Genomewide-Linkage and Haplotype-Association Studies Map Intracranial Aneurysm to Chromosome 7q11

Abstract

Rupture of intracranial aneurysms (IAs) causes subarachnoid hemorrhage, a devastating condition with high morbidity and mortality. Angiographic and autopsy studies show that IA is a common disorder, with a prevalence of 3%-6%. Although IA has a substantial genetic component, little attention has been given to the genetic determinants. We report here a genomewide linkage study of IA in 104 Japanese affected sib pairs in which positive evidence of linkage on chromosomes 5q22-31 (maximum LOD score [MLS] 2.24), 7q11 (MLS 3.22), and 14q22 (MLS 2.31) were found. The best evidence of linkage is detected at D7S2472, in the vicinity of the elastin gene (ELN), a candidate gene for IA. Fourteen distinct single-nucleotide polymorphisms (SNPs) were identified in ELN, and no obvious allelic association between IA and each SNP was observed. The haplotype between the intron-20/intron-23 polymorphism of ELN is strongly associated with IA (P=3.81x10-6), and homozygous patients are at high risk (P=.002), with an odds ratio of 4.39. These findings suggest that a genetic locus for IA lies within or close to the ELN locus on chromosome 7.

Impact of LIMK1, MMP2 and TNF-α variations for intracranial aneurysm in Japanese population

“…The LIMK1 gene is located on chromosome 7q11, in which the presence of a susceptible gene for IA was indicated by linkage studies of two different ethnic groups. 22,23 Akagawa et al 24 illustrated that SNPs in ELN and LIMK1 at chromosome 7q11 might exert the synergistic effect on development of IA by affecting the stability and synthesis of vascular walls by sharing elastin signaling pathway. However, our result failed to find association with genetic variations in the ELN gene with IA, in agreement with several other studies, 25,26 suggesting that the LIMK1 gene is more likely candidate for the IA susceptibility gene at this chromosomal region.…”

Meta-analysis of whole-genome linkage scans for intracranial aneurysm

“…Hand searching of reference lists of identified articles was also carried out. We identified eight whole-genome scans between the years 2001 and 2007 [3][4][5][6][7][8][9][10]. Studies included in our analysis all assessed the linkage of autosomal genome sites with familial intracranial aneurysm.…”

“…Prospective studies suggest that subarachnoid haemorrhage occurs in approximately 2% of first degree relative of patients who have presented with this problem, an incidence that is four to ten times that of the general population [1,2]. A number of whole-genome linkage studies have now been performed in families in which there are multiple members with a history of intracranial aneurysm [3][4][5][6][7][8][9][10]. The aim of this study was to carry out a genome search metaanalysis in order to identify genetic loci that may play a role in the development of intracranial aneurysm.…”

Genome-wide association study to identify genetic variants present in Japanese patients harboring intracranial aneurysms

“…[1][2][3] Much of the etiology of IA still remains unknown, but subjects with a family history of IA have a higher risk of being affected by IA, suggesting that some genetic components contribute to predisposition to developing an IA. Previously, we conducted a genome-wide linkage study in affected Japanese sib pairs 4 and showed through subsequent association studies that the single nucleotide polymorphisms (SNPs) of ELN and LIMK1 on chromosome 7 was significantly associated with IA. 5 We also discovered one SNP of LOXL2 on chromosome 8 associated with IA, and a possible genegene interaction of LOXL2 with ELN/LIMK1.…”