Identifying Genes Contributing to Intracranial Aneurysms

描述（由申请方提供）：本研究的主要目的是进行分析，旨在确定增加颅内动脉瘤（IA）易感性的新型遗传风险因素。我们将分析来自两种互补方法的数据，以确定常见变异的作用，使用病例对照全基因组关联研究（GWAS）和罕见变异，使用全外显子组测序（WES）在密集影响的家系。 作为最近完成的R 01资助研究（FIA研究; PI：Joseph Broderick）的一部分，我们招募了家族性和散发性IA病例。此外，利用ARRA基金，我们扩大了研究范围，采用最新的技术来识别常见和罕见的变异。通过这项正在进行的研究和合作，我们已经从5,000多个样本中生成了GWAS数据，以测试IA易感性中常见变异的作用。此外，我们选择了7个密集受影响的家庭，并进行WES，以确定候选基因窝藏罕见的变异，可能涉及IA。我们目前正在对一组IA病例进行基因分型，以获得通过WES鉴定的候选基因的进一步证据。 这个R 03应用程序的重点是分析使用GWAS和WES方法生成的数据。由于这些技术的成本迅速下降，这些数据被添加到作为ARRA资助的一部分而提出的工作范围中。作为ARRA资金的一部分，完成的工作范围超过了最初的计划，不包括现在需要的分析。本项目的具体目标是：1）在所有可用样本（2，600例IA病例和2，568例对照）中进行病例对照GWAS，以识别与IA易感性相关的常见SNP。2)分析96个候选基因的序列，并测试与公开可用的对照相比，在约400个家族性IA病例中罕见变异的频率是否更高。

DESCRIPTION (provided by applicant): The primary goal of this study is to perform analyses aimed at identifying novel genetic risk factors that increase the susceptibility for an intracrania aneurysm (IA). We will analyze data derived from two complementary approaches in order to determine the role of common variation using a case control genomewide association study (GWAS) and rare variation using whole exome sequencing (WES) in densely affected pedigrees. As part of a recently completed R01-funded study (FIA Study; PI: Joseph Broderick), we recruited both familial and sporadic IA cases. In addition, using ARRA funds, we expanded the scope of the study to employ the most current technologies to identify both common and rare variation. From this ongoing study and through collaborations, we have generated GWAS data from over 5,000 samples to test the role of common variation in IA susceptibility. In addition, we selected 7 densely affected families and performed WES to identify candidate genes harboring rare variants that may be implicated in IA. We are currently genotyping a set of IA cases to obtain further evidence for the candidate genes identified through WES. The focus of this R03 application is the analysis of the data generated using both the GWAS and WES approaches. These data were added to the scope of work proposed as part of ARRA funding due to the rapid decrease in the cost of these technologies. The scope of work completed as part of ARRA funding exceeded that initially planned and did not include analyses that are now required. The specific aims of this project are: 1) To perform a case control GWAS in all available samples (2,600 IA cases and 2,568 controls) to identify common SNPs associated with IA susceptibility. 2) To analyze the sequences of 96 candidate gene and to test whether the frequency of rare variants is greater in ~ 400 familial IA cases as compared with publicly available controls.