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Genetics of ischemic stroke in the SiGN Consortium

SiGN 联盟中缺血性中风的遗传学

基本信息

批准号：
10171625
负责人：
STEVEN J KITTNER
金额：
$ 53.17万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-06-01 至 2023-02-28
项目状态：
已结题

项目摘要

Ischemic stroke is the 4th leading cause of death in the U.S. and a major cause of disability. The etiology of stroke is multifactorial and poorly understood. Genetics is a potentially powerful tool for better understanding disease etiology as it can highlight biological mechanisms underlying disease and point the way to improved prevention and treatment. The NINDS-sponsored Stroke Genetics Network (SiGN) was formed in 2010 to identify common genetic variants associated with ischemic stroke and its subtypes using state-of-the-art stroke subtyping and the genome-wide association study approach in over 17,000 stroke cases from 25 sites. The initial meta-analysis, just completed, reveals several tantalizing results and a large number of additional analyses are planned by SiGN investigators. The goal of this application is to secure support for additional key analyses to be carried out on this unique resource and to make this resource available broadly to the international research community. Using already available genotype data, we will (1) Discover rare and low-frequency variants influencing stroke susceptibility by performing association analyses of low-frequency and exonic SNPs with ischemic stroke and its subtypes in 10,348 stroke cases and controls; (2) Identify the likely causal genes and variants at 7 established loci that have been robustly associated with ischemic stroke subtypes using integrative approaches to fine map these regions and define sets of credible causal variants; and (3) Contrast the nature of the genetic architecture among stroke subtypes between stroke and its risk factors using quantitative genetic analyses that partition SNPs across the genome into different bins, or categories, allowing us to test a variety of different hypotheses about the genetic architecture of stroke subtypes. A further goal of our proposal is to advance the pace of genetic discovery in stroke by making the SiGN resource (data and results) accessible to the stroke genetics community on a secure platform at the Broad Institute managed by the NINDS-funded Platform for Accelerating Genetic Discovery for Cerebrovascular Disease. As part of this effort we will create web-based look-up tools that allow investigators to query the meta- analysis results. In a very short period of time, SiGN has emerged as a unifying force in the stroke genetics field because of its inclusion of the leading stroke genetics groups internationally. The analyses and activities proposed in this application are key next steps that take advantage of this extraordinarily rich resource and set in place a mechanism for keeping this productive international consortium together and moving forward.

缺血性中风是美国第四大死亡原因，也是残疾的主要原因。的病因中风是多因素的，但人们对它了解甚少。遗传学是一个潜在的强大工具，疾病病因学，因为它可以突出疾病的生物学机制，并指出改善的方法预防和治疗。NINDS赞助的中风遗传学网络（SiGN）成立于2010年，使用最新卒中技术鉴定与缺血性卒中及其亚型相关的常见遗传变异亚型和全基因组关联研究方法在来自25个站点的17，000多个中风病例中进行。刚刚完成的初步荟萃分析揭示了几个诱人的结果和大量的由SIGN研究者计划进行额外分析。此应用程序的目标是确保支持对这一独特资源进行更多的关键分析，并广泛提供这一资源国际研究界。利用现有的基因型数据，我们将（1）发现罕见的，低频变异影响卒中易感性的相关分析 10,348例脑卒中患者和对照组中缺血性脑卒中及其亚型与外显子SNPs的相关性;（2） 7个已确定的与缺血性卒中密切相关的基因座上的可能致病基因和变异体使用综合方法精细绘制这些区域的亚型，并定义可信的因果变异集; （3）比较中风亚型之间的遗传结构的性质及其风险使用定量遗传分析将基因组中的SNP划分到不同的箱中的因素，或分类，使我们能够测试各种不同的假设，遗传结构的中风亚型我们建议的另一个目标是通过使SIGN基因在脑卒中中的表达，中风遗传学社区可在Broad的安全平台上访问的资源（数据和结果）由NINDS资助的加速脑血管疾病基因发现平台管理的研究所疾病作为这项工作的一部分，我们将创建基于网络的查找工具，使调查人员能够查询Meta，分析结果。在很短的时间内，SiGN已经成为中风遗传学中的统一力量因为它包含了国际上领先的中风遗传学团体。分析和活动本申请中提出的是利用这一极其丰富的资源和集合的关键后续步骤建立一个机制，使这一富有成效的国际联合体保持在一起并向前迈进。