Genetic variation influencing brain AVM

脑动静脉畸形是年轻人发生颅内出血的重要原因。 成年人。病因和发病机制尚不清楚，对信号转导途径有较好的了解。 影响疾病易感性和临床进展是优化患者护理所必需的。在当前 在资助期间，我们有了几个新的和重要的发现，报告了有史以来第一个基因 脑动静脉畸形易感性与颅内出血(ICH)的关系这些发现为工作奠定了基础 在下一阶段，我们将研究基因变异对疾病易感性的影响 使用来自AVM案例(n=647)的大量现有DMA集合，以集中和全面的方式 预计在项目过程中将登记新病例(n=370)，总样本量为1017 案子。 AIM 1是一项全基因组关联(GWAS)研究，旨在确定与 AVM，使用Affymetrix SNP阵列6.0，包含-100万个SNP和约100万个拷贝数探针 变异(CNV)。初步分析将在我们最大的子组中将AVM病例与健康对照组进行比较， 高加索人(520例和643名对照)，使用新的基因组方法对病例和 使用主成分分析对人口分层进行控制和调整。二次分析将 评估CNV是否与AVM易感性相关。 AIM 2将通过精细定位与易感性相关的候选变异 20个目标区域，包含来自GWAS分析的最显著的SNP和/或CNV 各种标准方法。我们最相关的候选SNPs将在AVM病例和对照中得到验证 来自波恩大学(德国)和乌得勒支大学(荷兰)。其他分析将测试 其他人种和动静脉畸形病例中继发出血的时间。此外，生物功能的生物功能 AVM相关变种将使用标准分子技术进行测试。 目标3将利用CNV分析来探索体细胞变异作为AVM的遗传机制 通过检测杂合性缺失将基因组DNA与从手术标本中分离的皮损DNA进行比较 或等位基因失衡。在100名患者中，我们将从动静脉畸形解剖的血管组织中进行DNA分型 用Affymetrix 6.0阵列在手术中切除病灶，并比较胚系DNA之间的全基因组CNV 和病变DNA，后续将包括亚克隆和深度重新测序的使用。

Brain arteriovenous malformations (AVMs) are an important cause of intracranial hemorrhage (ICH) in young adults. The etiology and pathogenesis are unknown and better understanding of the signaling pathways influencing disease susceptibility and clinical progression is needed to optimize patient care. In the current funding period, we have made several novel and important discoveries, reporting the first-ever genetic associations with AVM susceptibility and intracranial hemorrhage (ICH). These findings set the stage for work during the next period, during which we will study the influence of genetic variation on disease susceptibility in a focused and comprehensive fashion using a large existing DMA collection from AVM cases (n=647) and expected new cases to be enrolled (n=370) over the course of the project, yielding a total sample size of 1017 cases. Aim 1 is a Genome-wide association (GWAS) study to identify novel candidate variants associated with AVM, using the Affymetrix SNP Array 6.0, containing -1 million SNPs and ~1 million probes for copy number variation (CNV). The primary analysis will compare AVM cases to healthy controls in our largest sub-group, Caucasians (520 cases and 643 controls), using novel genomic methods to genetically match cases and controls and adjust for population stratification using principal components analysis. Secondary analysis will evaluate whether CNV is associated with AVM susceptibility. Aim 2 will follow-up candidate variants associated with susceptibility through fine-mapping of approximately 20 target regions containing the most highly significant SNPs and/or CNVs from GWAS analysis through a variety of standard methods. Our top-associated candidate SNPs will be validated in AVM cases and controls from the University of Bonn (Germany) and University of Utrecht (Netherlands). Additional analyses will test other race-ethnic groups and time-to-subsequent hemorrhage in AVM cases. Further, biological function of AVM-associated variants will be tested using standard molecular techniques. Aim 3 will be exploration of somatic variation as a genetic mechanism in AVM using CNV analysis to compare genomic DNA to lesional DNA isolated from surgical specimens by examining loss of heterozygosity or allelic imbalance. In 100 patients, we will genotype DNA from vascular tissue that is dissected from the AVM nidus removed at surgery with Affymetrix 6.0 arrays, and compare CNVs genome-wide between germline DNA and lesion DNA, and follow-up will include use of subcloning and deep re-sequencing.