Dataset Information

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

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.

SUBMITTER: Hong EP

PROVIDER: S-EPMC6572517 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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

Hong Eun Pyo EP Kim Bong Jun BJ Jeon Jin Pyeong JP

Journal of clinical medicine 20190516 5

Previous genome-wide association studies did not show a consistent association between the <i>BOLL</i> 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, wer ...[more]

PMID: 31100866

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Project description:Endoglin is an essential molecule during angiogenesis, vascular development, and integrity. Till now, many studies have investigated the association between endoglin polymorphisms and intracranial aneurysm (IA) risk, with the results remained inconclusive. Therefore, we performed a meta-analysis to summarize the possible association.We searched PubMed and Embase until June 2015 to identify studies addressing the association between endoglin polymorphisms and IA risk. The summary odds ratios (ORs) and their corresponding 95% confidence interval (CI) were calculated to assess the strength of the association.Eleven studies with a total of 1501 cases and 2012 controls were finally included in this meta-analysis, with 10 studies investigating endoglin 6-bp insertion (6bINS) polymorphism and 4 studies investigating 1800956 polymorphism. No significant association between endoglin 6bINS polymorphism and IA risk was detected in overall estimation (I/I vs wt/I?+?wt/wt: OR?=?1.21, 95% CI?=?0.87-1.69) or in the subgroup analysis by ethnicity, control source, or ruptured status. However, we observed an association with borderline significance of 6bINS with IA occurrence (I/I vs wt/I?+?wt/wt: OR?=?1.49, 95% CI?=?0.99-2.25, P?=?0.058) in studies applying matched controls. Furthermore, we detected a significant association for 6bINS polymorphism of endoglin with increased risk of familial IA (I vs wt, OR?=?1.64, 95% CI?=?1.10-2.42) but not sporadic IA (I vs wt, OR?=?1.09, 95% CI?=?0.68-1.45). With regard to rs1800956, our pooled results indicated a significantly decreased IA risk in individuals carrying C allele (C/C vs G/C?+?G/G: OR?=?0.65; 95% CI?=?0.45-0.94).This meta-analysis provided no evidence for the association between 6bINS polymorphism with overall IA risk. However, we detected a significant association of 6bINS allele with increased risk of familial IA. Also, we found that rs1800956 was significantly related to IA occurrence. Further, well-designed studies with large sample size are warranted and updated meta-analysis is needed to verify our findings.

Project description:Although genome-wide association studies (GWAS) have identified hundreds of complex trait loci, the pathomechanisms of most remain elusive. Studying the genetics of risk factors predisposing to disease is an attractive approach to identify targets for functional studies. Intracranial aneurysms (IA) are rupture-prone pouches at cerebral artery branching sites. IA is a complex disease for which GWAS have identified five loci with strong association and a further 14 loci with suggestive association. To decipher potential underlying disease mechanisms, we tested whether there are IA loci that convey their effect through elevating blood pressure (BP), a strong risk factor of IA. We performed a meta-analysis of four population-based Finnish cohorts (n(FIN)? = ?11 266) not selected for IA, to assess the association of previously identified IA candidate loci (n ?=? 19) with BP. We defined systolic BP (SBP), diastolic BP, mean arterial pressure, and pulse pressure as quantitative outcome variables. The most significant result was further tested for association in the ICBP-GWAS cohort of 200 000 individuals. We found that the suggestive IA locus at 5q23.2 in PRDM6 was significantly associated with SBP in individuals of European descent (p(FIN) ?=? 3.01E-05, p(ICBP-GWAS) ?= ?0.0007, p(ALL)? = ?8.13E-07). The risk allele of IA was associated with higher SBP. PRDM6 encodes a protein predominantly expressed in vascular smooth muscle cells. Our study connects a complex disease (IA) locus with a common risk factor for the disease (SBP). We hypothesize that common variants in PRDM6 can contribute to altered vascular wall structure, hence increasing SBP and predisposing to IA. True positive associations often fail to reach genome-wide significance in GWAS. Our findings show that analysis of traditional risk factors as intermediate phenotypes is an effective tool for deciphering hidden heritability. Further, we demonstrate that common disease loci identified in a population isolate may bear wider significance.

Dataset Information

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

Publications

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

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