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Meta-Analysis
. 2010 Jun;41(6):1123-31.
doi: 10.1161/STROKEAHA.110.580589. Epub 2010 Apr 15.

Chromosome 9p21 in ischemic stroke: population structure and meta-analysis

Christopher D Anderson  1 , Alessandro Biffi, Natalia S Rost, Lynelle Cortellini, Karen L Furie, Jonathan Rosand
Affiliations
Meta-Analysis

Chromosome 9p21 in ischemic stroke: population structure and meta-analysis

Christopher D Anderson et al. Stroke. 2010 Jun.

Abstract

Background and purpose: 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.

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Conflict of interest statement

DISCLOSURES

The authors have no Conflict of Interest/Disclosures

Figures

Figure 1
Figure 1. Meta-analysis workflow
See Appendix for search terms used to identify studies in PubMed
Figure 2
Figure 2. Meta-analysis results, genes, associations, and linkage disequilibrium at 9p21.3
Top panel. Plot of association strength (-log p-value) extracted from published studies (ref. ,–13) Middle panel. Genes located within the 9p21.3 locus and medical conditions associated with this locus in prior publications. Panel created using HapMap (http://hapmap.ncbi.nlm.nih.gov/) Bottom panel. Linkage disequilibrium (LD) at the 9p21.3 locus demonstrates four distinct regions of extended LD defined by triangular outlines. Rs10757278 and rs1537378 fall in separate LD blocks, allowing them to more easily demonstrate independent signal in association testing. Panel created using Haploview (http://www.broadinstitute.org/haploview/haploview-downloads)
Figure 3
Figure 3. Forest plots for rs10757278
A. rs10757278 − All Available Data, B.rs10757278 − Large Artery + Cardioembolic, C. rs10757278 − Large Artery AA = African American, AIS = All Ischemic Stroke Subtypes, CE = Cardioembolic Stroke, CH = Chinese Han, Ethno = Ethnicity, Cntrls = Controls, EU = European, LA = Large Artery Stroke, Pheno = Phenotype
Figure 4
Figure 4. Forest plots for rs1537378
A. rs1537378 − All Available Data, B. rs1537378 − Large Artery + GWAS, C. rs1537378 − Large Artery AA = African American, AIS = All Ischemic Stroke Subtypes, CE = Cardioembolic Stroke, Ethno = Ethnicity, Cntrls = Controls, EU = European, LA = Large Artery Stroke, Pheno = Phenotype
Figure 5
Figure 5. Effect size estimates (Odds Ratio), sample size and meta-analysis heterogeneity for rs10757278 and rs1537378
Restriction of cases to LA only results in increased effect size and decreased heterogeneity across studies for both SNPs. LA only effect persists despite controlling for MI, and approaches the odds-ratio observed in association studies for CAD/MI [ref. 4,17] CAD = Coronary Artery Disease, Candidate Studies = Gschwendtner et al. [ref. 7], Ikram GWAS = Ikram et al. [ref. 13], LA = Large Artery Stroke, MI = Myocardial Infarction, OR = Odds Ratio.
See this image and copyright information in PMC

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