New gene functions in megakaryopoiesis and platelet formation

Gieger, C; Radhakrishnan, A; Cvejic, A; Tang, Wh; Porcu, E; Pistis, G; Serbanovic Canic, J; Elling, U; Goodall, Ah; Labrune, Y; Lopez, Lm; Magi, R; Meacham, S; Okada, Y; Pirastu, N; Sorice, R; Teumer, A; Voss, K; Zhang, Wh; Ramirez Solis, R; Bis, Jc; Ellinghaus, D; Gogele, 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; van der Schoot CE,; Allayee, H; Attwood, A; Balkau, B; Bastardot, F; Basu, S; Baumeister, Se; Biino, G; Bomba, L; Bonnefond, A; Cambien, F; Chambers, Jc; Cucca, Francesco; D'Adamo, P; Davies, G; de Boer RA,; de Geus EJC,; Doring, 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; Rjf, Loos; Jolley, J; Khaw, Kt; Kuhnel, B; Kyrtsonis, Mc; Lagou, V; Lloyd Jones, H; Lumley, T; Mangino, M; Maschio, A; Leach, Im; Mcknight, B; Memari, Y; Mitchell, Bd; Montgomery, Gw; Nakamura, Y; Nauck, M; Navis, G; Nothlings, 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; Whw, Tang; Taylor, K; Tenesa, A; Thein, Sl; Tonjes, A; Uda, M; Ulivi, S; van Veldhuisen DJ,; Visscher, Pm; Volker, U; Wichmann, He; Wiggins, Kl; Willemsen, G; Yang, Tp; Zhao, Jh; Zitting, P; Bradley, Jr; Dedoussis, Gv; Gasparini, P; Hazen, Sl; Metspalu, A; Pirastu, M; Shuldiner, Ar; van Pelt LJ,; Zwaginga, Jj; Boomsma, Di; Deary, Ij; Franke, A; Froguel, P; Ganesh, Sk; Jarvelin, Mr; Martin, Ng; Meisinger, C; Psaty, Bm; Spector, Td; Wareham, Nj; Jwn, Akkerman; 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.

doi:10.1038/nature10659

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.

New gene functions in megakaryopoiesis and platelet formation / Gieger, C; Radhakrishnan, A; Cvejic, A; Tang, Wh; Porcu, E; Pistis, G; Serbanovic Canic, J; Elling, U; Goodall, Ah; Labrune, Y; Lopez, Lm; Magi, R; Meacham, S; Okada, Y; Pirastu, N; Sorice, R; Teumer, A; Voss, K; Zhang, Wh; Ramirez Solis, R; Bis, Jc; Ellinghaus, D; Gogele, 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; van der Schoot, Ce; Allayee, H; Attwood, A; Balkau, B; Bastardot, F; Basu, S; Baumeister, Se; Biino, G; Bomba, L; Bonnefond, A; Cambien, F; Chambers, Jc; Cucca, Francesco; D'Adamo, P; Davies, G; de Boer, Ra; de Geus, Ejc; Doring, 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; Khaw, Kt; Kuhnel, B; Kyrtsonis, Mc; Lagou, V; Lloyd Jones, H; Lumley, T; Mangino, M; Maschio, A; Leach, Im; Mcknight, B; Memari, Y; Mitchell, Bd; Montgomery, Gw; Nakamura, Y; Nauck, M; Navis, G; Nothlings, 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; Thein, Sl; Tonjes, A; Uda, M; Ulivi, S; van Veldhuisen, Dj; Visscher, Pm; Volker, U; Wichmann, He; Wiggins, Kl; Willemsen, G; Yang, Tp; Zhao, Jh; Zitting, P; Bradley, Jr; Dedoussis, Gv; Gasparini, P; Hazen, Sl; Metspalu, A; Pirastu, M; Shuldiner, Ar; van Pelt, Lj; 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.. - In: NATURE. - ISSN 0028-0836. - 480:7376(2011), pp. 201-208. [10.1038/nature10659]