This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.Cerebrovascular (CV) disease is the third leading cause of death in the U.S. and about one-quarter of the CV deaths are due to ruptured intracranial aneurysms (IA). Of those that survive rupture, more than half are left with neurological deficits. Elective surgery and treatment prior to rupture are very effective in preventing morbidity and mortality. Early identification of individuals susceptible to IA would therefore greatly enhance our ability to prevent most serious outcomes. Analysis of a genome scan of 48 affected sib pairs has now been completed. This is the first genome scan for IA. IA has resisted previous attempts to obtain family data because of its high mortality. Using extraordinary efforts, we obtained families with multiple affected members by using cerebrovascular imaging techniques to detect unruptured IA in siblings of IA patients. Several candidate regions have been implicated. The highest multipoint lod score (2.63) was obtained on chromosome 19 in the region 19q12-13. This gene-rich chromosome region contains a number of genes known to be involved in cardiovascular, cerebrovascular, and/or membrane physiology. Other tentative chromosomal regions implicated by this genome scan included chromosome Xp (lod score = 2.08), 7p (lod score = 1.67), 14q (lod score = 1.36), and 4p (lod score = 1.27). We have genotyped additional markers in these regions in this sample and a replicate sample of 91 ASPs. Linkage analysis confirmed linkage to chromosome 19 in the replicate sample. On chromosome 19, we obtained a lod score of 3.50 using the combined data. This lod score improved to 5.7 after including the number of affected relatives as a covariate, suggesting that families with more affected relatives more likely harbor a susceptibility locus on chromosome 19. We plan to follow up the result using fine mapping methods and to complete the genome scan on the replicate data set.
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