Genome-Wide Association Study of Intracranial Aneurysms Confirms Role of Anril and SOX17 in Disease Risk

Abstract

Background Genome-wide association studies have identified novel genetic factors that contribute to intracranial aneurysm (IA) susceptibility. We sought to confirm previously reported loci, to identify novel risk factors, and to evaluate the contribution of these factors to familial and sporadic IA. Method We utilized 2 complementary samples, one recruited on the basis of a dense family history of IA (discovery sample 1: 388 IA cases and 397 controls) and the other without regard to family history (discovery sample 2: 1095 IA cases and 1286 controls). Imputation was used to generate a common set of single nucleotide polymorphisms (SNP) across samples, and a logistic regression model was used to test for association in each sample. Results from each sample were then combined in a meta-analysis. Results There was only modest overlap in the association results obtained in the 2 samples. In neither sample did results reach genome-wide significance. However, the meta-analysis yielded genome-wide significance for SNP on chromosome 9p (CDKN2BAS; rs6475606; P=3.6×10−8) and provided further evidence to support the previously reported association of IA with SNP in SOX17 on chromosome 8q (rs1072737; P=8.7×10−5). Analyses suggest that the effect of smoking acts multiplicatively with the SNP genotype, and smoking has a greater effect on risk than SNP genotype. Conclusion In addition to replicating several previously reported loci, we provide further evidence that the association on chromosome 9p is attributable to variants in CDKN2BAS (also known as ANRIL, an antisense noncoding RNA).

Genetic risk factors for intracranial aneurysms

“…21 In the most recent GWAS 14 in a Caucasian population of familial and sporadic IA, 6 SNPs, also located in the 9p21.3 region, were associated with IA; one of these (rs6475606) achieved GWAS-level statistical significance (OR 1.34; p 5 4.29 3 10 207 ) for association with sporadic and familial IAs. Association with the rs1333040 SNP was also confirmed in this study, 14 further strengthening association of this locus with IA.…”

“…The heterogeneity observed in the meta-analysis of these 2 SNPs may partly be explained by the difference in risk allele frequencies in the white population (table e-1) 24 compared with the other populations studied (rs10958409, risk allele frequency 0.88 vs approximately 0.2; rs9298506, risk allele frequency 0.17 vs approximately 0.80). Further support implicating chromosome 8 loci was shown in a recent GWAS, 14 in which a novel SNP, also in the region of the SOX17 gene, was significantly associated with IAs (rs1072737: OR 1.22; 95% CI 1.07-1.39), independent of smoking. For both SOX17 loci, in the most recent GWAS, 14 smoking was an independent risk factor, acting in a multiplicative manner (chromosome 8: rs1072737; OR 2.12; 95% CI 1.76-2.56 and chromosome 9: rs6475606; OR 2.11; 95% CI 1.…”

“…Further support implicating chromosome 8 loci was shown in a recent GWAS, 14 in which a novel SNP, also in the region of the SOX17 gene, was significantly associated with IAs (rs1072737: OR 1.22; 95% CI 1.07-1.39), independent of smoking. For both SOX17 loci, in the most recent GWAS, 14 smoking was an independent risk factor, acting in a multiplicative manner (chromosome 8: rs1072737; OR 2.12; 95% CI 1.76-2.56 and chromosome 9: rs6475606; OR 2.11; 95% CI 1.…”

“…More recently, genome-wide association studies (GWAS) have identified novel genetic loci strongly associated with IAs, [9][10][11][12][13][14] but these still explain only a fraction of the genetic risk.…”

ADAMTS genes and the risk of cerebral aneurysm

“…10,11,17,26,37 Thedevelopmentandruptureof aneurysmsinvolvelocaldegradationofvascularstructuralproteinsandremodelingofthediseasedbloodvessels. Elastin and collagens are major structural components of the vascular wall, and it has been suggested that elastinolysis is particularly pertinent to vessel dilation, while collagenolysis relates to aneurysm rupture.…”