Genomewide association studies of stroke.
BACKGROUND
The genes underlying the risk of stroke in the general population remain undetermined.


METHODS
We carried out an analysis of genomewide association data generated from four large cohorts composing the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, including 19,602 white persons (mean [+/-SD] age, 63+/-8 years) in whom 1544 incident strokes (1164 ischemic strokes) developed over an average follow-up of 11 years. We tested the markers most strongly associated with stroke in a replication cohort of 2430 black persons with 215 incident strokes (191 ischemic strokes), another cohort of 574 black persons with 85 incident strokes (68 ischemic strokes), and 652 Dutch persons with ischemic stroke and 3613 unaffected persons.


RESULTS
Two intergenic single-nucleotide polymorphisms on chromosome 12p13 and within 11 kb of the gene NINJ2 were associated with stroke (P<5x10(-8)). NINJ2 encodes an adhesion molecule expressed in glia and shows increased expression after nerve injury. Direct genotyping showed that rs12425791 was associated with an increased risk of total (i.e., all types) and ischemic stroke, with hazard ratios of 1.30 (95% confidence interval [CI], 1.19 to 1.42) and 1.33 (95% CI, 1.21 to 1.47), respectively, yielding population attributable risks of 11% and 12% in the discovery cohorts. Corresponding hazard ratios were 1.35 (95% CI, 1.01 to 1.79; P=0.04) and 1.42 (95% CI, 1.06 to 1.91; P=0.02) in the large cohort of black persons and 1.17 (95% CI, 1.01 to 1.37; P=0.03) and 1.19 (95% CI, 1.01 to 1.41; P=0.04) in the Dutch sample; the results of an underpowered analysis of the smaller black cohort were nonsignificant.


CONCLUSIONS
A genetic locus on chromosome 12p13 is associated with an increased risk of stroke.
Department of Epidemiology, Erasmus MC University Medical Center, Rotterdam, The Netherlands.
M Arfan
MA
Ikram
Sudha
S
Seshadri
Joshua C
JC
Bis
Myriam
M
Fornage
Anita L
AL
DeStefano
Yurii S
YS
Aulchenko
Stephanie
S
Debette
Thomas
T
Lumley
Aaron R
AR
Folsom
Evita G
EG
van den Herik
Michiel J
MJ
Bos
Alexa
A
Beiser
Mary
M
Cushman
Lenore J
LJ
Launer
Eyal
E
Shahar
Maksim
M
Struchalin
Yangchun
Y
Du
Nicole L
NL
Glazer
Wayne D
WD
Rosamond
Fernando
F
Rivadeneira
Margaret
M
Kelly-Hayes
Oscar L
OL
Lopez
Josef
J
Coresh
Albert
A
Hofman
Charles
C
DeCarli
Susan R
SR
Heckbert
Peter J
PJ
Koudstaal
Qiong
Q
Yang
Nicholas L
NL
Smith
Carlos S
CS
Kase
Kenneth
K
Rice
Talin
T
Haritunians
Gerwin
G
Roks
Paul L M
PL
de Kort
Kent D
KD
Taylor
Lonneke M
LM
de Lau
Ben A
BA
Oostra
Andre G
AG
Uitterlinden
Jerome I
JI
Rotter
Eric
E
Boerwinkle
Bruce M
BM
Psaty
Thomas H
TH
Mosley
Cornelia M
CM
van Duijn
Monique M B
MM
Breteler
W T
WT
Longstreth
Philip A
PA
Wolf
D000368:Aged; D044383:Black People / Q000235:genetics; D002881:Chromosomes, Human, Pair 12 / Q000235:genetics*; D015331:Cohort Studies; D005260:Female; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D016016:Proportional Hazards Models; D012307:Risk Factors; D020521:Stroke / Q000235:genetics*; D044465:White People / Q000235:genetics
D005819:Genetic Markers