Genome-wide association study of intracranial aneurysms confirms role of Anril and SOX17 in disease risk

Abstract

Background: Genomewide 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 metaanalysis.

Results: There was only modest overlap in the association results obtained in the 2 samples. In neither sample did results reach genomewide significance. However, the metaanalysis yielded genomewide 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.

Conclusions: 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).

Figure 1

Results of the genome-wide association analysis for intracranial aneurysm (IA) susceptibility. A, Discovery sample 1. B, Discovery sample 2. C, Meta-analysis.

Figure 2

Comparison with selected previously reported results from genome-wide association studies.^, A, Chromosome 8q12.1. B, Chromosome 9p213. When the most significant single nucleotide polymorphism (SNP) from the initial report was available in the meta-analysis, a white diamond indicates the SNP, and the SNP is listed at the top of the Figure. If the SNP was not available in the meta-analysis sample, then an arrow is used to denote the position of that SNP. Each circle indicates the probability value for a SNP at that position in the meta-analysis. The color of the square symbol denotes the extent of linkage disequilibrium (as computed by r²) with the SNP reported in the initial report.