Genome screen to detect linkage to intracranial aneurysm susceptibility genes: the Familial Intracranial Aneurysm (FIA) study

Abstract

Background 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 gene x smoking (pack-years) interaction.

Results: The greatest evidence of linkage was found on chromosomes 4 (LOD=2.5; 156 cM), 7 (LOD=1.7; 183 cM), 8 (LOD=1.9; 70 cM), and 12 (LOD=1.6; 102 cM) using the broad disease definition. Using the average pack-years for the affected individuals in each family, the genes on chromosomes 4 (LOD=3.5; P=0.03), 7 (LOD=4.1; P=0.01) and 12 (LOD=3.6; P=0.02) 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 gene x smoking interaction with 3 of the loci.

Figure

Results of multipoint model-independent linkage analysis. The x-axis depicts the various chromosomes across the genome with chromosome 1 at the far left and the X chromosome at the far right. The y-axis indicates the LOD score at the various chromosomal positions across the genome. A, Narrow disease definition (n=170 families); B, Broad disease definition (n=192 families).