Molecular Variants that Determine Genetic Susceptibility to Intracranial Aneurysm

决定颅内动脉瘤遗传易感性的分子变异

• 批准号: 8305047
• 负责人: MURAT GUNEL
• 金额: $ 60.21万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8305047
• 关键词: 9p21; Accounting; Affect; Age; Alleles; Aneurysm; Aortic Aneurysm; Architecture; Asians; Biological; Biology; Brain hemorrhage; Caucasians; Caucasoid Race; Cause of Death; Cerebral hemisphere hemorrhage; Cessation of life; Chromosomes, Human, Pair 2; Clinical; Code; Collection; Control Groups; Copy Number Polymorphism; DNA; Data; Data Analyses; Databases; Deposition; Detection; Diagnosis; Disease; Europe; European; Event; Family; Finland; Frequencies; Functional RNA; Functional disorder; Future; Gender; Gene Expression Profile; Gene Frequency; General Population; Genes; Genetic; Genetic Polymorphism; Genetic Predisposition to Disease; Genome; Genotype; German population; Germany; Hand; Hemorrhage; Hypertension; Impairment; Individual; Intracranial Aneurysm; Intracranial Hemorrhages; Investigation; Japan; Lead; Left; Lesion; Life; Maps; Measures; Meta-Analysis; Methods; Minor; Molecular; Molecular Biology; Morbidity - disease rate; Mutation; Myocardial Infarction; Natural History; Nature; Netherlands; Neurologic; Odds Ratio; Operative Surgical Procedures; Pathogenesis; Patients; Pattern; Phase; Play; Population; Population Control; Positioning Attribute; Predisposition; Probability; Publishing; Recording of previous events; Recruitment Activity; Recurrence; Reporting; Research; Research Methodology; Research Personnel; Resources; Risk; Role; Rupture; SNP genotyping; Sample Size; Sampling; Siblings; Smoking; Staging; Stratification; Stroke; Subgroup; Survivors; Testing; Time; Transcript; United States National Institutes of Health; Variant; abstracting; base; case control; cerebral artery; cohort; cost; database of Genotypes and Phenotypes; follow-up; gene discovery; genome wide association study; genome-wide; insight; interest; mortality; novel; outcome forecast; prevent; proband; repaired; young adult

Abstract: 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.

摘要： 颅内动脉瘤（IA）影响约2%的人群，并导致50万例出血性卒中 每年在相对年轻的患者（中位年龄50岁）中， 损伤动脉瘤形成和破裂的发病机制尚不清楚， 识别对于防止灾难性出血是必不可少的。我们最近完成了一项 一项多阶段全基因组关联研究（GWAS），纳入了超过2，100例IA患者和8，000例对照 并确定了染色体2、8和9上超过严格阈值的常见SNP， 与IA重复相关（比值比1.24 - 1.36）。在这项初步研究中，我们还发现了 对于其他几个IA易感性位点，P值小于10 -4，优势比适中 (OR<1.25），并可能以累积的方式导致IA风险。为了增加我们的力量 为了检测和确认这些位点，我们招募了5,100多名新病例和22,000名对照 使病例总数和控制总数分别超过7,300和30500。这其中的主要重点 我们的建议是通过识别每个基因组中的致病等位基因，将我们的GWAS结果带入下一阶段。 基因座，从而可以确认IA基因。这些基因的发现将引领未来的应用 假设驱动的研究，旨在了解这些转录本的功能， 对IA病理生理学的机制性洞察。我们在这方面的努力可以分为三个方面 概念上不同但互补的努力：1）我们将描述具体的功能 每个位点的变异占常见的变异发现，通过我们的先验 GWAS; 2）我们将评估罕见和常见结构变异对 IA，和3）我们将寻求识别有助于IA的其他变体的证据。最终的结果 这些分析将是这种疾病的遗传结构的全面看法， 共同等位基因，将作为启动点的生物学研究IA和开始 创造机会，在任何病态事件发生之前， 动脉瘤破裂。