Stroke represents a major public health problem in the US, affecting nearly 700,000 individuals annually. Among the different types of stroke, subarachnoid hemorrhage (SAH), most commonly due to intracranial aneurysm (IA), carries the highest mortality rate. Lifetime prevalence estimates of IA range from 0.2%-9.9% (mean 5.5%). Despite this common prevalence, little is known regarding the pathophysiology of IA. While environmental factors are thought to play a role, there is also considerable support for a genetic contribution. In order to dissect the molecular genetics of IA and to clone disease causing transcripts, we have taken an outlier approach and searched nationally and internationally for extended IA kindreds. Over the past 10 years, we have screened over 3200 IA patients and identified 168 IA families, with a total of more than 450 affected individuals. Since the original submission, we have obtained additional samples from 18 Utah kindreds and identified over 250 independent Finnish IA index cases. We are now in the process of collecting these samples. Critically, eight of the already families are sufficiently large to support genome-wide significance independently. We have now completed genome-wide linkage analysis on four of these families (IAs 20, 100, 101 and 112) and have identified IA loci on chromosomes 1p, 6p, 11 q and 14q with lod scores >3. Importantly, the 11q and 14q loci have been shown likely to contain IA genes in previous sib pair linkage studies. In addition, we have identified multiple additional families that show suggestive linkages to each of these regions. Since the original application, we have also completed the first stage of genome wide linkage analysis of 5 extended Utah kindreds showing that two of them share a conserved haplotype linking and significantly narrowing the 11q locus. We are now confirming these preliminary results in our second stage analysis using STS markers. Our preliminary analysis of the remaining 3 extended Utah kindreds further confirm the presence of additional IA susceptibility loci throughout the genome.We propose to use this unique set of IA kindreds to fine map these loci and perform mutational analysis of coding and non-coding regions of candidate genes located within these intervals by using all families that link to a particular locus in order to identify IA disease genes. Once specific transcripts are cloned, we will be able to examine the pathophysiology of IA, which ultimately may lead to novel therapeutic approaches.
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