Cerebrovascular disease is the third leading cause of death in the United States and about one-quarter of cerebrovascular deaths due to ruptured intracranial aneurysms (IA). Of those who survive rupture of an IA, more than half are left with neurological deficits. In contrast, the morbidity of elective surgery and treatment before rupture is very low (1-2%), so that early intervention could be extremely valuable. Several reports suggest that some IAs are familial and probably genetic. Identification of family members at risk for developing IA will allow concentration of diagnostic effort on a small number of high-risk individuals and assist early identification of IAs. Characterization of one or more genes that predispose individuals to developing IA will significantly increase the effectiveness of this diagnostic effort.
The aim of this study is to use linkage analysis to identify one or more loci that are linked to IA in families. For this purpose, 1150 Finish families were initially ascertained on the basis of having an individual with proven IA. 85 families were identified with a second member who had IA and had no other known predisposing condition. Magnetic resonance angiography (MRA) was carried out in 531 asymptomatic first degree relatives of the probands. This effort resulted in sampling of DNA from 49 affected sibling pairs (ASPs) in a total of 24 families. DNA samples are available on all examined individuals. In this study, the investigators propose to: collect samples from an additional 35-40 affected sib pairs; 2) perform affected sib-pair linkage analysis in two phases, I) first with currently available sib pairs and II) with all 84-89 affected sib pairs in regions identified as suggestive of linkage from phase I; 3) collect information on a sample of families with one affected member; 4) fit genetic models using the data collected in 3 and the existing data on the 85 families and then perform parametric linkage analysis; 5) continue to collect genealogical information on the 85 families that may assist in subsequent fine-mapping efforts.
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