Molecular Variants that Determine Genetic Susceptibility to Intracranial Aneurysm

描述(申请人提供)：颅内动脉瘤(IA)影响约2%的人口，在相对年轻的患者(中位年龄50岁)中每年导致50万例出血性中风，导致死亡和严重的神经功能障碍。动脉瘤形成和破裂的机制尚不清楚，病前识别是预防灾难性出血的关键。我们最近完成了一项针对2,100多名IA患者和8,000名对照的多阶段全基因组关联研究，并确定了位于第2、8和9号染色体上的常见SNP，这些SNP超过了严格的阈值，并复制了与IA的关联(优势比1.24-1.36)。在这项初步研究中，我们还发现了其他几个IA易感基因座的证据，显示P值小于10-4，携带适度的优势比(OR&lt；1.25)，并可能以累积的方式导致IA风险。为了加强我们发现和确认这些基因座的能力，我们招募了5,100多个新病例和22,000个对照，使病例和对照总数超过7,300和30,500。这一建议的主要重点是通过识别每个基因座上的致病等位基因来将我们的Gwas结果带入下一阶段，以便可以确认IA基因。这些基因的发现将在未来的应用中引导假说驱动的研究，旨在了解这些转录本的功能，并获得对IA病理生理学的机械性见解。我们在这一应用方面的努力可以分为三个在概念上不同但相互补充的努力：1)我们将表征每个基因座上的特定功能变异，以解释通过我们先前的GWAS确定的共同变异结果；2)我们将评估罕见和共同结构变异对IA的潜在贡献；以及3)我们将寻求确定其他变异导致IA的证据。这些分析的最终结果将是对这种疾病的遗传结构的全面看法，重点放在共同的等位基因上，这将作为IA生物学研究的起点，并开始创造机会，在任何病态事件(如IA破裂)之前识别遗传风险个人。 公共卫生相关性：颅内动脉瘤(IA)影响约2%的人口，在相对年轻的患者(中位年龄50岁)中每年导致50万例出血性中风，导致死亡和严重的神经功能障碍。动脉瘤形成和破裂的机制尚不清楚，有证据表明遗传因素在形成和破裂中都起作用。我们最近完成了一个大规模的遗传学项目，包括2100名IA患者和8000名对照的DNA样本，并确定了3个携带动脉瘤基因的染色体区域。我们现在建议进行后续研究，以确定这些动脉瘤基因，并继续寻找其他基因。

DESCRIPTION (provided by applicant): Intracranial aneurysms (IA) affect ~2% of the population and cause 500,000 hemorrhagic strokes annually in relatively young patients (median age 50), resulting in death and severe neurological impairment. The pathogenesis of aneurysm formation and rupture is unknown, and pre-morbid identification is essential to prevent catastrophic hemorrhage. We have recently completed a multistage genome-wide association study (GWAS) with over 2,100 IA patients and 8,000 controls and identified common SNPs on chromosomes 2, 8 and 9 that surpass stringent thresholds and replicate association with IA (odds ratios 1.24 - 1.36). In this initial study, we also found evidence for several other IA susceptibility loci showing P values less than10-4, carrying modest odds ratios (OR<1.25) and likely contributing to IA risk in a cumulative fashion. In order to increase our power to detect and confirm these loci, we have recruited over 5,100 new cases and 22,000 controls bringing the total number of cases and controls over 7,300 and 30,500. The major emphasis of this proposal is to take our GWAS results to the next stage by identifying the causative alleles in each locus so that the IA genes can be confirmed. Discovery of these genes will lead in future applications to hypothesis driven research aimed at understanding the function of these transcripts and gaining mechanistic insight into IA pathophysiology. Our effort in this application can be divided into three conceptually distinct but complementary efforts: 1) we will characterize the specific functional variation at each locus accounting for the common variant findings, identified through our prior GWAS; 2) we will evaluate the potential contribution of both rare and common structural variation to IA, and 3) we will seek to identify evidence for additional variants contributing to IA. The end result of these analyses will be a comprehensive view of the genetic architecture of this disorder focusing on common alleles that will serve as the launching point for biological studies of IA and begin creating an opportunity to identify genetically at-risk individuals prior to any morbid events such as IA rupture. PUBLIC HEALTH RELEVANCE: Intracranial aneurysms (IA) affect ~2% of the population and cause 500,000 hemorrhagic strokes annually in relatively young patients (median age 50), resulting in death and severe neurological impairment. The pathogenesis of aneurysm formation and rupture is unknown, and there is evidence to suggest that genetic factors play a role both in formation and rupture. We have recently completed a large scale genetics project that included DNA samples from 2,100 IA patients and 8,000 controls and identified 3 chromosomal regions that carry aneurysm genes. We now propose to do follow-up studies to identify these aneurysm genes and continue to search for additional ones.