Genome-Wide Association between the 2q33.1 Locus and Intracranial Aneurysm Susceptibility: An Updated Meta-Analysis Including 18,019 Individuals.

Eun Pyo Hong,Jin Pyeong Jeon,Bong Jun Kim

doi:10.3390/jcm8050692

Abstract

Previous genome-wide association studies did not show a consistent association between the BOLL gene (rs700651, 2q33.1) and intracranial aneurysm (IA) susceptibility. We aimed to perform an updated meta-analysis for the potential IA-susceptibility locus in large-scale multi-ethnic populations. We conducted a systematic review of studies identified by an electronic search from January 1990 to March 2019. The overall estimates of the “G” allele of rs700651, indicating IA susceptibility, were calculated under the fixed- and random-effect models using the inverse-variance method. Subsequent in silico function and cis-expression quantitative trait loci (cis-eQTL) analyses were performed to evaluate biological functions and genotype-specific expressions in human tissues. We included 4513 IA patients and 13,506 controls from five studies with seven independent populations: three European-ancestry, three Japanese, and one Korean population. The overall result showed a genome-wide significance threshold between rs700651 and IA susceptibility after controlling for study heterogeneity (OR = 1.213, 95% CI: 1.135–1.296). Subsequent cis-eQTL analysis showed significant genome-wide expressions in three human tissues, i.e., testis (p = 8.04 × 10−15 for ANKRD44), tibial nerves (p = 3.18 × 10−10 for SF3B1), and thyroid glands (p = 4.61 × 10−9 for SF3B1). The rs700651 common variant of the 2q33.1 region may be involved in genetic mechanisms that increase the risk of IA and may play crucial roles in regulatory functions.

Highlights

The term unruptured intracranial aneurysm (UIA) refers to a localized outpouching of the cerebral artery due to a defect in the muscular layer [1,2]
Candidate loci have included EDNRA, SOX17 (8q11.23), CDKN2B-AS1 (9p21), CNNM2 (10q24.3), FGD6 (12q22), STARD13 (13q13), and RRBP1 (20p12.1) [8,9,10]. These candidate single-nucleotide polymorphisms (SNPs) associated with IAs may indicate that abnormalities in the extracellular matrix (ECM) and vascular endothelium may be involved in the biological mechanism of IA [10]
PubMed, Embase, and the HuGE Literature Finder electronic databases were searched for studies from January 1990 to March 2019 using the following keywords: “aneurysm(s)”, “intracranial aneurysm(s)”, “subarachnoid hemorrhage”, “genetic association”, “BOLL”, “boule homolog, RNA binding protein”, “PLCL1”, “phospholipase C like 1”, “rs700651”, “genetic”, and “Genome-wide association studies (GWASs)”

Summary

Introduction

The term unruptured intracranial aneurysm (UIA) refers to a localized outpouching of the cerebral artery due to a defect in the muscular layer [1,2]. If a subarachnoid hemorrhage (SAH) due to an IA rupture occurs, mortality rates up to 44%, early after the rupture, have been reported [4]. Candidate loci have included EDNRA (rs6841581, 4q31.23), SOX17 (8q11.23), CDKN2B-AS1 (9p21), CNNM2 (10q24.3), FGD6 (12q22), STARD13 (13q13), and RRBP1 (20p12.1) [8,9,10]. These candidate single-nucleotide polymorphisms (SNPs) associated with IAs may indicate that abnormalities in the extracellular matrix (ECM) and vascular endothelium may be involved in the biological mechanism of IA [10]

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Conclusion