Intracranial Aneurysms in Finnish Families: Confirmation of Linkage and Refinement of the Interval to Chromosome 19q13.3

Abstract

We recently reported a two-stage genomewide screen of 48 sib pairs affected with intracranial aneurysms (IAs) that revealed suggestive linkage to chromosome 19q13, with a LOD score of 2.58. The region supporting linkage spanned approximately 22 cM. Here, we report a follow-up study of the locus at 19q13, with a sample size expanded to 139 affected sib pairs, along with 83 other affected relative pairs (222 affected relative pairs in total). Suggestive linkage was observed in both independent sample sets, and linkage was significant in the combined set at 70 cM (LOD score 3.50; P=.00006) and at 80 cM (LOD score 3.93; P=.00002). Linkage was highly significant at 70 cM (LOD score 5.70; P=.000001) and at 80 cM (LOD score 3.99; P=.00005) when a covariate measuring the number of affected individuals in the nuclear family was included. To evaluate further the contribution to the linkage signal from families with more than two affected relatives, we performed model-based linkage analysis with a recessive model and a range of penetrances, and we obtained maximum linkage at 70 cM (LOD score 3.16; P=.00007) with a penetrance of 0.3. We then estimated location by using GENEFINDER. The most likely location for a gene predisposing to IAs in the Finnish population is in a region with a 95% confidence interval of 11.6 cM (P=.00007) centered 2.0 cM proximal to D19S246.

Genome-Wide Scan for Japanese Familial Intracranial Aneurysms

“…Collectively, candidate regions that have to date been replicated in Ͼ1 study include 7q11 (Onda et al and Farnham et al) and 19q13 (Olson et al and Van Der Voet et al). [3][4][5]7 The regions of 17cen (Onda et al 3 ) and Xp22 (Olson et al 4 ) are extended in the present study. Such concordant regions should be considered as high-priority loci and provide promising scaffolds for future studies to identify the exact genetic mechanisms for IA.…”

“…4 The region on chromosome 19q13 was also replicated by another Finish study. 7 The region on chromosome 19q13 may thus not be specific to Finnish population. Collectively, candidate regions that have to date been replicated in Ͼ1 study include 7q11 (Onda et al and Farnham et al) and 19q13 (Olson et al and Van Der Voet et al).…”

“…6 Olson et al 4 found suggestive linkages on chromosomes 19q12-13 (MLS 2.58) and Xp22 (MLS 2.08) in 48 Finnish affected sibling pairs, a linkage confirmed by another study. 7 These results suggest that multiple genes determine susceptibility to IA.…”

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.…”

Genomewide Linkage in a Large Caucasian Family Maps a New Locus for Intracranial Aneurysms to Chromosome 13q

“…Up to 20% of patients with IA have a positive family history [1][2][3] and there is up to a 7-fold increased risk of IA rupture among first-degree relatives compared with second-degree relatives. 4 Although many genetic loci have been linked to familial IA, [5][6][7][8][9][10][11][12][13][14][15] no single disease-causing gene variant has been identified. In this study, we performed genomewide linkage analysis on a single family to identify an IA susceptibility locus.…”