Common variant near the endothelin receptor type A (EDNRA) gene is associated with intracranial aneurysm risk

Abstract

The pathogenesis of intracranial aneurysm (IA) formation and rupture is complex, with significant contribution from genetic factors. We previously reported genome-wide association studies based on European discovery and Japanese replication cohorts of 5,891 cases and 14,181 controls that identified five disease-related loci. These studies were based on testing replication of genomic regions that contained SNPs with posterior probability of association (PPA) greater than 0.5 in the discovery cohort. To identify additional IA risk loci, we pursued 14 loci with PPAs in the discovery cohort between 0.1 and 0.5. Twenty-five SNPs from these loci were genotyped using two independent Japanese cohorts, and the results from discovery and replication cohorts were combined by meta-analysis. The results demonstrated significant association of IA with rs6841581 on chromosome 4q31.23, immediately 5' of the endothelin receptor type A with P = 2.2 × 10(-8) [odds ratio (OR) = 1.22, PPA = 0.986]. We also observed substantially increased evidence of association for two other regions on chromosomes 12q22 (OR = 1.16, P = 1.1 × 10(-7), PPA = 0.934) and 20p12.1 (OR = 1.20, P = 6.9 × 10(-7), PPA = 0.728). Although endothelin signaling has been hypothesized to play a role in various cardiovascular disorders for over two decades, our results are unique in providing genetic evidence for a significant association with IA and suggest that manipulation of the endothelin pathway may have important implications for the prevention and treatment of IA.

Fig. 1.

Distribution of the PPA along the genome The PPAs for SNPs analyzed in ref. are plotted along the genomic coordinates [National Center for Biotechnology Information (NCBI) build 36]. We omitted 767,877 SNPs with PPA < 0.0001 from a total of 831,532 SNPs. Fifteen regions analyzed in this article (i.e., those regions containing a SNP with 0.1 < PPA < 0.5 but no SNPs with PPA > 0.5) are shaded in gray.

Fig. 2.

Regional plots for associated regions. For each chromosomal interval, −log₁₀ P values for association test are plotted against the genomic coordinates (NCBI build 36) (Upper); the recombination rates obtained from the HapMap database and the RefSeq genes (hg18) within the regions (Lower). The rs identifier of the SNP listed in Table 2 is shown for each chromosomal interval, and its position is indicated by the gray vertical line (Upper). Dark and light blue dots represent results of the genotyped and imputed SNPs for the discovery cohort, respectively. Orange squares represent the association result from the replication cohort using the JP1 plus JP2 (rs6541581 and rs6538595) or JP2-only (rs1132274); combined P values of the discovery and replication cohorts based on the fixed-effects model are shown by red diamonds.

Fig. 3.

Consistency of association across cohorts. Forest plots are shown for meta-analysis of SNPs listed in Table 2. Squares and horizontal segments represent estimated per-allele ORs and 95% confidence intervals (CIs) for individual cohorts. Diamonds represent the summary OR estimates and 95% CIs for the meta-analyses of six cohorts (fixed- and random-effects models). A log₁₀(BF) > 0 supports association with IA, and a log₁₀(BF) < 0 supports no association with IA.