Risk variants for atrial fibrillation on chromosome 4q25 associate with ischemic stroke.
OBJECTIVE
To find sequence variants that associate with the risk for ischemic stroke (IS), we performed a genome-wide association study.


METHODS
We genotyped 1,661 Icelandic IS patients and 10,815 control subjects using the Infinium HumanHap300 chip (Illumina, San Diego, CA). A total of 310,881 single nucleotide polymorphisms (SNPs) were tested for association with IS, and the most significant signals were replicated in two large European IS sample sets (2,224 cases/2,583 control subjects). Two SNPs, rs2200733 and rs10033464, were tested further in additional European IS samples (2,327 patients and 16,760 control subjects).


RESULTS
In the Icelandic samples and the two replication sets combined, rs2200733 associated significantly with cardioembolic stroke (CES) (odds ratio [OR], 1.54; p = 8.05 x 10(-9)). No other variants associated with IS or any of its subtypes. rs2200733 associated significantly with IS in all sample sets combined (OR, 1.26; p = 2.18 x 10(-10)), and both rs2200733 and its neighbour, rs10033464 associated strongly with CES (rs2200733: OR, 1.52; p = 5.8 x 10(-12); rs10033464: OR, 1.27; p = 6.1 x 10(-4)). Interestingly, rs2200733 also showed significant association to IS not classified as CES.


CONCLUSIONS
We discovered that variants previously shown to associate with atrial fibrillation (AF), rs2200733 and rs10033464, significantly associated with IS, with the strongest risk for CES. The association with noncardiogenic stroke is intriguing and suggests that atrial fibrillation may be underdiagnosed in patients presenting with stroke. This discovery may have implications for workup and treatment of IS.
Gretarsdottir
Solveig
S
DeCODE Genetics, Reykjavik, Iceland. solveig.gretarsdottir@decode.is
Thorleifsson
Gudmar
G
Manolescu
Andrei
A
Styrkarsdottir
Unnur
U
Helgadottir
Anna
A
Gschwendtner
Andreas
A
Kostulas
Konstantinos
K
Kuhlenbäumer
Gregor
G
Bevan
Steve
S
Jonsdottir
Thorbjorg
T
Bjarnason
Hjordis
H
Saemundsdottir
Jona
J
Palsson
Stefan
S
Arnar
David O
DO
Holm
Hilma
H
Thorgeirsson
Gudmundur
G
Valdimarsson
Einar Mar
EM
Sveinbjörnsdottir
Sigurlaug
S
Gieger
Christian
C
Berger
Klaus
K
Wichmann
H-Erich
HE
Hillert
Jan
J
Markus
Hugh
H
Gulcher
Jeffrey Robert
JR
Ringelstein
E Bernd
EB
Kong
Augustine
A
Dichgans
Martin
M
Gudbjartsson
Daniel Fannar
DF
Thorsteinsdottir
Unnur
U
Stefansson
Kari
K
D001281:Atrial Fibrillation / Q000150:complications / Q000235:genetics*; D002894:Chromosomes, Human, Pair 4; D016001:Confidence Intervals; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008297:Male; D016017:Odds Ratio; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012307:Risk Factors; D020521:Stroke / Q000209:etiology / Q000235:genetics*; D044465:White People / Q000235:genetics