Molecular Variants that Determine Genetic Susceptibility to Intracranial Aneurysm

描述（由申请人提供）：颅内动脉瘤（IA）影响约2%的人群，每年在相对年轻的患者（中位年龄50岁）中导致500，000例出血性卒中，导致死亡和严重神经功能损害。动脉瘤形成和破裂的发病机制尚不清楚，病前识别对于预防灾难性出血至关重要。我们最近完成了一项多阶段全基因组关联研究（GWAS），其中包括2，100多名IA患者和8，000名对照，并确定了染色体2，8和9上的常见SNP，这些SNP超过了严格的阈值并与IA重复关联（比值比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，P值小于10 -4，具有中等优势比（OR<1.25），可能以累积的方式增加IA的风险。为了提高我们检测和确认这些基因座的能力，我们招募了5,100多名新病例和22,000名对照，使病例和对照总数分别超过7,300和30500。这个建议的主要重点是把我们的GWAS结果到下一个阶段，确定致病等位基因在每个位点，使IA基因可以被确认。这些基因的发现将导致在未来的应用，以假设驱动的研究，旨在了解这些转录本的功能，并获得机械洞察IA的病理生理。我们在本申请中的努力可以分为三个概念上不同但互补的努力：1）我们将表征每个位点的特定功能变异，解释通过我们先前的GWAS鉴定的常见变异结果; 2）我们将评估罕见和常见结构变异对IA的潜在贡献，以及3）我们将寻求鉴定有助于IA的其他变异的证据。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，重点是常见的等位基因，这将作为IA生物学研究的起点，并开始创造一个机会，在任何病态事件（如IA破裂）之前识别遗传风险个体。 公共卫生相关性：颅内动脉瘤（IA）影响约2%的人群，每年在相对年轻的患者（中位年龄50岁）中导致500，000例出血性卒中，导致死亡和严重神经功能损害。动脉瘤形成和破裂的发病机制尚不清楚，有证据表明遗传因素在形成和破裂中起作用。我们最近完成了一个大规模的遗传学项目，包括来自2,100名IA患者和8,000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.