Systems Genetics Approach to Intracranial Aneurysms

项目总结 动脉瘤性蛛网膜下腔出血(SAH)是由破裂的颅内动脉瘤引起的，影响 以年轻人为主的人口，导致大量生产寿命损失年数较高 关联的生命周期成本。动脉瘤性蛛网膜下腔出血的预后很差，死亡率超过50%，只有 25%的幸存者预后良好。因为毁灭性的出血通常是最初的症状 由于涉及的是年轻人群，经济高效的早期检测未破裂的动脉瘤将导致 对更有针对性的筛查是至关重要的。动脉瘤形成的遗传学基础是 全基因组关联研究证实了这一点，在这些研究中，一些相关基因已经被识别出来。 然而，这些研究中发现的遗传变异只解释了表型差异的一小部分， 暗示了其他遗传和表观遗传机制的参与。我们假设这两种基因 表观遗传学改变是动脉瘤形成的关键组成部分，目的是确定关键途径 涉及到使用系统遗传学方法。我们的研究将提供对 动脉瘤形成的表观遗传靶点可能导致新的治疗方法的开发 战略，并提供一个成本效益高的手段，以确定个人的高风险的动脉瘤形成。

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.