Genome screen in familial intracranial aneurysm

Background: Individuals with 1st degree relatives harboring an intracranial aneurysm (IA) are at an increased risk of IA, suggesting genetic variation is an important risk factor. Methods: Families with multiple members having ruptured or unruptured A were recruited and all available medical records and imaging data were reviewed to classify possible A subjects as definite, probable or possible A or not a case. A 6 K SNP genome screen was performed in 333 families, representing the largest linkage study of A reported to date. A 'narrow' (n = 705 definite A cases) and 'broad' (n = 866 definite or probable IA) disease definition were used in multipoint model-free linkage analysis and parametric linkage analysis, maximizing disease parameters. Ordered subset analysis (OSA) was used to detect gene x smoking interaction. Results: Model-free linkage analyses detected modest evidence of possible linkage (all LOD < 1.5). Parametric analyses yielded an unadjusted LOD score of 2.6 on chromosome 4q (162 cM) and 3.1 on chromosome 12p (50 cM). Significant evidence for a gene x smoking interaction was detected using both disease models on chromosome 7p (60 cM; p <= 0.01). Our study provides modest evidence of possible linkage to several chromosomes. Conclusion: These data suggest it is unlikely that there is a single common variant with a strong effect in the majority of the A families. Rather, it is likely that multiple genetic and environmental risk factors contribute to the susceptibility for intracranial aneurysms.