Our long-term objective is to identify susceptibility genes that are related to the formation of intracranial aneurysms (IA). Rupture of IAs occurs in 16,000 to 17,000 persons in the U.S. annually, and nearly half of affected persons are dead within the first 30 days. An additional 6,000 to 7,000 persons with unruptured IAs are identified each year. Accumulated evidence indicates that a genetic component plays an important role in the development of IAs, but specific loci affecting the risk of IA have not been identified. The primary hypothesis of this study is that there are specific human chromosomal regions that are associated with an increased risk of IAs.
Specific Aims of the proposal are: 1. Recruitment of 400 families with multiple individuals who have an IA through 23 referral centers throughout North America, Australia, and New Zealand that represent 35 recruitment sites. 2. Ascertainment of interviews and blood samples from all affected family members, as well as their first-degree relatives. White blood cells from living persons with an IA will be cryopreserved at Cornell Institute for Medical Research for future immortalization of cells lines as indicated. 3. Identification of unruptured IAs by obtaining MRAs in selected asymptomatic siblings (of affected individuals). 4. Completion of a 10 cM genome series in persons with IAs, as well as the spouses and children of persons with an IA who are deceased. We will perform finer mapping of chromosomal regions with suggestive evidence of linkage in the genome screen. 5. Performance of a nonparametric (allele sharing) linkage analysis, including relevant environmental factors such as smoking, to identify chromosomal regions linked to IA. Reconstruction of the genotypes of deceased affected family members will be performed. Identification of individuals who are genetically at high risk for the development of IAs would enable targeted and effective screening/prevention/treatment strategies to reduce the substantial mortality and morbidity associated with this devastating type of stroke. Only a multidisciplinary, collaborative effort to identify, accrue, and genotype FIA families will be successful in identifying sufficient high-risk families to characterize the genetic basis of IA.
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