Genome-Wide Linkage in a Large Dutch Consanguineous Family Maps a Locus for Intracranial Aneurysms to Chromosome 2p13

Abstract

Background and Purpose-Familial occurrence of intracranial aneurysms suggests a genetic factor in the development of these aneurysms. In this study, we present the identification of a susceptibility locus for the development of intracranial aneurysms detected by a genome-wide linkage approach in a large consanguineous pedigree. Methods-Patients with clinical signs and symptoms of intracranial aneurysms, confirmed by radiological, surgical, or postmortem investigations, were included in the study. Magnetic resonance angiography was used to detect asymptomatic aneurysms in relatives. Results-Seven out of 20 siblings had an intracranial aneurysm. Genome-wide multipoint linkage analysis showed a significant logarithm of the odds score of 3.55. Conclusion-In a large consanguineous pedigree intracranial aneurysms are linked to chromosome 2p13 in a region between markers D2S2206 and D2S2977.

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

“…All computations were performed using the HEGESMA_v2.0 software available online at http://biomath.med.uth.gr. Two large Japanese studies [8,10] were included in a sensitivity analysis, excluding the three Caucasian studies [6,7,9] with the highest maximum log of the odds ratio (LOD) reported, which were also the three smallest studies.…”

“…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.…”

“…Two studies were not included due to a lack of linkage scores [4,5]. Finally, five intracranial aneurysm wholegenome scans met the inclusion criteria and were included in the genome scan meta-analyses [6][7][8][9][10]. The following information was recorded from the selected studies: Number of families assessed, definition of affected and unaffected cases, ethnicity, number of affected cases, and method of analysis and linkage sites identified.…”

“…The characteristics of five individual genome scans [6][7][8][9][10] included in our meta-analyses are given in Table 1. These five studies assessed a total of 263 individuals from 118 families, with two studies providing over 90% of the cases [8,10].…”

“…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.…”