Chromosome 9p21 in ischemic stroke: population structure and meta-analysis.
OBJECTIVE
Sequence variants on chromosome 9p21.3 are implicated in coronary artery disease and myocardial infarction, but studies in ischemic stroke have produced inconsistent results. We investigated whether these conflicting findings were due to false-positive studies confounded by population stratification or false-negative studies that failed to account for effects specific to certain stroke subtypes.


METHODS
After assessing for population stratification at 9p21.3 using genomewide data, we meta-analyzed 8 ischemic stroke studies. This analysis focused on 2 single nucleotide polymorphisms, rs1537378 and rs10757278, because these variants are in strong linkage disequilibrium with most single nucleotide polymorphisms analyzed in prior studies of the region.


RESULTS
Principal component analysis of the genomewide data showed no evidence of population stratification at that locus. Meta-analysis confirmed that both rs1537378 and rs10757278 are risk factors for ischemic stroke (ORs, 1.09 [P=0.0014] and 1.11 [P=0.001], respectively). Subtype analysis revealed a substantial increase in the effect of each single nucleotide polymorphism for risk of large artery stroke, achieving an effect size similar to that seen in coronary artery disease/myocardial infarction.


CONCLUSIONS
Variants on 9p21.3 are associated with ischemic stroke, and restriction of analysis to large artery stroke increases effect size toward that observed in prior association studies of coronary artery disease/myocardial infarction. Previous inconsistent findings are best explained by this subtype specificity rather than any unmeasured confounding by population stratification.
Anderson
Christopher D
CD
Center for Human Genetic Research, Massachusetts General Hospital, 185 Cambridge Street, CPZN-6818, Boston, MA 02114, USA.
Biffi
Alessandro
A
Rost
Natalia S
NS
Cortellini
Lynelle
L
Furie
Karen L
KL
Rosand
Jonathan
J
D002545:Brain Ischemia / Q000209:etiology / Q000235:genetics*; D002899:Chromosomes, Human, Pair 9 / Q000235:genetics*; D003324:Coronary Artery Disease / Q000150:complications / Q000235:genetics; D005260:Female; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D009203:Myocardial Infarction / Q000150:complications / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D020521:Stroke / Q000209:etiology / Q000235:genetics*
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