New gene functions in megakaryopoiesis and platelet formation

被引：322

作者：

Gieger, Christian ^{[1
]}

Radhakrishnan, Aparna ^{[2
,3
,4
]}

Cvejic, Ana ^{[2
,3
,4
]}

Tang, Weihong ^{[5
]}

Porcu, Eleonora ^{[6
]}

Pistis, Giorgio ^{[7
]}

Serbanovic-Canic, Jovana ^{[2
,3
,4
]}

Elling, Ulrich ^{[8
]}

Goodall, Alison H. ^{[9
,10
]}

Labrune, Yann ^{[11
]}

Lopez, Lorna M. ^{[12
,13
]}

Maegi, Reedik ^{[14
,29
]}

Meacham, Stuart ^{[2
,3
,4
]}

Okada, Yukinori ^{[15
,16
]}

Pirastu, Nicola ^{[17
,109
]}

Sorice, Rossella ^{[18
]}

Teumer, Alexander ^{[19
]}

Voss, Katrin ^{[2
]}

Zhang, Weihua ^{[20
]}

Ramirez-Solis, Ramiro ^{[3
,4
]}

Bis, Joshua C. ^{[21
]}

Ellinghaus, David ^{[22
]}

Goegele, Martin ^{[23
]}

Hottenga, Jouke-Jan ^{[24
]}

Langenberg, Claudia ^{[25
]}

Kovacs, Peter ^{[26
]}

O'Reilly, Paul F. ^{[27
]}

Shin, So-Youn ^{[3
,4
,28
]}

Esko, Toenu ^{[29
,30
,31
]}

Hartiala, Jaana ^{[32
,33
]}

Kanoni, Stavroula ^{[3
,4
,34
]}

Murgia, Federico ^{[35
]}

Parsa, Afshin ^{[36
]}

Stephens, Jonathan ^{[2
]}

van der Harst, Pim ^{[37
]}

van der Schoot, C. Ellen ^{[38
,39
]}

Allayee, Hooman ^{[32
,33
]}

Attwood, Antony ^{[2
,3
,4
]}

Balkau, Beverley ^{[40
,41
]}

Bastardot, Francois ^{[42
]}

Basu, Saonli ^{[43
]}

Baumeister, Sebastian E. ^{[44
]}

Biino, Ginevra ^{[35
,45
,46
]}

Bomba, Lorenzo ^{[47
]}

Bonnefond, Amelie ^{[11
]}

Cambien, Francois ^{[48
,49
]}

Chambers, John C. ^{[20
]}

Cucca, Francesco ^{[6
]}

D'Adamo, Pio ^{[17
,109
]}

Davies, Gail ^{[13
]}

机构：

[1] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Genet Epidemiol, D-85764 Neuherberg, Germany

[2] Univ Cambridge & NHS Blood & Transplant, Dept Haematol, Cambridge CB2 0PT, England

[3] Wellcome Trust Sanger Inst, Cambridge CB10 1HH, England

[4] Wellcome Trust Sanger Inst, Cambridge CB10 1SA, England

[5] Univ Minnesota, Div Epidemiol & Community Hlth, Minneapolis, MN 55455 USA

[6] Cittadella Univ Monserrato, CNR, Ist Ric Genet & Biomed, I-09042 Cagliari, Italy

[7] Ist Sci San Raffaele, I-20132 Milan, Italy

[8] Austrian Acad Sci, Inst Mol Biotechnol, IMBA, A-1030 Vienna, Austria

[9] Univ Leicester, Glenfield Hosp, Dept Cardiovasc Sci, Leicester LE3 9QP, Leics, England

[10] Glenfield Hosp, Leicester NIHR Biomed Res Unit Cardiovasc Dis, Leicester LE3 9QP, Leics, England

[11] Inst Biol Lille, CNRS, UMR 8199, F-59019 Lille, France

[12] Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol, Edinburgh EH8 9JZ, Midlothian, Scotland

[13] Univ Edinburgh, Dept Psychol, Edinburgh EH8 9JZ, Midlothian, Scotland

[14] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford OX3 7BN, England

[15] RIKEN Ctr Genom Med, Inst Phys & Chem Res, Lab Stat Anal, Tsurumi Ku, Yokohama, Kanagawa 2300045, Japan

[16] Univ Tokyo, Grad Sch Med, Dept Allergy & Rheumatol, Bunkyo Ku, Tokyo 1138654, Japan

[17] IRCCS Burlo Garofolo, Inst Maternal & Child Hlth, I-34137 Trieste, Italy

[18] CNR, Inst Genet & Biophys A Buzzati Traverso, I-8031 Naples, Italy

[19] Ernst Moritz Arndt Univ Greifswald, Interfac Inst Genet & Funct Genom, D-17487 Greifswald, Germany

[20] Fac Med, Sch Publ Hlth, Dept Epidemiol & Biostat, London W2 1PG, England

[21] Univ Washington, Dept Med, Seattle, WA 98195 USA

[22] Univ Kiel, Inst Clin Mol Biol, D-24105 Kiel, Germany

[23] European Acad Bozen Bolzano, Ctr Biomed, I-39100 Bolzano, Italy

[24] Vrije Univ Amsterdam, Dept Biol Psychol, NL-1081 BT Amsterdam, Netherlands

[25] Addenbrookes Hosp, Inst Metab Sci, MRC Epidemiol Unit, Cambridge CB2 0QQ, England

[26] Univ Leipzig, Interdisciplinary Ctr Clin Res, D-04103 Leipzig, Germany

[27] Univ London Imperial Coll Sci Technol & Med, Dept Epidemiol & Biostat, London W2 1PG, England

[28] Kings Coll London, Dept Twin Res & Genet Epidemiol, London SE1 7EH, England

[29] Univ Tartu, Estonian Genome Ctr, EE-50410 Tartu, Estonia

[30] Estonian Bioctr, EE-51010 Tartu, Estonia

[31] Univ Tartu, Inst Mol & Cell Biol, EE-50410 Tartu, Estonia

[32] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90089 USA

[33] Univ So Calif, Keck Sch Med, Inst Med Genet, Los Angeles, CA 90089 USA

[34] Harokopio Univ, Dept Nutr Dietet, Athens 17671, Greece

[35] CNR, Inst Populat Genet, I-07100 Sassari, Italy

[36] Univ Maryland, Sch Med, Baltimore, MD 21201 USA

[37] Univ Groningen, Univ Med Ctr Groningen, Dept Cardiol, NL-9713 GZ Groningen, Netherlands

[38] Sanquin Res, Dept Expt Immunohaematol, NL-1066 CX Amsterdam, Netherlands

[39] Univ Amsterdam, Acad Med Ctr, Landsteiner Lab, NL-1105 AZ Amsterdam, Netherlands

[40] INSERM, U1018, CESP Ctr Res Epidemiol & Populat Hlth, F-94807 Villejuif, France

[41] Univ Paris 11, UMRS 1018, F-94807 Villejuif, France

[42] CHU Vaudois, Serv Med Interne, CH-1011 Lausanne, Switzerland

[43] Univ Minnesota, Sch Publ Hlth, Div Biostat, Minneapolis, MN 55455 USA

[44] Ernst Moritz Arndt Univ Greifswald, Inst Community Med, D-17475 Greifswald, Germany

[45] Shardna Life Sci, Loc Piscinamanna, I-09010 Pula, CA, Italy

[46] CNR, Inst Mol Genet, I-27100 Pavia, Italy

[47] Univ Cattolica Sacro Cuore Sede Piacenza, Ist Zootecnia, I-29122 Piacenza, Italy

[48] Univ Paris 06, INSERM, UMRS 937, F-75013 Paris, France

[49] Sch Med, F-75013 Paris, France

[50] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Epidemiol 1, D-85764 Neuherberg, Germany

来源：

NATURE | 2011年 / 480卷 / 7376期

基金：

英国生物技术与生命科学研究理事会; 美国国家卫生研究院; 英国惠康基金;

关键词：

GENOME-WIDE ASSOCIATION; LOCI; BLOOD;

D O I：

10.1038/nature10659

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页码：201 / 208

页数：8

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