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.
authors.affiliation: Institute of Genetic Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Ingolstädter Landstr 1, 85764 Neuherberg, Germany. christian.gieger@helmholtz-muenchen.de
authors.forename: Christian
authors.initials: C
authors.lastname: Gieger
authors.forename: Aparna
authors.initials: A
authors.lastname: Radhakrishnan
authors.forename: Ana
authors.initials: A
authors.lastname: Cvejic
authors.forename: Weihong
authors.initials: W
authors.lastname: Tang
authors.forename: Eleonora
authors.initials: E
authors.lastname: Porcu
authors.forename: Giorgio
authors.initials: G
authors.lastname: Pistis
authors.forename: Jovana
authors.initials: J
authors.lastname: Serbanovic-Canic
authors.forename: Ulrich
authors.initials: U
authors.lastname: Elling
authors.forename: Alison H
authors.initials: AH
authors.lastname: Goodall
authors.forename: Yann
authors.initials: Y
authors.lastname: Labrune
authors.forename: Lorna M
authors.initials: LM
authors.lastname: Lopez
authors.forename: Reedik
authors.initials: R
authors.lastname: Mägi
authors.forename: Stuart
authors.initials: S
authors.lastname: Meacham
authors.forename: Yukinori
authors.initials: Y
authors.lastname: Okada
authors.forename: Nicola
authors.initials: N
authors.lastname: Pirastu
authors.forename: Rossella
authors.initials: R
authors.lastname: Sorice
authors.forename: Alexander
authors.initials: A
authors.lastname: Teumer
authors.forename: Katrin
authors.initials: K
authors.lastname: Voss
authors.forename: Weihua
authors.initials: W
authors.lastname: Zhang
authors.forename: Ramiro
authors.initials: R
authors.lastname: Ramirez-Solis
authors.forename: Joshua C
authors.initials: JC
authors.lastname: Bis
authors.forename: David
authors.initials: D
authors.lastname: Ellinghaus
authors.forename: Martin
authors.initials: M
authors.lastname: Gögele
authors.forename: Jouke-Jan
authors.initials: JJ
authors.lastname: Hottenga
authors.forename: Claudia
authors.initials: C
authors.lastname: Langenberg
authors.forename: Peter
authors.initials: P
authors.lastname: Kovacs
authors.forename: Paul F
authors.initials: PF
authors.lastname: O'Reilly
authors.forename: So-Youn
authors.initials: SY
authors.lastname: Shin
authors.forename: Tõnu
authors.initials: T
authors.lastname: Esko
authors.forename: Jaana
authors.initials: J
authors.lastname: Hartiala
authors.forename: Stavroula
authors.initials: S
authors.lastname: Kanoni
authors.forename: Federico
authors.initials: F
authors.lastname: Murgia
authors.forename: Afshin
authors.initials: A
authors.lastname: Parsa
authors.forename: Jonathan
authors.initials: J
authors.lastname: Stephens
authors.forename: Pim
authors.initials: P
authors.lastname: van der Harst
authors.forename: C
authors.initials: C
authors.lastname: Ellen van der Schoot
authors.forename: Hooman
authors.initials: H
authors.lastname: Allayee
authors.forename: Antony
authors.initials: A
authors.lastname: Attwood
authors.forename: Beverley
authors.initials: B
authors.lastname: Balkau
authors.forename: François
authors.initials: F
authors.lastname: Bastardot
authors.forename: Saonli
authors.initials: S
authors.lastname: Basu
authors.forename: Sebastian E
authors.initials: SE
authors.lastname: Baumeister
authors.forename: Ginevra
authors.initials: G
authors.lastname: Biino
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Bomba
authors.forename: Amélie
authors.initials: A
authors.lastname: Bonnefond
authors.forename: François
authors.initials: F
authors.lastname: Cambien
authors.forename: John C
authors.initials: JC
authors.lastname: Chambers
authors.forename: Francesco
authors.initials: F
authors.lastname: Cucca
authors.forename: Pio
authors.initials: P
authors.lastname: D'Adamo
authors.forename: Gail
authors.initials: G
authors.lastname: Davies
authors.forename: Rudolf A
authors.initials: RA
authors.lastname: de Boer
authors.forename: Eco J C
authors.initials: EJ
authors.lastname: de Geus
authors.forename: Angela
authors.initials: A
authors.lastname: Döring
authors.forename: Paul
authors.initials: P
authors.lastname: Elliott
authors.forename: Jeanette
authors.initials: J
authors.lastname: Erdmann
authors.forename: David M
authors.initials: DM
authors.lastname: Evans
authors.forename: Mario
authors.initials: M
authors.lastname: Falchi
authors.forename: Wei
authors.initials: W
authors.lastname: Feng
authors.forename: Aaron R
authors.initials: AR
authors.lastname: Folsom
authors.forename: Ian H
authors.initials: IH
authors.lastname: Frazer
authors.forename: Quince D
authors.initials: QD
authors.lastname: Gibson
authors.forename: Nicole L
authors.initials: NL
authors.lastname: Glazer
authors.forename: Chris
authors.initials: C
authors.lastname: Hammond
authors.forename: Anna-Liisa
authors.initials: AL
authors.lastname: Hartikainen
authors.forename: Susan R
authors.initials: SR
authors.lastname: Heckbert
authors.forename: Christian
authors.initials: C
authors.lastname: Hengstenberg
authors.forename: Micha
authors.initials: M
authors.lastname: Hersch
authors.forename: Thomas
authors.initials: T
authors.lastname: Illig
authors.forename: Ruth J F
authors.initials: RJ
authors.lastname: Loos
authors.forename: Jennifer
authors.initials: J
authors.lastname: Jolley
authors.forename: Kay Tee
authors.initials: KT
authors.lastname: Khaw
authors.forename: Brigitte
authors.initials: B
authors.lastname: Kühnel
authors.forename: Marie-Christine
authors.initials: MC
authors.lastname: Kyrtsonis
authors.forename: Vasiliki
authors.initials: V
authors.lastname: Lagou
authors.forename: Heather
authors.initials: H
authors.lastname: Lloyd-Jones
authors.forename: Thomas
authors.initials: T
authors.lastname: Lumley
authors.forename: Massimo
authors.initials: M
authors.lastname: Mangino
authors.forename: Andrea
authors.initials: A
authors.lastname: Maschio
authors.forename: Irene
authors.initials: I
authors.lastname: Mateo Leach
authors.forename: Barbara
authors.initials: B
authors.lastname: McKnight
authors.forename: Yasin
authors.initials: Y
authors.lastname: Memari
authors.forename: Braxton D
authors.initials: BD
authors.lastname: Mitchell
authors.forename: Grant W
authors.initials: GW
authors.lastname: Montgomery
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Nakamura
authors.forename: Matthias
authors.initials: M
authors.lastname: Nauck
authors.forename: Gerjan
authors.initials: G
authors.lastname: Navis
authors.forename: Ute
authors.initials: U
authors.lastname: Nöthlings
authors.forename: Ilja M
authors.initials: IM
authors.lastname: Nolte
authors.forename: David J
authors.initials: DJ
authors.lastname: Porteous
authors.forename: Anneli
authors.initials: A
authors.lastname: Pouta
authors.forename: Peter P
authors.initials: PP
authors.lastname: Pramstaller
authors.forename: Janne
authors.initials: J
authors.lastname: Pullat
authors.forename: Susan M
authors.initials: SM
authors.lastname: Ring
authors.forename: Jerome I
authors.initials: JI
authors.lastname: Rotter
authors.forename: Daniela
authors.initials: D
authors.lastname: Ruggiero
authors.forename: Aimo
authors.initials: A
authors.lastname: Ruokonen
authors.forename: Cinzia
authors.initials: C
authors.lastname: Sala
authors.forename: Nilesh J
authors.initials: NJ
authors.lastname: Samani
authors.forename: Jennifer
authors.initials: J
authors.lastname: Sambrook
authors.forename: David
authors.initials: D
authors.lastname: Schlessinger
authors.forename: Stefan
authors.initials: S
authors.lastname: Schreiber
authors.forename: Heribert
authors.initials: H
authors.lastname: Schunkert
authors.forename: James
authors.initials: J
authors.lastname: Scott
authors.forename: Nicholas L
authors.initials: NL
authors.lastname: Smith
authors.forename: Harold
authors.initials: H
authors.lastname: Snieder
authors.forename: John M
authors.initials: JM
authors.lastname: Starr
authors.forename: Michael
authors.initials: M
authors.lastname: Stumvoll
authors.forename: Atsushi
authors.initials: A
authors.lastname: Takahashi
authors.forename: W H Wilson
authors.initials: WH
authors.lastname: Tang
authors.forename: Kent
authors.initials: K
authors.lastname: Taylor
authors.forename: Albert
authors.initials: A
authors.lastname: Tenesa
authors.forename: Swee
authors.initials: S
authors.lastname: Lay Thein
authors.forename: Anke
authors.initials: A
authors.lastname: Tönjes
authors.forename: Manuela
authors.initials: M
authors.lastname: Uda
authors.forename: Sheila
authors.initials: S
authors.lastname: Ulivi
authors.forename: Dirk J
authors.initials: DJ
authors.lastname: van Veldhuisen
authors.forename: Peter M
authors.initials: PM
authors.lastname: Visscher
authors.forename: Uwe
authors.initials: U
authors.lastname: Völker
authors.forename: H-Erich
authors.initials: HE
authors.lastname: Wichmann
authors.forename: Kerri L
authors.initials: KL
authors.lastname: Wiggins
authors.forename: Gonneke
authors.initials: G
authors.lastname: Willemsen
authors.forename: Tsun-Po
authors.initials: TP
authors.lastname: Yang
authors.forename: Jing
authors.initials: J
authors.lastname: Hua Zhao
authors.forename: Paavo
authors.initials: P
authors.lastname: Zitting
authors.forename: John R
authors.initials: JR
authors.lastname: Bradley
authors.forename: George V
authors.initials: GV
authors.lastname: Dedoussis
authors.forename: Paolo
authors.initials: P
authors.lastname: Gasparini
authors.forename: Stanley L
authors.initials: SL
authors.lastname: Hazen
authors.forename: Andres
authors.initials: A
authors.lastname: Metspalu
authors.forename: Mario
authors.initials: M
authors.lastname: Pirastu
authors.forename: Alan R
authors.initials: AR
authors.lastname: Shuldiner
authors.forename: L
authors.initials: L
authors.lastname: Joost van Pelt
authors.forename: Jaap-Jan
authors.initials: JJ
authors.lastname: Zwaginga
authors.forename: Dorret I
authors.initials: DI
authors.lastname: Boomsma
authors.forename: Ian J
authors.initials: IJ
authors.lastname: Deary
authors.forename: Andre
authors.initials: A
authors.lastname: Franke
authors.forename: Philippe
authors.initials: P
authors.lastname: Froguel
authors.forename: Santhi K
authors.initials: SK
authors.lastname: Ganesh
authors.forename: Marjo-Riitta
authors.initials: MR
authors.lastname: Jarvelin
authors.forename: Nicholas G
authors.initials: NG
authors.lastname: Martin
authors.forename: Christa
authors.initials: C
authors.lastname: Meisinger
authors.forename: Bruce M
authors.initials: BM
authors.lastname: Psaty
authors.forename: Timothy D
authors.initials: TD
authors.lastname: Spector
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Wareham
authors.forename: Jan-Willem N
authors.initials: JW
authors.lastname: Akkerman
authors.forename: Marina
authors.initials: M
authors.lastname: Ciullo
authors.forename: Panos
authors.initials: P
authors.lastname: Deloukas
authors.forename: Andreas
authors.initials: A
authors.lastname: Greinacher
authors.forename: Steve
authors.initials: S
authors.lastname: Jupe
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Kamatani
authors.forename: Jyoti
authors.initials: J
authors.lastname: Khadake
authors.forename: Jaspal S
authors.initials: JS
authors.lastname: Kooner
authors.forename: Josef
authors.initials: J
authors.lastname: Penninger
authors.forename: Inga
authors.initials: I
authors.lastname: Prokopenko
authors.forename: Derek
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authors.lastname: Stemple
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authors.lastname: Toniolo
authors.forename: Lorenz
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authors.lastname: Wernisch
authors.forename: Serena
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authors.lastname: Sanna
authors.forename: Andrew A
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authors.lastname: Hicks
authors.forename: Augusto
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authors.lastname: Rendon
authors.forename: Manuel A
authors.initials: MA
authors.lastname: Ferreira
authors.forename: Willem H
authors.initials: WH
authors.lastname: Ouwehand
authors.forename: Nicole
authors.initials: N
authors.lastname: Soranzo
mesh_terms: D000818:Animals; D001792:Blood Platelets / Q000166:cytology* / Q000378:metabolism; D048429:Cell Size; D029721:Drosophila Proteins / Q000235:genetics; D004331:Drosophila melanogaster / Q000235:genetics; D005060:Europe; D020869:Gene Expression Profiling; D020868:Gene Silencing; D015894:Genome, Human / Q000235:genetics; D055106:Genome-Wide Association Study; D006410:Hematopoiesis / Q000235:genetics*; D006801:Humans; D008533:Megakaryocytes / Q000166:cytology* / Q000378:metabolism; D010976:Platelet Count; D060066:Protein Interaction Maps; D014158:Transcription, Genetic / Q000235:genetics; D015027:Zebrafish / Q000235:genetics; D029961:Zebrafish Proteins / Q000235:genetics
chemical_list: D029721:Drosophila Proteins; D029961:Zebrafish Proteins