PROJECT SUMMARY Aneurysmal subarachnoid hemorrhage (SAH) is caused by ruptured intracranial aneurysms and affects a predominantly young population and results in a large number of productive life years lost with a high associated lifetime cost. Aneurysmal SAH carries a poor prognosis with greater than 50% mortality and only 25% of survivors with good outcome. Because a devastating hemorrhage is usually the initial presentation and because of the young population involved, cost-effective early detection of unruptured aneurysms that will lead to more focused screening is of paramount importance. The genetic basis of aneurysm formation has been confirmed by genome-wide association studies in which a number of associated genes have been identified. However, the genetic variants identified in these studies explain only a fraction of the phenotypic variance, suggesting the involvement of other genetic and epigenetic mechanisms. We hypothesize that both genetic and epigenetic changes are crucial components of aneurysm formation and aim to identify the key pathways involved using a systems genetics approach. Our research will provide mechanistic insights into the epigenetic/genetic targets in aneurysm formation which may lead to the development of novel therapeutic strategies and provide a cost-effective means to identify individuals at high risk of aneurysm formation.

PROJECT NARRATIVE Subarachnoid hemorrhage from ruptured brain aneurysms is a devastating disease that affects predominantly middle-aged adults. The goal of this study is to further understand the mechanisms behind the formation of aneurysms and thereby develop new treatments as well as a blood test for early detection of individuals at risk for aneurysm formation.