Genome Screen to Detect Linkage to Intracranial Aneurysm Susceptibility Genes

Abstract

the FIA Study InvestigatorsBackground and Purpose-Evidence supports a substantial genetic contribution to the risk of intracranial aneurysm (IA).The purpose of this study was to identify chromosomal regions likely to harbor genes that contribute to the risk of IA. Methods-Multiplex families having at least 2 individuals with "definite" or "probable" IA were ascertained through an international consortium. First-degree relatives of individuals with IA who were at increased risk of an IA because of a history of hypertension or present smoking were offered cerebral magnetic resonance angiography. A genome screen was completed using the Illumina 6K SNP system, and the resulting data from 192 families, containing 1155 genotyped individuals, were analyzed. Narrow and broad disease definitions were used when testing for linkage using multipoint model-independent methods. Ordered subset analysis was performed to test for a geneϫsmoking (pack-years) interaction. Results-The greatest evidence of linkage was found on chromosomes 4 (LODϭ2.5; 156 cM), 7 (LODϭ1.7; 183 cM), 8 (LODϭ1.9; 70 cM), and 12 (LODϭ1.6; 102 cM) using the broad disease definition. Using the average pack-years for the affected individuals in each family, the genes on chromosomes 4 (LODϭ3.5; Pϭ0.03), 7 (LODϭ4.1; Pϭ0.01) and 12 (LODϭ3.6; Pϭ0.02) all appear to be modulated by the degree of smoking in the affected members of the family. On chromosome 8, inclusion of smoking as a covariate did not significantly strengthen the linkage evidence, suggesting no interaction between the loci in this region and smoking. Conclusions-We have detected possible evidence of linkage to 4 chromosomal regions. There is potential evidence for a geneϫsmoking interaction with 3 of the loci.

Guidelines for the Management of Patients With Unruptured Intracranial Aneurysms

“…74,185,186 Eligible families included those with at least 2 affected siblings or ≥3 affected family members. The first-degree relatives of those affected with IA were offered screening if they were previously unaffected, were >30 years of age, and had a history of smoking or hypertension.…”

A Genome-Wide Study of Moyamoya-Type Cerebrovascular Disease in the Korean Population

“…This approach was recently exemplified by an elegant study from Gunel's group into the pathogenesis of intracranial aneurysm 2) , and this pivotal effort resulted in the identification of common SNPs on chromosomes 2q, 8q, and 9p that show significant association with intracranial aneurysm. However, similar to moyamoya disease, genome-wide linkage studies of intracranial aneurysms in familial cases have been unable to identify a replicable loci, and candidate gene-based case-control association study have failed to produce replicable results 3,13,15) . Genome-wide association approaches are now being applied in moyamoya disease to uncover the underlying pathogenic mechanisms.…”

A mathematical model of utility for single screening of asymptomatic unruptured intracranial aneurysms at the age of 50 years

“…With recent studies demonstrating the association of several genetic loci with FIA, genetic testing may have potential as a screening tool if strong linkage with a few key genes could be established [8,10]. However, many of these loci have shown moderate linkage at best, and there is a strong interaction between genetic and environmental factors, such as smoking, on development and rupture of IAs in FIA [8,10,11].…”