: Revised Abstract Our primary objective is to identify specific gene variants that are related to the formation and rupture of intracranial aneurysms (IA). Our experienced collaborative and highly productive team of Familial Intracranial Aneurysm (FIA) Investigators at 27 original sites in North America, Australia and New Zealand accomplished and surpassed our original goals during FIA I. We completely characterized 441 families (2800 subjects) with multiple members with an IA including collection of genetic material, extensive interviews, and magnetic resonance angiography to detect unruptured aneurysms in 20% of eligible subjects. Genotyping using the Illumina 6K SNP linkage set in the majority of the FIA I family sample was used to perform a linkage analysis which did not identify statistically significant evidence of linkage by traditional criteria. Subsequently, we performed a genome-wide case-control association study (GWAS) using the Affymetrix 6.0 array with one affected case from each white FIA family and age,gender and race matched population controls. In a final GWAS dataset of 407 FIA cases and 396 controls, we identified COL9A1 (collagen 9A1 gene) and PDE1A (phosphodiesterase 1A gene) as high priority candidate genes based not only the strength of the association with FIA but also on their biological function. Using a larger GWAS dataset of IA cases and controls, we have replicated the recent findings for SNPs in the regions of chromosome 9 (CDKN2A and CDKN2B closest genes) and 8 (SOX17 closest gene) but not chromosome 2. We are currently completing genotyping for a replication set consisting of additional IA cases and controls. Our collaborator, Dr. Ituro Inoue, will genotype out most significant 50 SNPs from our GWAS in his sample of1000 IA Japanese cases and 950 controls. In FIA II, we will enroll an additional 1800 sporadic and 200 familial IA patients (as well as other affected and genetically informative members from these 200 families). The 1675 white IA cases will be used for a case-control GWAS (Affymetrix 6.0 platform) that will be a critical replication data set for FIA I and just completed GWAS studies. We have already enrolled >205 (167 white) IA cases thus far. 3000+ white controls from the publicly available national databases (ongoing collaborations with Framingham and ARIC investigators), with available information regarding smoking and hypertension and who are genotyped with the same platform, will be matched for gender and age to the FIA II IA cases. Second, we propose to take the highest priority SNPs from our replicated case-control analyses for a family-based test of association using the 600+ multiplex IA families collected as part of FIA I and FIA II. We will enroll and genotype 500+ minority IA cases (Blacks and Hispanics) in whom SNPs of interest from the FIA I and II GWAS will be compared with minority controls from ARIC and other national databases (such as REGARDS). Finally, we will use bioinformatics, statistical methods, and gene sequencing, to identify specific disease producing mutations and/or high risk haplotypes whose functional relevance will be subsequently explored.
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