Mapping a Mendelian Form of Intracranial Aneurysm to 1p34.3-p36.13

Abstract

The identification of pathways that underlie common disease has been greatly impacted by the study of rare families that segregate single genes with large effect. Intracranial aneurysm is a common neurological problem; the rupture of these aneurysms constitutes a frequently catastrophic neurologic event. The pathogenesis of these aneurysms is largely unknown, although genetic and environmental factors are believed to play a role. Previous genomewide studies in affected relative pairs have suggested linkage to several loci, but underlying genes have not been identified. We have identified a large kindred that segregates nonsyndromic intracranial aneurysm as a dominant trait with high penetrance. Genomewide analysis of linkage was performed using a two-stage approach: an analysis of ~10,000 single-nucleotide polymorphisms in the 6 living affected subjects, followed by the genotyping of simple tandem repeats across resulting candidate intervals in all 23 kindred members. Analysis revealed significant linkage to a single locus, with a LOD score of 4.2 at 1p34.3-p36.13 under a dominant model with high penetrance. These findings identify a Mendelian form of intracranial aneurysm and map the location of the underlying disease locus.

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.…”