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 D'Adamo; 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 D'Adamo, 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

Bristol Medical School (PHS)

Research output: Contribution to journal › Article (Academic Journal) › peer-review

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

Keywords

Animals
Zebrafish Proteins
Cell Size
Genome, Human
Protein Interaction Maps
Gene Silencing
Humans
Transcription, Genetic
Europe
Hematopoiesis
Zebrafish
Genome-Wide Association Study
Gene Expression Profiling
Blood Platelets
Drosophila melanogaster
Drosophila Proteins
Megakaryocytes
Platelet Count

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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), 201-8. https://doi.org/10.1038/nature10659

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 ; Balkau, Beverley ; Bastardot, François ; Basu, Saonli ; Baumeister, Sebastian E ; Biino, Ginevra ; Bomba, Lorenzo ; Bonnefond, Amélie ; Cambien, François ; Chambers, John C ; Cucca, Francesco ; D'Adamo, Pio ; Davies, Gail ; de Boer, Rudolf A ; de Geus, Eco J C ; Döring, Angela ; Elliott, Paul ; Erdmann, Jeanette ; Evans, David M ; Falchi, Mario ; Feng, Wei ; Folsom, Aaron R ; Frazer, Ian H ; Gibson, Quince D ; Glazer, Nicole L ; Hammond, Chris ; Hartikainen, Anna-Liisa ; Heckbert, Susan R ; Hengstenberg, Christian ; Hersch, Micha ; Illig, Thomas ; Loos, Ruth J F ; Jolley, Jennifer ; Khaw, Kay Tee ; Kühnel, Brigitte ; Kyrtsonis, Marie-Christine ; Lagou, Vasiliki ; Lloyd-Jones, Heather ; Lumley, Thomas ; Mangino, Massimo ; Maschio, Andrea ; Mateo Leach, Irene ; McKnight, Barbara ; Memari, Yasin ; Mitchell, Braxton D ; Montgomery, Grant W ; Nakamura, Yusuke ; Nauck, Matthias ; Navis, Gerjan ; Nöthlings, Ute ; Nolte, Ilja M ; Porteous, David J ; Pouta, Anneli ; Pramstaller, Peter P ; Pullat, Janne ; Ring, Susan M ; Rotter, Jerome I ; Ruggiero, Daniela ; Ruokonen, Aimo ; Sala, Cinzia ; Samani, Nilesh J ; Sambrook, Jennifer ; Schlessinger, David ; Schreiber, Stefan ; Schunkert, Heribert ; Scott, James ; Smith, Nicholas L ; Snieder, Harold ; Starr, John M ; Stumvoll, Michael ; Takahashi, Atsushi ; Tang, W H Wilson ; Taylor, Kent ; Tenesa, Albert ; Lay Thein, Swee ; Tönjes, Anke ; Uda, Manuela ; Ulivi, Sheila ; van Veldhuisen, Dirk J ; Visscher, Peter M ; Völker, Uwe ; Wichmann, H-Erich ; Wiggins, Kerri L ; Willemsen, Gonneke ; Yang, Tsun-Po ; Hua Zhao, Jing ; Zitting, Paavo ; Bradley, John R ; Dedoussis, George V ; Gasparini, Paolo ; Hazen, Stanley L ; Metspalu, Andres ; Pirastu, Mario ; Shuldiner, Alan R ; Joost van Pelt, L ; Zwaginga, Jaap-Jan ; Boomsma, Dorret I ; Deary, Ian J ; Franke, Andre ; Froguel, Philippe ; Ganesh, Santhi K ; Jarvelin, Marjo-Riitta ; Martin, Nicholas G ; Meisinger, Christa ; Psaty, Bruce M ; Spector, Timothy D ; Wareham, Nicholas J ; Akkerman, Jan-Willem N ; Ciullo, Marina ; Deloukas, Panos ; Greinacher, Andreas ; Jupe, Steve ; Kamatani, Naoyuki ; Khadake, Jyoti ; Kooner, Jaspal S ; Penninger, Josef ; Prokopenko, Inga ; Stemple, Derek ; Toniolo, Daniela ; Wernisch, Lorenz ; Sanna, Serena ; Hicks, Andrew A ; Rendon, Augusto ; Ferreira, Manuel A ; Ouwehand, Willem H ; Soranzo, Nicole. / New gene functions in megakaryopoiesis and platelet formation. In: Nature. 2011 ; Vol. 480, No. 7376. pp. 201-8.

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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.",

keywords = "Animals, Zebrafish Proteins, Cell Size, Genome, Human, Protein Interaction Maps, Gene Silencing, Humans, Transcription, Genetic, Europe, Hematopoiesis, Zebrafish, Genome-Wide Association Study, Gene Expression Profiling, Blood Platelets, Drosophila melanogaster, Drosophila Proteins, Megakaryocytes, Platelet Count",

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 Jouke-Jan Hottenga and Claudia Langenberg and Peter Kovacs and O'Reilly, {Paul F} and So-Youn Shin 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 D'Adamo 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 Anna-Liisa Hartikainen and Heckbert, {Susan R} and Christian Hengstenberg and Micha Hersch and Thomas Illig and Loos, {Ruth J F} and Jennifer Jolley and Khaw, {Kay Tee} and Brigitte K{\"u}hnel and Marie-Christine Kyrtsonis 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 Tang, {W H Wilson} 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 H-Erich Wichmann and Wiggins, {Kerri L} and Gonneke Willemsen and Tsun-Po Yang 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 Jaap-Jan Zwaginga and Boomsma, {Dorret I} and Deary, {Ian J} and Andre Franke and Philippe Froguel and Ganesh, {Santhi K} and Marjo-Riitta Jarvelin 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",

year = "2011",

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doi = "10.1038/nature10659",

language = "English",

volume = "480",

pages = "201--8",

journal = "Nature",

issn = "0028-0836",

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}

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, J-J, Langenberg, C, Kovacs, P, O'Reilly, PF, Shin, S-Y, 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, D'Adamo, 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, A-L, Heckbert, SR, Hengstenberg, C, Hersch, M, Illig, T, Loos, RJF, Jolley, J, Khaw, KT, Kühnel, B, Kyrtsonis, M-C, 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, Tang, WHW, Taylor, K, Tenesa, A, Lay Thein, S, Tönjes, A, Uda, M, Ulivi, S, van Veldhuisen, DJ, Visscher, PM, Völker, U, Wichmann, H-E, Wiggins, KL, Willemsen, G, Yang, T-P, Hua Zhao, J, Zitting, P, Bradley, JR, Dedoussis, GV, Gasparini, P, Hazen, SL, Metspalu, A, Pirastu, M, Shuldiner, AR, Joost van Pelt, L, Zwaginga, J-J, Boomsma, DI, Deary, IJ, Franke, A, Froguel, P, Ganesh, SK, Jarvelin, M-R, Martin, NG, Meisinger, C, Psaty, BM, Spector, TD, Wareham, NJ, Akkerman, J-WN, 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. 201-8. https://doi.org/10.1038/nature10659

New gene functions in megakaryopoiesis and platelet formation. / 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; Balkau, Beverley; Bastardot, François; Basu, Saonli; Baumeister, Sebastian E; Biino, Ginevra; Bomba, Lorenzo; Bonnefond, Amélie; Cambien, François; Chambers, John C; Cucca, Francesco; D'Adamo, Pio; Davies, Gail; de Boer, Rudolf A; de Geus, Eco J C; Döring, Angela; Elliott, Paul; Erdmann, Jeanette; Evans, David M; Falchi, Mario; Feng, Wei; Folsom, Aaron R; Frazer, Ian H; Gibson, Quince D; Glazer, Nicole L; Hammond, Chris; Hartikainen, Anna-Liisa; Heckbert, Susan R; Hengstenberg, Christian; Hersch, Micha; Illig, Thomas; Loos, Ruth J F; Jolley, Jennifer; Khaw, Kay Tee; Kühnel, Brigitte; Kyrtsonis, Marie-Christine; Lagou, Vasiliki; Lloyd-Jones, Heather; Lumley, Thomas; Mangino, Massimo; Maschio, Andrea; Mateo Leach, Irene; McKnight, Barbara; Memari, Yasin; Mitchell, Braxton D; Montgomery, Grant W; Nakamura, Yusuke; Nauck, Matthias; Navis, Gerjan; Nöthlings, Ute; Nolte, Ilja M; Porteous, David J; Pouta, Anneli; Pramstaller, Peter P; Pullat, Janne; Ring, Susan M; Rotter, Jerome I; Ruggiero, Daniela; Ruokonen, Aimo; Sala, Cinzia; Samani, Nilesh J; Sambrook, Jennifer; Schlessinger, David; Schreiber, Stefan; Schunkert, Heribert; Scott, James; Smith, Nicholas L; Snieder, Harold; Starr, John M; Stumvoll, Michael; Takahashi, Atsushi; Tang, W H Wilson; Taylor, Kent; Tenesa, Albert; Lay Thein, Swee; Tönjes, Anke; Uda, Manuela; Ulivi, Sheila; van Veldhuisen, Dirk J; Visscher, Peter M; Völker, Uwe; Wichmann, H-Erich; Wiggins, Kerri L; Willemsen, Gonneke; Yang, Tsun-Po; Hua Zhao, Jing; Zitting, Paavo; Bradley, John R; Dedoussis, George V; Gasparini, Paolo; Hazen, Stanley L; Metspalu, Andres; Pirastu, Mario; Shuldiner, Alan R; Joost van Pelt, L; Zwaginga, Jaap-Jan; Boomsma, Dorret I; Deary, Ian J; Franke, Andre; Froguel, Philippe; Ganesh, Santhi K; Jarvelin, Marjo-Riitta; Martin, Nicholas G; Meisinger, Christa; Psaty, Bruce M; Spector, Timothy D; Wareham, Nicholas J; Akkerman, Jan-Willem N; Ciullo, Marina; Deloukas, Panos; Greinacher, Andreas; Jupe, Steve; Kamatani, Naoyuki; Khadake, Jyoti; Kooner, Jaspal S; Penninger, Josef; Prokopenko, Inga; Stemple, Derek; Toniolo, Daniela; Wernisch, Lorenz; Sanna, Serena; Hicks, Andrew A; Rendon, Augusto; Ferreira, Manuel A; Ouwehand, Willem H; Soranzo, Nicole.

In: Nature, Vol. 480, No. 7376, 08.12.2011, p. 201-8.

Research output: Contribution to journal › Article (Academic Journal) › peer-review

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 - D'Adamo, 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 - Khaw, Kay Tee

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 - Tang, W H Wilson

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

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.

KW - Animals

KW - Zebrafish Proteins

KW - Cell Size

KW - Genome, Human

KW - Protein Interaction Maps

KW - Gene Silencing

KW - Humans

KW - Transcription, Genetic

KW - Europe

KW - Hematopoiesis

KW - Zebrafish

KW - Genome-Wide Association Study

KW - Gene Expression Profiling

KW - Blood Platelets

KW - Drosophila melanogaster

KW - Drosophila Proteins

KW - Megakaryocytes

KW - Platelet Count

U2 - 10.1038/nature10659

DO - 10.1038/nature10659

M3 - Article (Academic Journal)

C2 - 22139419

VL - 480

SP - 201

EP - 208

JO - Nature

JF - Nature

SN - 0028-0836

IS - 7376

ER -