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 ~2% of the population and accounts for 500,000 hemorrhagic strokes annually in midlife (median age 50), most often resulting in death or severe neurological impairment1. 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 aneurysm2-5. Associated SNPs on 8q likely act via SOX17, which is required for formation and maintenance of endothelial cells6-8, suggesting a role in development and repair of the vasculature; CDKN2A at 9p may have a similar role9. These findings have implications for the pathophysiology, diagnosis and therapy of intracranial aneurysm.

Genome-wide association study to identify genetic variants present in Japanese patients harboring intracranial aneurysms

“…In our study, we tested for association between the three SNPs and IA at the first stage of the current GWAS (194 IA cases and 288 controls) and obtained ORs and 95% CIs for the SNPs as follows: rs1429412, OR¼1.13 (95% CI, 0.79-1.33); rs10958409, 1.20 (0.78-1.53); and rs1333040, 1.29 (0.98-1.72). The ORs were not so different from those in the previous study, 11 but the effect sizes showed no statistical significance. This GWAS has limited power to detect loci with small effect sizes (for example, o10% power to detect common variants with genotypic relative risk of 1.3; also see Supplementary Figure 1).…”

“…Because Bilguvar et al 11 have replicated three SNPs significantly associated with IA by using a subset of our Japanese cohort (rs1429412 on chromosome 2q, rs10958409 on chromosome 8q and rs1333040 on chromosome 9p in 495 IA cases and 676 non-IA controls), the SNPs are likely to be true positives. In our study, we tested for association between the three SNPs and IA at the first stage of the current GWAS (194 IA cases and 288 controls) and obtained ORs and 95% CIs for the SNPs as follows: rs1429412, OR¼1.13 (95% CI, 0.79-1.33); rs10958409, 1.20 (0.78-1.53); and rs1333040, 1.29 (0.98-1.72).…”

“…We recruited a total of 1069 IA patients and 904 controls from the three university hospitals described above and their affiliated hospitals. The 495 cases (48.9%) and 676 controls (74.8%) have been also used in the previous GWAS by Bilguvar et al 11 Of the cases, 27.7% had familial history of IA, and SAH was observed in 727 cases (68.0%). The female to male ratio of cases and controls were 1.56 and 0.62, respectively.…”

“…11,12 In a previous study, a multicenter collaboration regarding IA genetics led to complete a multistage GWAS that identified common variants that contribute to IA formation in three large cohorts: a Finnish cohort of 920 cases and 985 controls, a Dutch cohort of 781 cases and 6424 controls and a Japanese cohort of 495 cases and 676 controls. 11 Consequently, common SNPs with odds ratios (ORs) of 1.22-1.36 on chromosomes 2q, 8q and 9p were identified and showed significant association with IA. Because the three loci account only for a small fraction of the genetic variance underlying IA, it remains a challenge to identify another genetic variant such as common variants with population-specific impacts on the risk of IA.…”

Impact of LIMK1, MMP2 and TNF-α variations for intracranial aneurysm in Japanese population

“…Although several common variants were identified to be associated with the increased risk of IA development through candidate gene approaches [12][13][14][15][16] and genome-wide association studies, 17,18 only few associations were consistently replicated. 19,20 These might be because of the lack of statistical power of the study or differences in the allele frequencies across different populations.…”