Genome-wide association study identifies a variant in HDAC9 associated with large vessel ischemic stroke.
Genetic factors have been implicated in stroke risk, but few replicated associations have been reported. We conducted a genome-wide association study (GWAS) for ischemic stroke and its subtypes in 3,548 affected individuals and 5,972 controls, all of European ancestry. Replication of potential signals was performed in 5,859 affected individuals and 6,281 controls. We replicated previous associations for cardioembolic stroke near PITX2 and ZFHX3 and for large vessel stroke at a 9p21 locus. We identified a new association for large vessel stroke within HDAC9 (encoding histone deacetylase 9) on chromosome 7p21.1 (including further replication in an additional 735 affected individuals and 28,583 controls) (rs11984041; combined P = 1.87 × 10(-11); odds ratio (OR) = 1.42, 95% confidence interval (CI) = 1.28-1.57). All four loci exhibited evidence for heterogeneity of effect across the stroke subtypes, with some and possibly all affecting risk for only one subtype. This suggests distinct genetic architectures for different stroke subtypes.
Wellcome Trust Centre for Human Genetics, University of Oxford, UK.
Céline
C
Bellenguez
Steve
S
Bevan
Andreas
A
Gschwendtner
Chris C A
CC
Spencer
Annette I
AI
Burgess
Matti
M
Pirinen
Caroline A
CA
Jackson
Matthew
M
Traylor
Amy
A
Strange
Zhan
Z
Su
Gavin
G
Band
Paul D
PD
Syme
Rainer
R
Malik
Joanna
J
Pera
Bo
B
Norrving
Robin
R
Lemmens
Colin
C
Freeman
Renata
R
Schanz
Tom
T
James
Deborah
D
Poole
Lee
L
Murphy
Helen
H
Segal
Lynelle
L
Cortellini
Yu-Ching
YC
Cheng
Daniel
D
Woo
Michael A
MA
Nalls
Bertram
B
Müller-Myhsok
Christa
C
Meisinger
Udo
U
Seedorf
Helen
H
Ross-Adams
Steven
S
Boonen
Dorota
D
Wloch-Kopec
Valerie
V
Valant
Julia
J
Slark
Karen
K
Furie
Hossein
H
Delavaran
Cordelia
C
Langford
Panos
P
Deloukas
Sarah
S
Edkins
Sarah
S
Hunt
Emma
E
Gray
Serge
S
Dronov
Leena
L
Peltonen
Solveig
S
Gretarsdottir
Gudmar
G
Thorleifsson
Unnur
U
Thorsteinsdottir
Kari
K
Stefansson
Giorgio B
GB
Boncoraglio
Eugenio A
EA
Parati
John
J
Attia
Elizabeth
E
Holliday
Chris
C
Levi
Maria-Grazia
MG
Franzosi
Anuj
A
Goel
Anna
A
Helgadottir
Jenefer M
JM
Blackwell
Elvira
E
Bramon
Matthew A
MA
Brown
Juan P
JP
Casas
Aiden
A
Corvin
Audrey
A
Duncanson
Janusz
J
Jankowski
Christopher G
CG
Mathew
Colin N A
CN
Palmer
Robert
R
Plomin
Anna
A
Rautanen
Stephen J
SJ
Sawcer
Richard C
RC
Trembath
Ananth C
AC
Viswanathan
Nicholas W
NW
Wood
Bradford B
BB
Worrall
Steven J
SJ
Kittner
Braxton D
BD
Mitchell
Brett
B
Kissela
James F
JF
Meschia
Vincent
V
Thijs
Arne
A
Lindgren
Mary Joan
MJ
Macleod
Agnieszka
A
Slowik
Matthew
M
Walters
Jonathan
J
Rosand
Pankaj
P
Sharma
Martin
M
Farrall
Cathie L M
CL
Sudlow
Peter M
PM
Rothwell
Martin
M
Dichgans
Peter
P
Donnelly
Hugh S
HS
Markus
D002897:Chromosomes, Human, Pair 7 / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D055106:Genome-Wide Association Study; D005838:Genotype; D006655:Histone Deacetylases / Q000235:genetics*; D006801:Humans; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics*; D020521:Stroke / Q000235:genetics*; D044465:White People / Q000235:genetics
D012097:Repressor Proteins; C486544:HDAC9 protein, human; D006655:Histone Deacetylases