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Loci associated with ischaemic stroke and its subtypes (SiGN): a genome-wide association study.

Journal article
Authors SL Pulit
PF McArdle
Q Wong
R Malik
K Gwinn
S Achterberg
A Algra
P Amouyel
CD Anderson
DK Arnett
EM Arsava
J Attia
H Ay
TM Bartz
T Battey
OR Benavente
S Bevan
A Biffi
JC Bis
SH Blanton
GB Boncoraglio
RD Brown Jr
AI Burgess
C Carrera
SN Chapman Smith
DI Chasman
G Chauhan
W-M Chen
Y-C Cheng
M Chong
LK Cloonan
JW Cole
I Cotlarciuc
C Cruchaga
E Cuadrado-Godia
T Dave
J Dawson
S Debette
H Delavaran
CA Dell
M Dichgans
KF Doheny
C Dong
DJ Duggan
G Engström
MK Evans
X Estivill Pallejà
JD Faul
I Fernández-Cadenas
M Fornage
PM Frossard
K Furie
DM Gamble
C Gieger
A-K Giese
E Giralt-Steinhauer
HM González
A Goris
S Gretarsdottir
RP Grewal
U Grittner
S Gustafsson
B Han
GJ Hankey
L Heitsch
P Higgins
MC Hochberg
E Holliday
JC Hopewell
RB Horenstein
G Howard
MA Ikram
A Ilinca
E Ingelsson
MR Irvin
RD Jackson
Christina Jern
J Jiménez Conde
JA Johnson
Katarina Jood
MS Kahn
R Kaplan
LJ Kappelle
SLR Kardia
KL Keene
BM Kissela
DO Kleindorfer
S Koblar
D Labovitz
LJ Launer
CC Laurie
CA Laurie
C Hyunkyu Lee
J-M Lee
M Lehm
R Lemmens
C Levi
D Leys
A Lindgren
WT Longstreth Jr
J Maguire
A Manichaikul
HS Markus
LA McClure
CW McDonough
C Meisinger
O Melander
JF Meschia
M Mola-Caminal
J Montaner
TH Mosley
M Müller-Nurasyid
MA Nalls
JR O’Connell
M O’Donnell
Á Ois
GJ Papanicolaou
G Paré
L Reddy Peddareddygari
Annie Pedersen
J Pera
A Peters
D Poole
BM Psaty
R Rabionet
MR Raffeld
K Rannikmäe
A Rasheed
Petra Redfors
AP Reiner
K Rexrode
M Ribasés
SS Rich
W Robberecht
A Rodriguez-Campello
A Rolfs
J Roquer
LM Rose
D Rosenbaum
NS Rost
PM Rothwell
T Rundek
KA Ryan
RL Sacco
MM Sale
D Saleheen
V Salomaa
C Sánchez-Mora
C Oliver Schmidt
H Schmidt
R Schmidt
M Schürks
R Scott
HC Segal
S Seiler
S Seshadri
P Sharma
AR Shuldiner
B Silver
A Slowik
JA Smith
M Söderholm
C Soriano
MJ Sparks
Tara M Stanne
K Stefansson
OC Stine
K Strauch
J Sturm
CLM Sudlow
SM Tajuddin
RL Talbert
Turgut Tatlisumak
V Thijs
G Thorleifsson
U Thorsteindottir
S Tiedt
M Traylor
S Trompet
V Valant
M Waldenberger
M Walters
L Wang
S Wassertheil-Smoller
DR Weir
KL Wiggins
SR Williams
D Wloch-Kopec
D Woo
R Woodfield
O Wu
H Xu
AB Zonderman
Published in The Lancet. Neurology
Volume 15
Issue 2
Pages 174-84
ISSN 1474-4465
Publication year 2016
Published at Institute of Biomedicine, Department of Medical and Clinical Genetics
Institute of Neuroscience and Physiology
Institute of Neuroscience and Physiology, Department of Clinical Neuroscience and Rehabilitation
Institute of Biomedicine, Department of Pathology
Pages 174-84
Language en
Subject categories Basic Medicine


The discovery of disease-associated loci through genome-wide association studies (GWAS) is the leading genetic approach to the identification of novel biological pathways underlying diseases in humans. Until recently, GWAS in ischaemic stroke have been limited by small sample sizes and have yielded few loci associated with ischaemic stroke. We did a large-scale GWAS to identify additional susceptibility genes for stroke and its subtypes.To identify genetic loci associated with ischaemic stroke, we did a two-stage GWAS. In the first stage, we included 16 851 cases with state-of-the-art phenotyping data and 32 473 stroke-free controls. Cases were aged 16 to 104 years, recruited between 1989 and 2012, and subtypes of ischaemic stroke were recorded by centrally trained and certified investigators who used the web-based protocol, Causative Classification of Stroke (CCS). We constructed case-control strata by identifying samples that were genotyped on nearly identical arrays and were of similar genetic ancestral background. We cleaned and imputed data by use of dense imputation reference panels generated from whole-genome sequence data. We did genome-wide testing to identify stroke-associated loci within each stratum for each available phenotype, and we combined summary-level results using inverse variance-weighted fixed-effects meta-analysis. In the second stage, we did in-silico lookups of 1372 single nucleotide polymorphisms identified from the first stage GWAS in 20 941 cases and 364 736 unique stroke-free controls. The ischaemic stroke subtypes of these cases had previously been established with the Trial of Org 10 172 in Acute Stroke Treatment (TOAST) classification system, in accordance with local standards. Results from the two stages were then jointly analysed in a final meta-analysis.We identified a novel locus (G allele at rs12122341) at 1p13.2 near TSPAN2 that was associated with large artery atherosclerosis-related stroke (first stage odds ratio [OR] 1·21, 95% CI 1·13-1·30, p=4·50 × 10(-8); joint OR 1·19, 1·12-1·26, p=1·30 × 10(-9)). Our results also supported robust associations with ischaemic stroke for four other loci that have been reported in previous studies, including PITX2 (first stage OR 1·39, 1·29-1·49, p=3·26 × 10(-19); joint OR 1·37, 1·30-1·45, p=2·79 × 10(-32)) and ZFHX3 (first stage OR 1·19, 1·11-1·27, p=2·93 × 10(-7); joint OR 1·17, 1·11-1·23, p=2·29 × 10(-10)) for cardioembolic stroke, and HDAC9 (first stage OR 1·29, 1·18-1·42, p=3·50 × 10(-8); joint OR 1·24, 1·15-1·33, p=4·52 × 10(-9)) for large artery atherosclerosis stroke. The 12q24 locus near ALDH2, which has previously been associated with all ischaemic stroke but not with any specific subtype, exceeded genome-wide significance in the meta-analysis of small artery stroke (first stage OR 1·20, 1·12-1·28, p=6·82 × 10(-8); joint OR 1·17, 1·11-1·23, p=2·92 × 10(-9)). Other loci associated with stroke in previous studies, including NINJ2, were not confirmed.Our results suggest that all ischaemic stroke-related loci previously implicated by GWAS are subtype specific. We identified a novel gene associated with large artery atherosclerosis stroke susceptibility. Follow-up studies will be necessary to establish whether the locus near TSPAN2 can be a target for a novel therapeutic approach to stroke prevention. In view of the subtype-specificity of the associations detected, the rich phenotyping data available in the Stroke Genetics Network (SiGN) are likely to be crucial for further genetic discoveries related to ischaemic stroke.US National Institute of Neurological Disorders and Stroke, National Institutes of Health.

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