Genome-wide association analysis identifies new candidate risk loci for familial intracranial aneurysm in the French-Canadian population

Abstract

Intracranial Aneurysm (IA) is a common disease with a worldwide prevalence of 1–3%. In the French-Canadian (FC) population, where there is an important founder effect, the incidence of IA is higher and is frequently seen in families. In this study, we genotyped a cohort of 257 mostly familial FC IA patients and 1,992 FC controls using the Illumina NeuroX SNP-chip. The most strongly associated loci were tested in 34 Inuit IA families and in 32 FC IA patients and 106 FC controls that had been exome sequenced (WES). After imputation, one locus at 3p14.2 (FHIT, rs1554600, p = 4.66 × 10–9) reached a genome-wide significant level of association and a subsequent validation in Nunavik Inuit cohort further confirmed the significance of the FHIT variant association (rs780365, FBAT-O, p = 0.002839). Additionally, among the other promising loci (p < 5 × 10−6), the one at 3q13.2 (rs78125721, p = 4.77 × 10−7), which encompasses CCDC80, also showed an increased mutation burden in the WES data (CCDC80, SKAT-O, p = 0.0005). In this study, we identified two new potential IA loci in the FC population: FHIT, which is significantly associated with hypertensive IA, and CCDC80, which has potential genetic and functional relevance to IA pathogenesis, providing evidence on the additional risk loci for familial IA. We also replicated the previous IA GWAS risk locus 18q11.2, and suggested a potential locus at 8p23.1 that warrants further study.

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“…Intracranial aneurysm (IA), also known as cerebral aneurysm, is caused by the increase of intracranial pressure induced by the local abnormal widening of the cerebral artery cavity or arterial wall [1]. IA is a severe disease with high mortality and morbidity, and the prevalence rate is about 1-3% in the general population [2]. The main clinical features of IA are cerebral vasospasm, spontaneous cerebral hemorrhage, and oculomotor nerve palsy [3].…”

Morphological and Hemodynamic Risk Factors for Middle Cerebral Artery Aneurysm: a Case-Control Study of 190 Patients

“…In studies conducted by Meng et al 2,24 , involving CFD and histological analysis of canine and rabbit models, a combination of high wall shear stress (WSS) and high WSS gradient at arterial bifurcation was shown to lead to cerebral aneurysm formation by disruption of the internal elastic lamina, loss of smooth muscle cells (SMCs) and a decrease in SMC proliferation rate. Recent evidence suggests than aneurysm formation might be also associated with the influence of multiple genetic factors which determine the strength of the arterial wall, which is further modified by environmental factors, such as smoking and hypertension 25,26 . However, the www.nature.com/scientificreports www.nature.com/scientificreports/ majority of cerebral aneurysms are located solely in a few arterial bifurcations, i.e.…”

Exome sequencing in 38 patients with intracranial aneurysms and subarachnoid hemorrhage

“…However, the genetic background of the disease is still poorly understood. Although large genome or exome wide association studies (GWAS or EWAS) identified several risk loci, valid disease genes have not been established [3]. In addition to GWAS providing associations between genomic regions and a disease, novel advanced approaches using exome sequencing (ES) promise to detect causal relations.…”