, C, Psaty, BM, Spector, TD, Wareham, NJ, Akkerman, JWN, Ciullo, M, Deloukas, P, Greinacher, A, Jupe, S, Kamatani, N, Khadake, J, Kooner, JS, Penninger, J, Prokopenko, I, Stemple, D, Toniolo, D, Wernisch, L, Sanna, S, Hicks, AA, Rendon, A, Ferreira, MA, Ouwehand, WH & Soranzo, N 2011, 'New gene functions in megakaryopoiesis and platelet formation', Nature, vol. 480, no. 7376, pp. 201-208. https://doi.org/10.1038/nature10659

@article{36e60bd5fb8743b7a743ac9676b0f0ee,

title = "New gene functions in megakaryopoiesis and platelet formation",

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 = "Christian Gieger and Aparna Radhakrishnan and Ana Cvejic and Weihong Tang and Eleonora Porcu and Giorgio Pistis and Jovana Serbanovic-Canic and Ulrich Elling and Goodall, {Alison H.} and Yann Labrune and Lopez, {Lorna M.} and Reedik M{\"a}gi and Stuart Meacham and Yukinori Okada and Nicola Pirastu and Rossella Sorice and Alexander Teumer and Katrin Voss and Weihua Zhang and Ramiro Ramirez-Solis and Bis, {Joshua C.} and David Ellinghaus and Martin G{\"o}gele and Hottenga, {Jouke Jan} and Claudia Langenberg and Peter Kovacs and O'reilly, {Paul F.} and Shin, {So Youn} and T{\~o}nu Esko and Jaana Hartiala and Stavroula Kanoni and Federico Murgia and Afshin Parsa and Jonathan Stephens and {Van Der Harst}, Pim and {Ellen Van Der Schoot}, C. and Hooman Allayee and Antony Attwood and Beverley Balkau and Fran{\c c}ois Bastardot and Saonli Basu and Baumeister, {Sebastian E.} and Ginevra Biino and Lorenzo Bomba and Am{\'e}lie Bonnefond and Fran{\c c}ois Cambien and Chambers, {John C.} and Francesco Cucca and Pio Dadamo and Gail Davies and {De Boer}, {Rudolf A.} and {De Geus}, {Eco J C} and Angela D{\"o}ring and Paul Elliott and Jeanette Erdmann and Evans, {David M.} and Mario Falchi and Wei Feng and Folsom, {Aaron R.} and Frazer, {Ian H.} and Gibson, {Quince D.} and Glazer, {Nicole L.} and Chris Hammond and Hartikainen, {Anna Liisa} and Heckbert, {Susan R.} and Christian Hengstenberg and Micha Hersch and Thomas Illig and Loos, {Ruth J F} and Jennifer Jolley and {Tee Khaw}, Kay and Brigitte K{\"u}hnel and Kyrtsonis, {Marie Christine} and Vasiliki Lagou and Heather Lloyd-Jones and Thomas Lumley and Massimo Mangino and Andrea Maschio and {Mateo Leach}, Irene and Barbara Mcknight and Yasin Memari and Mitchell, {Braxton D.} and Montgomery, {Grant W.} and Yusuke Nakamura and Matthias Nauck and Gerjan Navis and Ute N{\"o}thlings and Nolte, {Ilja M.} and Porteous, {David J.} and Anneli Pouta and Pramstaller, {Peter P.} and Janne Pullat and Ring, {Susan M.} and Rotter, {Jerome I.} and Daniela Ruggiero and Aimo Ruokonen and Cinzia Sala and Samani, {Nilesh J.} and Jennifer Sambrook and David Schlessinger and Stefan Schreiber and Heribert Schunkert and James Scott and Smith, {Nicholas L.} and Harold Snieder and Starr, {John M.} and Michael Stumvoll and Atsushi Takahashi and {Wilson Tang}, {W. H.} and Kent Taylor and Albert Tenesa and {Lay Thein}, Swee and Anke T{\"o}njes and Manuela Uda and Sheila Ulivi and {Van Veldhuisen}, {Dirk J.} and Visscher, {Peter M.} and Uwe V{\"o}lker and Wichmann, {H. Erich} and Wiggins, {Kerri L.} and Gonneke Willemsen and Yang, {Tsun Po} and {Hua Zhao}, Jing and Paavo Zitting and Bradley, {John R.} and Dedoussis, {George V.} and Paolo Gasparini and Hazen, {Stanley L.} and Andres Metspalu and Mario Pirastu and Shuldiner, {Alan R.} and {Joost Van Pelt}, L. and Zwaginga, {Jaap Jan} and Boomsma, {Dorret I.} and Deary, {Ian J.} and Andre Franke and Philippe Froguel and Ganesh, {Santhi K.} and Jarvelin, {Marjo Riitta} and Martin, {Nicholas G.} and Christa Meisinger and Psaty, {Bruce M.} and Spector, {Timothy D.} and Wareham, {Nicholas J.} and Akkerman, {Jan Willem N} and Marina Ciullo and Panos Deloukas and Andreas Greinacher and Steve Jupe and Naoyuki Kamatani and Jyoti Khadake and Kooner, {Jaspal S.} and Josef Penninger and Inga Prokopenko and Derek Stemple and Daniela Toniolo and Lorenz Wernisch and Serena Sanna and Hicks, {Andrew A.} and Augusto Rendon and Ferreira, {Manuel A.} and Ouwehand, {Willem H.} and Nicole Soranzo",

note = "Funding Information: Acknowledgements Reactome is supported by grants from the US National Institutes of Health (P41 HG003751), EU grant LSHG-CT-2005-518254 {\textquoteleft}ENFIN{\textquoteright}, and the EBI Industry Programme. A.C. and D.L.S. are supported by the Wellcome Trust grants WT 082597/Z/07/Z and WT 077037/Z/05/Z and WT 077047/Z/05/Z, respectively. J.S.C. and K.V. are supported by the European Union NetSim training fellowship scheme (number 215820). A. Radhakrishnan, A.A., H.L.J., J.J., J.S. and W.H.O. are funded by the National Institute for Health Research, UK. Augusto Rendon is funded by programme grant RG/09/012/28096 from the British Heart Foundation. J.M.P. is supported by an Advanced ERC grant. IntAct is funded by the EC under SLING, grant agreement no. 226073 (Integrating Activity) within Research Infrastructures of the FP7, under PSIMEX, contract no. FP7-HEALTH-2007-223411. C.G. received support by the European Community{\textquoteright}s Seventh Framework Programme (FP7/2007-2013), ENGAGE Consortium, grant agreement HEALTH-F4-2007-201413. N.S. is supported by the Wellcome Trust (Grant Number 098051). Acknowledgements by individual participating studies are provided in Supplementary Information.",

year = "2011",

month = dec,

day = "8",

doi = "10.1038/nature10659",

language = "English (US)",

volume = "480",

pages = "201--208",

journal = "Nature",

issn = "0028-0836",

publisher = "Nature Research",

number = "7376",

}

TY - JOUR

T1 - New gene functions in megakaryopoiesis and platelet formation

AU - Gieger, Christian

AU - Radhakrishnan, Aparna

AU - Cvejic, Ana

AU - Tang, Weihong

AU - Porcu, Eleonora

AU - Pistis, Giorgio

AU - Serbanovic-Canic, Jovana

AU - Elling, Ulrich

AU - Goodall, Alison H.

AU - Labrune, Yann

AU - Lopez, Lorna M.

AU - Mägi, Reedik

AU - Meacham, Stuart

AU - Okada, Yukinori

AU - Pirastu, Nicola

AU - Sorice, Rossella

AU - Teumer, Alexander

AU - Voss, Katrin

AU - Zhang, Weihua

AU - Ramirez-Solis, Ramiro

AU - Bis, Joshua C.

AU - Ellinghaus, David

AU - Gögele, Martin

AU - Hottenga, Jouke Jan

AU - Langenberg, Claudia

AU - Kovacs, Peter

AU - O'reilly, Paul F.

AU - Shin, So Youn

AU - Esko, Tõnu

AU - Hartiala, Jaana

AU - Kanoni, Stavroula

AU - Murgia, Federico

AU - Parsa, Afshin

AU - Stephens, Jonathan

AU - Van Der Harst, Pim

AU - Ellen Van Der Schoot, C.

AU - Allayee, Hooman

AU - Attwood, Antony

AU - Balkau, Beverley

AU - Bastardot, François

AU - Basu, Saonli

AU - Baumeister, Sebastian E.

AU - Biino, Ginevra

AU - Bomba, Lorenzo

AU - Bonnefond, Amélie

AU - Cambien, François

AU - Chambers, John C.

AU - Cucca, Francesco

AU - Dadamo, Pio

AU - Davies, Gail

AU - De Boer, Rudolf A.

AU - De Geus, Eco J C

AU - Döring, Angela

AU - Elliott, Paul

AU - Erdmann, Jeanette

AU - Evans, David M.

AU - Falchi, Mario

AU - Feng, Wei

AU - Folsom, Aaron R.

AU - Frazer, Ian H.

AU - Gibson, Quince D.

AU - Glazer, Nicole L.

AU - Hammond, Chris

AU - Hartikainen, Anna Liisa

AU - Heckbert, Susan R.

AU - Hengstenberg, Christian

AU - Hersch, Micha

AU - Illig, Thomas

AU - Loos, Ruth J F

AU - Jolley, Jennifer

AU - Tee Khaw, Kay

AU - Kühnel, Brigitte

AU - Kyrtsonis, Marie Christine

AU - Lagou, Vasiliki

AU - Lloyd-Jones, Heather

AU - Lumley, Thomas

AU - Mangino, Massimo

AU - Maschio, Andrea

AU - Mateo Leach, Irene

AU - Mcknight, Barbara

AU - Memari, Yasin

AU - Mitchell, Braxton D.

AU - Montgomery, Grant W.

AU - Nakamura, Yusuke

AU - Nauck, Matthias

AU - Navis, Gerjan

AU - Nöthlings, Ute

AU - Nolte, Ilja M.

AU - Porteous, David J.

AU - Pouta, Anneli

AU - Pramstaller, Peter P.

AU - Pullat, Janne

AU - Ring, Susan M.

AU - Rotter, Jerome I.

AU - Ruggiero, Daniela

AU - Ruokonen, Aimo

AU - Sala, Cinzia

AU - Samani, Nilesh J.

AU - Sambrook, Jennifer

AU - Schlessinger, David

AU - Schreiber, Stefan

AU - Schunkert, Heribert

AU - Scott, James

AU - Smith, Nicholas L.

AU - Snieder, Harold

AU - Starr, John M.

AU - Stumvoll, Michael

AU - Takahashi, Atsushi

AU - Wilson Tang, W. H.

AU - Taylor, Kent

AU - Tenesa, Albert

AU - Lay Thein, Swee

AU - Tönjes, Anke

AU - Uda, Manuela

AU - Ulivi, Sheila

AU - Van Veldhuisen, Dirk J.

AU - Visscher, Peter M.

AU - Völker, Uwe

AU - Wichmann, H. Erich

AU - Wiggins, Kerri L.

AU - Willemsen, Gonneke

AU - Yang, Tsun Po

AU - Hua Zhao, Jing

AU - Zitting, Paavo

AU - Bradley, John R.

AU - Dedoussis, George V.

AU - Gasparini, Paolo

AU - Hazen, Stanley L.

AU - Metspalu, Andres

AU - Pirastu, Mario

AU - Shuldiner, Alan R.

AU - Joost Van Pelt, L.

AU - Zwaginga, Jaap Jan

AU - Boomsma, Dorret I.

AU - Deary, Ian J.

AU - Franke, Andre

AU - Froguel, Philippe

AU - Ganesh, Santhi K.

AU - Jarvelin, Marjo Riitta

AU - Martin, Nicholas G.

AU - Meisinger, Christa

AU - Psaty, Bruce M.

AU - Spector, Timothy D.

AU - Wareham, Nicholas J.

AU - Akkerman, Jan Willem N

AU - Ciullo, Marina

AU - Deloukas, Panos

AU - Greinacher, Andreas

AU - Jupe, Steve

AU - Kamatani, Naoyuki

AU - Khadake, Jyoti

AU - Kooner, Jaspal S.

AU - Penninger, Josef

AU - Prokopenko, Inga

AU - Stemple, Derek

AU - Toniolo, Daniela

AU - Wernisch, Lorenz

AU - Sanna, Serena

AU - Hicks, Andrew A.

AU - Rendon, Augusto

AU - Ferreira, Manuel A.

AU - Ouwehand, Willem H.

AU - Soranzo, Nicole

N1 - Funding Information: Acknowledgements Reactome is supported by grants from the US National Institutes of Health (P41 HG003751), EU grant LSHG-CT-2005-518254 ‘ENFIN’, and the EBI Industry Programme. A.C. and D.L.S. are supported by the Wellcome Trust grants WT 082597/Z/07/Z and WT 077037/Z/05/Z and WT 077047/Z/05/Z, respectively. J.S.C. and K.V. are supported by the European Union NetSim training fellowship scheme (number 215820). A. Radhakrishnan, A.A., H.L.J., J.J., J.S. and W.H.O. are funded by the National Institute for Health Research, UK. Augusto Rendon is funded by programme grant RG/09/012/28096 from the British Heart Foundation. J.M.P. is supported by an Advanced ERC grant. IntAct is funded by the EC under SLING, grant agreement no. 226073 (Integrating Activity) within Research Infrastructures of the FP7, under PSIMEX, contract no. FP7-HEALTH-2007-223411. C.G. received support by the European Community’s Seventh Framework Programme (FP7/2007-2013), ENGAGE Consortium, grant agreement HEALTH-F4-2007-201413. N.S. is supported by the Wellcome Trust (Grant Number 098051). Acknowledgements by individual participating studies are provided in Supplementary Information.

PY - 2011/12/8

Y1 - 2011/12/8

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=83055161438&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=83055161438&partnerID=8YFLogxK

U2 - 10.1038/nature10659

DO - 10.1038/nature10659

M3 - Article

C2 - 22139419

AN - SCOPUS:83055161438

SN - 0028-0836

VL - 480

SP - 201

EP - 208

JO - Nature

JF - Nature

IS - 7376

ER -

New gene functions in megakaryopoiesis and platelet formation

Abstract

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