Susceptibility loci for intracranial aneurysm in European and Japanese populations

Abstract

Stroke is the world's third leading cause of death. One cause of stroke, intracranial aneurysm, affects approximately 2% of the population and accounts for 500,000 hemorrhagic strokes annually in mid-life (median age 50), most often resulting in death or severe neurological impairment. The pathogenesis of intracranial aneurysm is unknown, and because catastrophic hemorrhage is commonly the first sign of disease, early identification is essential. We carried out a multistage genome-wide association study (GWAS) of Finnish, Dutch and Japanese cohorts including over 2,100 intracranial aneurysm cases and 8,000 controls. Genome-wide genotyping of the European cohorts and replication studies in the Japanese cohort identified common SNPs on chromosomes 2q, 8q and 9p that show significant association with intracranial aneurysm with odds ratios 1.24-1.36. The loci on 2q and 8q are new, whereas the 9p locus was previously found to be associated with arterial diseases, including intracranial aneurysm. Associated SNPs on 8q likely act via SOX17, which is required for formation and maintenance of endothelial cells, suggesting a role in development and repair of the vasculature; CDKN2A at 9p may have a similar role. These findings have implications for the pathophysiology, diagnosis and therapy of intracranial aneurysm.

Figure 1

Genome-wide association of SNPs with intracranial aneurysm in the combined European cohort. (a) Quantile-quantile plot of the observed χ² values derived from the Mantel-extension test statistics versus the expected χ² distribution. The solid line represents concordance of observed and expected values. The slope of the dashed line represents the genomic inflation factor (λ = 1.11). (b) The plot of expected and observed χ² values for association of SNPs with intracranial aneurysm after correction for the genomic inflation factor (λ = 1.0). Significant deviation from the expected values suggests association of these SNPs with intracranial aneurysm phenotype. (c) The -log₁₀ of uncorrected P values for association of each SNP and intracranial aneurysm is plotted according to its physical position on successive chromosomes. Green dots indicate SNPs yielding P values <1 × 10^-5, and red dots denote SNPs that surpass a significance level of 5 × 10^-7.

Figure 2

Regional association plots and linkage disequilibrium structure. (a-c) The -log₁₀ of the P value for association of each SNP and intracranial aneurysm in discovery phase across segments of 2q (a), 8q (b) and 9q (c) are shown as small diamonds (using NCBI build 36 for map locations). Fifteen SNPs that were genotyped in the Japanese replication cohort are shown as triangles that show the combined (discovery + replication) P values: blue triangles represent SNPs that demonstrate replication in the Japanese cohort with P < 0.05, and gray triangles denote SNPs with P > 0.05 in the replication study. SNPs with the most significant P values in each interval in the combined analysis are marked with their SNP IDs. Known transcripts (RefSeq database) are represented as horizontal bars at the bottom of each panel. Population-specific LD structures based on D’ are shown for the HapMap European (CEU) and Asian (CHB + JPT) cohorts. The results demonstrate that on chromosome 2, SNPs spanning an ~800-kb interval are in strong LD in the CEU population and show evidence of association with intracranial aneurysm in the Finnish and Dutch cohorts. In Asia, this segment is broken into two smaller blocks of LD that are not strongly correlated with one another, and significant association with intracranial aneurysm in Japanese cohort is seen only for the telomeric segment. For chromosome 8, SNPs in two blocks that are not in significant LD with one another both show significant association with intracranial aneurysm in the European cohort; only SNPs located within the proximal block replicate in Japan. Cohort-specific r² values among all SNPs genotyped in the replication studies are shown in Supplementary Table 4.