Genetic Epidemiology, Translational Neurogenomics, Psychiatric Genetics and Statistical Genetics Laboratories investigate the pattern of disease in families, particularly identical and non-identical twins, to assess the relative importance of genes and environment in a variety of important health problems.
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PMID
22139419
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.
DATE PUBLISHED
2011 Dec 8
HISTORY
PUBSTATUS PUBSTATUSDATE
received 2010/12/17
accepted 2011/10/21
aheadofprint 2011/11/30
entrez 2011/12/06 06:00
pubmed 2011/12/06 06:00
medline 2012/02/24 06:00
AUTHORS
NAME COLLECTIVENAME LASTNAME FORENAME INITIALS AFFILIATION AFFILIATIONINFO
Gieger C Gieger Christian C Institute of Genetic Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Ingolstädter Landstr 1, 85764 Neuherberg, Germany. christian.gieger@helmholtz-muenchen.de
Radhakrishnan A Radhakrishnan Aparna A
Cvejic A Cvejic Ana A
Tang W Tang Weihong W
Porcu E Porcu Eleonora E
Pistis G Pistis Giorgio G
Serbanovic-Canic J Serbanovic-Canic Jovana J
Elling U Elling Ulrich U
Goodall AH Goodall Alison H AH
Labrune Y Labrune Yann Y
Lopez LM Lopez Lorna M LM
Mägi R Mägi Reedik R
Meacham S Meacham Stuart S
Okada Y Okada Yukinori Y
Pirastu N Pirastu Nicola N
Sorice R Sorice Rossella R
Teumer A Teumer Alexander A
Voss K Voss Katrin K
Zhang W Zhang Weihua W
Ramirez-Solis R Ramirez-Solis Ramiro R
Bis JC Bis Joshua C JC
Ellinghaus D Ellinghaus David D
Gögele M Gögele Martin M
Hottenga JJ Hottenga Jouke-Jan JJ
Langenberg C Langenberg Claudia C
Kovacs P Kovacs Peter P
O'Reilly PF O'Reilly Paul F PF
Shin SY Shin So-Youn SY
Esko T Esko Tõnu T
Hartiala J Hartiala Jaana J
Kanoni S Kanoni Stavroula S
Murgia F Murgia Federico F
Parsa A Parsa Afshin A
Stephens J Stephens Jonathan J
van der Harst P van der Harst Pim P
Ellen van der Schoot C Ellen van der Schoot C C
Allayee H Allayee Hooman H
Attwood A Attwood Antony A
Balkau B Balkau Beverley B
Bastardot F Bastardot François F
Basu S Basu Saonli S
Baumeister SE Baumeister Sebastian E SE
Biino G Biino Ginevra G
Bomba L Bomba Lorenzo L
Bonnefond A Bonnefond Amélie A
Cambien F Cambien François F
Chambers JC Chambers John C JC
Cucca F Cucca Francesco F
D'Adamo P D'Adamo Pio P
Davies G Davies Gail G
de Boer RA de Boer Rudolf A RA
de Geus EJ de Geus Eco J C EJ
Döring A Döring Angela A
Elliott P Elliott Paul P
Erdmann J Erdmann Jeanette J
Evans DM Evans David M DM
Falchi M Falchi Mario M
Feng W Feng Wei W
Folsom AR Folsom Aaron R AR
Frazer IH Frazer Ian H IH
Gibson QD Gibson Quince D QD
Glazer NL Glazer Nicole L NL
Hammond C Hammond Chris C
Hartikainen AL Hartikainen Anna-Liisa AL
Heckbert SR Heckbert Susan R SR
Hengstenberg C Hengstenberg Christian C
Hersch M Hersch Micha M
Illig T Illig Thomas T
Loos RJ Loos Ruth J F RJ
Jolley J Jolley Jennifer J
Khaw KT Khaw Kay Tee KT
Kühnel B Kühnel Brigitte B
Kyrtsonis MC Kyrtsonis Marie-Christine MC
Lagou V Lagou Vasiliki V
Lloyd-Jones H Lloyd-Jones Heather H
Lumley T Lumley Thomas T
Mangino M Mangino Massimo M
Maschio A Maschio Andrea A
Mateo Leach I Mateo Leach Irene I
McKnight B McKnight Barbara B
Memari Y Memari Yasin Y
Mitchell BD Mitchell Braxton D BD
Montgomery GW Montgomery Grant W GW
Nakamura Y Nakamura Yusuke Y
Nauck M Nauck Matthias M
Navis G Navis Gerjan G
Nöthlings U Nöthlings Ute U
Nolte IM Nolte Ilja M IM
Porteous DJ Porteous David J DJ
Pouta A Pouta Anneli A
Pramstaller PP Pramstaller Peter P PP
Pullat J Pullat Janne J
Ring SM Ring Susan M SM
Rotter JI Rotter Jerome I JI
Ruggiero D Ruggiero Daniela D
Ruokonen A Ruokonen Aimo A
Sala C Sala Cinzia C
Samani NJ Samani Nilesh J NJ
Sambrook J Sambrook Jennifer J
Schlessinger D Schlessinger David D
Schreiber S Schreiber Stefan S
Schunkert H Schunkert Heribert H
Scott J Scott James J
Smith NL Smith Nicholas L NL
Snieder H Snieder Harold H
Starr JM Starr John M JM
Stumvoll M Stumvoll Michael M
Takahashi A Takahashi Atsushi A
Tang WH Tang W H Wilson WH
Taylor K Taylor Kent K
Tenesa A Tenesa Albert A
Lay Thein S Lay Thein Swee S
Tönjes A Tönjes Anke A
Uda M Uda Manuela M
Ulivi S Ulivi Sheila S
van Veldhuisen DJ van Veldhuisen Dirk J DJ
Visscher PM Visscher Peter M PM
Völker U Völker Uwe U
Wichmann HE Wichmann H-Erich HE
Wiggins KL Wiggins Kerri L KL
Willemsen G Willemsen Gonneke G
Yang TP Yang Tsun-Po TP
Hua Zhao J Hua Zhao Jing J
Zitting P Zitting Paavo P
Bradley JR Bradley John R JR
Dedoussis GV Dedoussis George V GV
Gasparini P Gasparini Paolo P
Hazen SL Hazen Stanley L SL
Metspalu A Metspalu Andres A
Pirastu M Pirastu Mario M
Shuldiner AR Shuldiner Alan R AR
Joost van Pelt L Joost van Pelt L L
Zwaginga JJ Zwaginga Jaap-Jan JJ
Boomsma DI Boomsma Dorret I DI
Deary IJ Deary Ian J IJ
Franke A Franke Andre A
Froguel P Froguel Philippe P
Ganesh SK Ganesh Santhi K SK
Jarvelin MR Jarvelin Marjo-Riitta MR
Martin NG Martin Nicholas G NG
Meisinger C Meisinger Christa C
Psaty BM Psaty Bruce M BM
Spector TD Spector Timothy D TD
Wareham NJ Wareham Nicholas J NJ
Akkerman JW Akkerman Jan-Willem N JW
Ciullo M Ciullo Marina M
Deloukas P Deloukas Panos P
Greinacher A Greinacher Andreas A
Jupe S Jupe Steve S
Kamatani N Kamatani Naoyuki N
Khadake J Khadake Jyoti J
Kooner JS Kooner Jaspal S JS
Penninger J Penninger Josef J
Prokopenko I Prokopenko Inga I
Stemple D Stemple Derek D
Toniolo D Toniolo Daniela D
Wernisch L Wernisch Lorenz L
Sanna S Sanna Serena S
Hicks AA Hicks Andrew A AA
Rendon A Rendon Augusto A
Ferreira MA Ferreira Manuel A MA
Ouwehand WH Ouwehand Willem H WH
Soranzo N Soranzo Nicole N
INVESTIGATORS
JOURNAL
VOLUME: 480
ISSUE: 7376
TITLE: Nature
ISOABBREVIATION: Nature
YEAR: 2011
MONTH: Dec
DAY: 8
MEDLINEDATE:
SEASON:
CITEDMEDIUM: Internet
ISSN: 1476-4687
ISSNTYPE: Electronic
MEDLINE JOURNAL
MEDLINETA: Nature
COUNTRY: England
ISSNLINKING: 0028-0836
NLMUNIQUEID: 0410462
PUBLICATION TYPE
PUBLICATIONTYPE TEXT
Journal Article
Meta-Analysis
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
COMMENTS AND CORRECTIONS
REFTYPE REFSOURCE REFPMID NOTE
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GRANTS
GRANTID AGENCY COUNTRY
092731 Wellcome Trust United Kingdom
098051 Wellcome Trust United Kingdom
BB/F019394/1 Biotechnology and Biological Sciences Research Council United Kingdom
CZB/4/505 Chief Scientist Office United Kingdom
ETM/55 Chief Scientist Office United Kingdom
G0000111 Medical Research Council United Kingdom
G0601966 Medical Research Council United Kingdom
G0700704 Medical Research Council United Kingdom
G0700931 Medical Research Council United Kingdom
G0701120 Medical Research Council United Kingdom
G0701863 Medical Research Council United Kingdom
G0801056 Medical Research Council United Kingdom
G1000143 Medical Research Council United Kingdom
K12 RR023250 NCRR NIH HHS United States
K12 RR023250-05 NCRR NIH HHS United States
M01 RR016500 NCRR NIH HHS United States
M01 RR016500-08 NCRR NIH HHS United States
MC_PC_15018 Medical Research Council United Kingdom
MC_U105260799 Medical Research Council United Kingdom
MC_U106179471 Medical Research Council United Kingdom
MC_U106188470 Medical Research Council United Kingdom
N01 HC055015 NHLBI NIH HHS United States
N01 HC055016 NHLBI NIH HHS United States
N01 HC055018 NHLBI NIH HHS United States
N01 HC055019 NHLBI NIH HHS United States
N01 HC055020 NHLBI NIH HHS United States
N01 HC055021 NHLBI NIH HHS United States
N01 HC055022 NHLBI NIH HHS United States
N01 HC085079 NHLBI NIH HHS United States
P01 HL076491 NHLBI NIH HHS United States
P01 HL076491-09 NHLBI NIH HHS United States
P01 HL098055 NHLBI NIH HHS United States
P01 HL098055-03 NHLBI NIH HHS United States
P30 DK072488 NIDDK NIH HHS United States
P30 DK072488-08 NIDDK NIH HHS United States
P41 HG003751 NHGRI NIH HHS United States
R01 AG018728 NIA NIH HHS United States
R01 AG018728-05S1 NIA NIH HHS United States
R01 GM053275 NIGMS NIH HHS United States
R01 GM053275-14 NIGMS NIH HHS United States
R01 HD042157 NICHD NIH HHS United States
R01 HD042157-01A1 NICHD NIH HHS United States
R01 HL059367 NHLBI NIH HHS United States
R01 HL059367-11 NHLBI NIH HHS United States
R01 HL068986 NHLBI NIH HHS United States
R01 HL068986-06 NHLBI NIH HHS United States
R01 HL073410 NHLBI NIH HHS United States
R01 HL073410-08 NHLBI NIH HHS United States
R01 HL085251 NHLBI NIH HHS United States
R01 HL085251-04 NHLBI NIH HHS United States
R01 HL086694 NHLBI NIH HHS United States
R01 HL086694-05 NHLBI NIH HHS United States
R01 HL087641 NHLBI NIH HHS United States
R01 HL087641-03 NHLBI NIH HHS United States
R01 HL087679-03 NHLBI NIH HHS United States
R01 HL088119 NHLBI NIH HHS United States
R01 HL088119-04 NHLBI NIH HHS United States
R01 HL103866 NHLBI NIH HHS United States
R01 HL103866-03 NHLBI NIH HHS United States
R01 HL105756 NHLBI NIH HHS United States
RG/09/012/28096 British Heart Foundation United Kingdom
RL1 MH083268 NIMH NIH HHS United States
RL1 MH083268-05 NIMH NIH HHS United States
U01 GM074518 NIGMS NIH HHS United States
U01 GM074518-04 NIGMS NIH HHS United States
U01 HL072515 NHLBI NIH HHS United States
U01 HL072515-06 NHLBI NIH HHS United States
U01 HL084756 NHLBI NIH HHS United States
U01 HL084756-03 NHLBI NIH HHS United States
U54 RR020278 NCRR NIH HHS United States
U54 RR020278-06 NCRR NIH HHS United States
UL1 RR025005 NCRR NIH HHS United States
UL1 RR025005-05 NCRR NIH HHS United States
WT077037/Z/05/Z Wellcome Trust United Kingdom
WT077047/Z/05/Z Wellcome Trust United Kingdom
WT082597/Z/07/Z Wellcome Trust United Kingdom
GENERAL NOTE
KEYWORDS
MESH HEADINGS
DESCRIPTORNAME QUALIFIERNAME
Animals
Blood Platelets metabolism
Cell Size metabolism
Drosophila Proteins genetics
Drosophila melanogaster genetics
Europe genetics
Gene Expression Profiling genetics
Gene Silencing genetics
Genome, Human genetics
Genome-Wide Association Study genetics
Hematopoiesis genetics
Humans genetics
Megakaryocytes metabolism
Platelet Count metabolism
Protein Interaction Maps metabolism
Transcription, Genetic genetics
Zebrafish genetics
Zebrafish Proteins genetics
SUPPLEMENTARY MESH
GENE SYMBOLS
CHEMICALS
REGISTRYNUMBER NAMEOFSUBSTANCE
0 Drosophila Proteins
0 Zebrafish Proteins
OTHER ID's
OTHERID SOURCE
NIHMS362305 NLM
PMC3335296 NLM