Systems Genetics Approach to Intracranial Aneurysms

项目摘要 动脉瘤性蛛网膜下腔出血（SAH）由颅内动脉瘤破裂引起， 主要是年轻人口，导致大量生产寿命年的损失， 相关的寿命成本。动脉瘤性SAH预后不良，死亡率超过50%， 25%的幸存者预后良好。因为毁灭性的大出血通常是最初的表现， 由于涉及年轻人群，未破裂动脉瘤的早期检测具有成本效益， 进行更集中的筛查至关重要。动脉瘤形成的遗传基础是 全基因组关联研究证实了这一点，在这些研究中已经鉴定出了许多相关基因。 然而，这些研究中发现的遗传变异只能解释表型变异的一小部分， 这表明其他遗传和表观遗传机制的参与。我们假设， 和表观遗传变化是动脉瘤形成的关键组成部分， 使用系统遗传学方法。我们的研究将提供机械的见解， 动脉瘤形成中的表观遗传/遗传靶点，这可能导致开发新的治疗药物 战略，并提供一个具有成本效益的手段，以确定个人在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.