PMID |
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TITLE |
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New gene functions in megakaryopoiesis and platelet formation. |
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ABSTRACT |
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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. |
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DATE PUBLISHED |
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HISTORY |
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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 |
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AUTHORS |
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NAME |
COLLECTIVENAME |
LASTNAME |
FORENAME |
INITIALS |
AFFILIATION |
AFFILIATIONINFO |
Gieger C |
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Gieger |
Christian |
C |
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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 |
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Radhakrishnan |
Aparna |
A |
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Cvejic A |
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Cvejic |
Ana |
A |
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Tang W |
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Tang |
Weihong |
W |
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Porcu E |
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Porcu |
Eleonora |
E |
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Pistis G |
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Pistis |
Giorgio |
G |
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Serbanovic-Canic J |
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Serbanovic-Canic |
Jovana |
J |
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Elling U |
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Elling |
Ulrich |
U |
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Goodall AH |
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Goodall |
Alison H |
AH |
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Labrune Y |
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Labrune |
Yann |
Y |
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Lopez LM |
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Lopez |
Lorna M |
LM |
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Mägi R |
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Mägi |
Reedik |
R |
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Meacham S |
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Meacham |
Stuart |
S |
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Okada Y |
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Okada |
Yukinori |
Y |
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Pirastu N |
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Pirastu |
Nicola |
N |
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Sorice R |
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Sorice |
Rossella |
R |
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Teumer A |
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Teumer |
Alexander |
A |
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Voss K |
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Voss |
Katrin |
K |
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Zhang W |
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Zhang |
Weihua |
W |
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Ramirez-Solis R |
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Ramirez-Solis |
Ramiro |
R |
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Bis JC |
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Bis |
Joshua C |
JC |
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Ellinghaus D |
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Ellinghaus |
David |
D |
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Gögele M |
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Gögele |
Martin |
M |
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Hottenga JJ |
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Hottenga |
Jouke-Jan |
JJ |
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Langenberg C |
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Langenberg |
Claudia |
C |
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Kovacs P |
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Kovacs |
Peter |
P |
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O'Reilly PF |
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O'Reilly |
Paul F |
PF |
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Shin SY |
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Shin |
So-Youn |
SY |
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Esko T |
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Esko |
Tõnu |
T |
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Hartiala J |
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Hartiala |
Jaana |
J |
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Kanoni S |
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Kanoni |
Stavroula |
S |
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Murgia F |
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Murgia |
Federico |
F |
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Parsa A |
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Parsa |
Afshin |
A |
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Stephens J |
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Stephens |
Jonathan |
J |
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van der Harst P |
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van der Harst |
Pim |
P |
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Ellen van der Schoot C |
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Ellen van der Schoot |
C |
C |
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Allayee H |
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Allayee |
Hooman |
H |
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Attwood A |
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Attwood |
Antony |
A |
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Balkau B |
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Balkau |
Beverley |
B |
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Bastardot F |
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Bastardot |
François |
F |
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Basu S |
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Basu |
Saonli |
S |
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Baumeister SE |
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Baumeister |
Sebastian E |
SE |
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Biino G |
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Biino |
Ginevra |
G |
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Bomba L |
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Bomba |
Lorenzo |
L |
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Bonnefond A |
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Bonnefond |
Amélie |
A |
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Cambien F |
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Cambien |
François |
F |
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Chambers JC |
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Chambers |
John C |
JC |
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Cucca F |
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Cucca |
Francesco |
F |
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D'Adamo P |
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D'Adamo |
Pio |
P |
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Davies G |
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Davies |
Gail |
G |
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de Boer RA |
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de Boer |
Rudolf A |
RA |
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de Geus EJ |
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de Geus |
Eco J C |
EJ |
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Döring A |
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Döring |
Angela |
A |
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Elliott P |
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Elliott |
Paul |
P |
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Erdmann J |
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Erdmann |
Jeanette |
J |
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Evans DM |
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Evans |
David M |
DM |
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Falchi M |
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Falchi |
Mario |
M |
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Feng W |
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Feng |
Wei |
W |
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Folsom AR |
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Folsom |
Aaron R |
AR |
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Frazer IH |
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Frazer |
Ian H |
IH |
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Gibson QD |
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Gibson |
Quince D |
QD |
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Glazer NL |
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Glazer |
Nicole L |
NL |
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Hammond C |
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Hammond |
Chris |
C |
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Hartikainen AL |
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Hartikainen |
Anna-Liisa |
AL |
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Heckbert SR |
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Heckbert |
Susan R |
SR |
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Hengstenberg C |
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Hengstenberg |
Christian |
C |
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Hersch M |
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Hersch |
Micha |
M |
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Illig T |
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Illig |
Thomas |
T |
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Loos RJ |
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Loos |
Ruth J F |
RJ |
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Jolley J |
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Jolley |
Jennifer |
J |
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Khaw KT |
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Khaw |
Kay Tee |
KT |
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Kühnel B |
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Kühnel |
Brigitte |
B |
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Kyrtsonis MC |
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Kyrtsonis |
Marie-Christine |
MC |
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Lagou V |
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Lagou |
Vasiliki |
V |
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Lloyd-Jones H |
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Lloyd-Jones |
Heather |
H |
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Lumley T |
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Lumley |
Thomas |
T |
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Mangino M |
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Mangino |
Massimo |
M |
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Maschio A |
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Maschio |
Andrea |
A |
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Mateo Leach I |
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Mateo Leach |
Irene |
I |
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McKnight B |
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McKnight |
Barbara |
B |
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Memari Y |
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Memari |
Yasin |
Y |
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Mitchell BD |
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Mitchell |
Braxton D |
BD |
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Montgomery GW |
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Montgomery |
Grant W |
GW |
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Nakamura Y |
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Nakamura |
Yusuke |
Y |
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Nauck M |
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Nauck |
Matthias |
M |
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Navis G |
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Navis |
Gerjan |
G |
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Nöthlings U |
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Nöthlings |
Ute |
U |
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Nolte IM |
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Nolte |
Ilja M |
IM |
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Porteous DJ |
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Porteous |
David J |
DJ |
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Pouta A |
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Pouta |
Anneli |
A |
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Pramstaller PP |
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Pramstaller |
Peter P |
PP |
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Pullat J |
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Pullat |
Janne |
J |
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Ring SM |
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Ring |
Susan M |
SM |
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Rotter JI |
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Rotter |
Jerome I |
JI |
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Ruggiero D |
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Ruggiero |
Daniela |
D |
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Ruokonen A |
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Ruokonen |
Aimo |
A |
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Sala C |
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Sala |
Cinzia |
C |
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Samani NJ |
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Samani |
Nilesh J |
NJ |
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Sambrook J |
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Sambrook |
Jennifer |
J |
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Schlessinger D |
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Schlessinger |
David |
D |
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Schreiber S |
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Schreiber |
Stefan |
S |
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Schunkert H |
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Schunkert |
Heribert |
H |
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Scott J |
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Scott |
James |
J |
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Smith NL |
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Smith |
Nicholas L |
NL |
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Snieder H |
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Snieder |
Harold |
H |
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Starr JM |
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Starr |
John M |
JM |
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Stumvoll M |
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Stumvoll |
Michael |
M |
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Takahashi A |
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Takahashi |
Atsushi |
A |
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Tang WH |
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Tang |
W H Wilson |
WH |
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Taylor K |
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Taylor |
Kent |
K |
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Tenesa A |
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Tenesa |
Albert |
A |
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Lay Thein S |
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Lay Thein |
Swee |
S |
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Tönjes A |
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Tönjes |
Anke |
A |
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Uda M |
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Uda |
Manuela |
M |
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Ulivi S |
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Ulivi |
Sheila |
S |
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van Veldhuisen DJ |
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van Veldhuisen |
Dirk J |
DJ |
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Visscher PM |
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Visscher |
Peter M |
PM |
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Völker U |
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Völker |
Uwe |
U |
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Wichmann HE |
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Wichmann |
H-Erich |
HE |
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Wiggins KL |
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Wiggins |
Kerri L |
KL |
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Willemsen G |
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Willemsen |
Gonneke |
G |
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Yang TP |
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Yang |
Tsun-Po |
TP |
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Hua Zhao J |
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Hua Zhao |
Jing |
J |
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Zitting P |
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Zitting |
Paavo |
P |
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Bradley JR |
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Bradley |
John R |
JR |
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Dedoussis GV |
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Dedoussis |
George V |
GV |
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Gasparini P |
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Gasparini |
Paolo |
P |
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Hazen SL |
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Hazen |
Stanley L |
SL |
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Metspalu A |
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Metspalu |
Andres |
A |
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Pirastu M |
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Pirastu |
Mario |
M |
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Shuldiner AR |
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Shuldiner |
Alan R |
AR |
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Joost van Pelt L |
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Joost van Pelt |
L |
L |
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Zwaginga JJ |
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Zwaginga |
Jaap-Jan |
JJ |
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Boomsma DI |
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Boomsma |
Dorret I |
DI |
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Deary IJ |
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Deary |
Ian J |
IJ |
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Franke A |
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Franke |
Andre |
A |
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Froguel P |
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Froguel |
Philippe |
P |
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Ganesh SK |
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Ganesh |
Santhi K |
SK |
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Jarvelin MR |
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Jarvelin |
Marjo-Riitta |
MR |
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Martin NG |
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Martin |
Nicholas G |
NG |
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Meisinger C |
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Meisinger |
Christa |
C |
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Psaty BM |
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Psaty |
Bruce M |
BM |
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Spector TD |
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Spector |
Timothy D |
TD |
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Wareham NJ |
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Wareham |
Nicholas J |
NJ |
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Akkerman JW |
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Akkerman |
Jan-Willem N |
JW |
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Ciullo M |
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Ciullo |
Marina |
M |
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Deloukas P |
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Deloukas |
Panos |
P |
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Greinacher A |
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Greinacher |
Andreas |
A |
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Jupe S |
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Jupe |
Steve |
S |
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Kamatani N |
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Kamatani |
Naoyuki |
N |
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Khadake J |
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Khadake |
Jyoti |
J |
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Kooner JS |
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Kooner |
Jaspal S |
JS |
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Penninger J |
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Penninger |
Josef |
J |
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Prokopenko I |
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Prokopenko |
Inga |
I |
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Stemple D |
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Stemple |
Derek |
D |
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Toniolo D |
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Toniolo |
Daniela |
D |
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Wernisch L |
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Wernisch |
Lorenz |
L |
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Sanna S |
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Sanna |
Serena |
S |
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Hicks AA |
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Hicks |
Andrew A |
AA |
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Rendon A |
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Rendon |
Augusto |
A |
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Ferreira MA |
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Ferreira |
Manuel A |
MA |
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Ouwehand WH |
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Ouwehand |
Willem H |
WH |
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Soranzo N |
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Soranzo |
Nicole |
N |
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INVESTIGATORS |
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JOURNAL |
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VOLUME: 480 |
ISSUE: 7376 |
TITLE: Nature |
ISOABBREVIATION: Nature |
YEAR: 2011 |
MONTH: Dec |
DAY: 8 |
MEDLINEDATE: |
SEASON: |
CITEDMEDIUM: Internet |
ISSN: 1476-4687 |
ISSNTYPE: Electronic |
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MEDLINE JOURNAL |
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MEDLINETA: Nature |
COUNTRY: England |
ISSNLINKING: 0028-0836 |
NLMUNIQUEID: 0410462 |
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PUBLICATION TYPE |
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PUBLICATIONTYPE TEXT |
Journal Article |
Meta-Analysis |
Research Support, N.I.H., Extramural |
Research Support, Non-U.S. Gov't |
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COMMENTS AND CORRECTIONS |
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REFTYPE |
REFSOURCE |
REFPMID |
NOTE |
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GRANTS |
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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 |
|