Model-Based Linkage Analyses Confirm Chromosome 19q13.3 as a Susceptibility Locus for Intracranial Aneurysm

Abstract

Background and Purpose-In previous studies of familial intracranial aneurysm (IA), parametric linkage analyses have been undertaken for five unrelated families, four providing maximum logarithm of odds (LOD) scores with dominant models and one with a recessive model. Each family was linked to a distinct locus, indicating locus heterogeneity. This study aimed to examine whether Japanese IA families consistent with autosomal-dominant mode of inheritance support linkage to these loci. Methods-We performed genomewide linkage analysis using the GENEHUNTER program. Affected-only parametric linkage analysis was used for 41 affected members in nine unrelated IA families with dominant models, which were selected from 29 families used for a nonparametric (model-free) linkage analysis in our previous study. Results-We failed to support the linkage to previously reported autosomal-dominant loci. Instead, we found linkage to chromosome 19q13.3 with a maximum multipoint LOD score of 4.10. The LOD-1 interval (regions with LOD scores of Ͼ1) was 8.0 cM between D19S198 and D19S902. Conclusions-A genomewide scan for IA families with dominant models in Japan confirmed the locus at chromosome 19q13.3, which has also been reported as a candidate locus in a Finnish population. (Stroke. 2007;38:1174-1178.)Key Words: autosomal-dominant Ⅲ familial Ⅲ genetics Ⅲ intracranial aneurysm Ⅲ linkage I ntracranial aneurysm (IA) is of great concern in public health fields because of its high morbidity and mortality rate in ruptured cases. Rupture of an IA causes subarachnoid hemorrhage (SAH), and results in immediate death in 50% of cases with an additional 30% of cases left with a severe disability. 1,2 However, despite advances in diagnostic and treatment techniques, the mortality and morbidity rates associated with SAH remain unimproved.Several factors such as age, hypertension, smoking, heavy alcohol intake, perceived mental stress, lean body mass index, and blood transfusion have been reported to be associated with SAH. [3][4][5] Evidence suggests that genetic factors also contribute to the pathogenesis of IA. The risk of SAH is four times higher in first-degree relatives and six times higher in siblings of patients with SAH than in the general population. 6,7 To clarify the genetic background of IA formation, several linkage analyses have been conducted. A total of 10 suggestive linkage regions have been identified to date: chromosomes 1p34. 2p13, 17cen, Among these, elastin (ELN) and the LIM domain kinase 1 (LIMK1) genes in 7q11, 8,16 collagen alpha2(I) (COL1A2) in 7q22, 17 and tumor necrosis factor receptor, superfamily member 13B (TNFRSF13B) in 17cen have been reported to be associated with IA. 18 It is noteworthy that mutations were detected in TNFRSF13B. However, a linkage to 7q11 or the association of ELN polymorphisms with IA has failed to be replicated in several studies, 19 -23 and the association of COL1A2 or TNFRSF13B with IA has not been replicated in an independent study.Most of the linkage studies applied nonparametric (model...

Confirmation of an Association of Single-Nucleotide Polymorphism rs1333040 on 9p21 With Familial and Sporadic Intracranial Aneurysms in Japanese Patients

“…Nonparametric linkage analysis revealed 3 loci located on 17cent, 19q13, and Xp22, 6 and parametric analysis revealed a locus on 19q13. 7 On 17cent, we found TNFRSF13B to be a candidate gene for IA. 8 Several other studies have revealed several loci or candidate genes in different populations.…”

Distal Anterior Cerebral Artery Aneurysms

“…So far, different genome-wide linkage studies have identified several loci [44], but only four (p4.-p6., 7q, 9q. and Xp22) have been replicated in different populations [75,246,259,28,284,45,420,49]. Knowledge on the genetic determinants may provide insight into the development of aneurysms, and thereby give clues on how to stop aneurysm formation.…”

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.…”

“…We did not consider the second stage of scans where candidate regions from the first stage were fine mapped. One study was excluded because data from affected individuals had already been included in a previous report [3]. Where studies failed to present sufficient data for analysis the information was requested from the corresponding authors.…”

“…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.…”