Fine Mapping of Intracranial Aneurysm Susceptibility Based on a Genome-wide Association Study

Abstract

In addition to conventional genome-wide association studies (GWAS), a fine-mapping is increasingly used to identify the genetic function of variants associated with disease susceptibilities. Here, we used a fine-mapping approach to evaluate the casual variants based on a previous GWAS involving patients with intracranial aneurysm (IA). Fine-mapping analysis was conducted based on the chromosomal data provided by GWAS consisting 250 patients diagnosed with IA and 296 controls using posterior inclusion probability (PIP) and log10 transformed Bayes factor (log10BF). The narrow sense of heritability (h2) explained by each casual variant was estimated. Subsequent gene expression and functional network analyses were used to calculate the transcripts per million (TPM) values. Twenty causal candidate single nucleotide polymorphisms (SNPs) surpassed a genome-wide significance threshold for creditable evidence (log10BF > 6.1). Four SNPs including rs75822236 (R535H, GBA; log10BF = 15.06), rs112859779 (G141S, TCF24; log10BF = 12.12), rs79134766 (A208T, OLFML2A; log10BF = 14.92), and rs371331393 (Q1932X, ARHGAP32; log10BF = 20.88) showed a completed PIP value in each chromosomal region, suggesting a high probability of variant causality associated with IA. Expression in GBA was highly enriched in the whole blood (TPM = 33.13), while TCF24 were rarely expressed in all tissues and cells. No direct interaction was observed between the four casual genes; however, PSAP appeared to be particularly important via indirect correlation between other genes. Our results suggested that four mutations of GBA, TCF24, OLFML2A, and ARHGAP32 were linked to IA susceptibility and pathogenesis. Our approach may promise more informative mutations in the following GWAS.

Identifying and validating key genes mediating intracranial aneurysm rupture using weighted correlation network analysis and exploration of personalized treatment

“…They identified (PLOD3 c.1315G>A, NTM c.968C>T and CHST14 c.58C>T) as any significant copy number variants in the family (38). In one other study, based on chromosomal data from genome-wide association studies (GWAS) of 250 patients diagnosed with IA and 296 controls, our fine mapping analysis showed that four functional candidate variants, GBA, TCF24, OLFML2A and ARHGAP32, were associated with susceptibility and pathogenesis of IA (39). and the presence of the T allele in the rs12976445 polymorphism was associated with a lower risk of IA rebleeding (40).…”

Novel Genome-Wide Interactions Mediated via <i>BOLL</i> and <i>EDNRA</i> Polymorphisms in Intracranial Aneurysm

“…In this study, we aimed to investigate gene-gene interaction using the previous GWAS data for Korean patients with IA for the first time 11) . However, due to the relative small number of the enrolled patients and possible false positives 14) , we did not perform all possible pairwise SNP-SNP interaction and inevitably focused on two IA candidates of BOLL and EDNRA by referring to previous studies 12,13) . Nevertheless, we required further replication GWAS and exhaustive searching for SNP-SNP interaction in a large dataset of GWAS 19) .…”