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.
Ikram
M Arfan
MA
Department of Epidemiology, Erasmus MC University Medical Center, Rotterdam, The Netherlands.
Seshadri
Sudha
S
Bis
Joshua C
JC
Fornage
Myriam
M
DeStefano
Anita L
AL
Aulchenko
Yurii S
YS
Debette
Stephanie
S
Lumley
Thomas
T
Folsom
Aaron R
AR
van den Herik
Evita G
EG
Bos
Michiel J
MJ
Beiser
Alexa
A
Cushman
Mary
M
Launer
Lenore J
LJ
Shahar
Eyal
E
Struchalin
Maksim
M
Du
Yangchun
Y
Glazer
Nicole L
NL
Rosamond
Wayne D
WD
Rivadeneira
Fernando
F
Kelly-Hayes
Margaret
M
Lopez
Oscar L
OL
Coresh
Josef
J
Hofman
Albert
A
DeCarli
Charles
C
Heckbert
Susan R
SR
Koudstaal
Peter J
PJ
Yang
Qiong
Q
Smith
Nicholas L
NL
Kase
Carlos S
CS
Rice
Kenneth
K
Haritunians
Talin
T
Roks
Gerwin
G
de Kort
Paul L M
PL
Taylor
Kent D
KD
de Lau
Lonneke M
LM
Oostra
Ben A
BA
Uitterlinden
Andre G
AG
Rotter
Jerome I
JI
Boerwinkle
Eric
E
Psaty
Bruce M
BM
Mosley
Thomas H
TH
van Duijn
Cornelia M
CM
Breteler
Monique M B
MM
Longstreth
W T
WT
Wolf
Philip A
PA
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