A Genome-Wide Association Study of Ischemic Brain Vascular Injury

描述(申请人提供)：根据世界卫生组织的数据，全世界每年有1500万人中风。其中，500万人死亡，500万人永久残疾，给家庭、社区和政府带来了沉重的负担。虽然有急性缺血性中风症状和体征的患者代表了很容易被识别的冰山一角，但人们普遍认为，缺血性脑血管疾病的有害影响早在临床症状显现之前就开始了。事实上，磁共振成像(MRI)可检测到的缺血性脑血管异常，包括白质高信号(WMH)和无症状脑梗塞(SBI)，在中年开始的无症状人群中很常见。两者都与随后的缺血性中风的风险增加密切相关，而且有证据表明，它们可能具有共同的致病机制。然而，这些关系的分子基础是未知的。基因组科学的进展为通过全基因组连锁不平衡作图识别缺血性脑血管损伤的基因提供了新的机会。这项拟议的研究代表了一项合作努力，利用现有的样本、先前收集的关于单核苷酸多态(SNPs)的全基因组集合的基因数据、高质量的表型数据和最先进的分析方法来识别和复制在临床和亚临床阶段影响缺血性脑血管损伤的遗传效应。主要背景是社区动脉粥样硬化风险研究，这是一项前瞻性研究，调查了15,792名非洲裔美国人和45-年龄的欧洲裔美国人，以调查心血管疾病的病因和自然病史及其危险因素。关于906,600个SNPs集合的基因数据在整个队列中都是可用的，这些数据将被用来进行临床缺血性中风事件和亚临床缺血性脑血管损伤的全基因组关联分析，这些分析是由WMH或SBI的MRI所定义的。结果的复制将通过对Framingham心脏研究和心血管健康研究(CHS)中收集的相同表型的全基因组关联数据进行荟萃分析，以及在其他队列中进行后续基因分型和关联分析来促进，包括与中风风险和结果研究相关的基因(GASROS)和动脉硬化遗传网络(GENOA)。这项研究为在临床和亚临床阶段识别影响缺血性脑血管损伤的新基因提供了一个独特的机会，并开始揭示显性和隐性脑血管疾病之间关系的分子基础。公共卫生相关性：基因组科学的进步为通过全基因组连锁不平衡图谱识别缺血性脑血管损伤的基因提供了新的机会。这项拟议的研究代表了一项合作努力，利用现有的样本、先前收集的关于单核苷酸多态(SNPs)的全基因组集合的基因数据、高质量的表型数据和最先进的分析方法来识别和复制在临床和亚临床阶段影响缺血性脑血管损伤的遗传效应。

DESCRIPTION (provided by applicant): According to the World Health Organization, 15 million people worldwide suffer a stroke every year. Of these, 5 million die and another 5 million are left permanently disabled, placing a heavy burden on families, communities, and governments. While patients with symptoms and signs of acute ischemic stroke represent the easily recognized "tip of the iceberg", it is well accepted that the deleterious effects of ischemic brain vascular disease begin well before clinical symptoms become apparent. Indeed, ischemic brain vascular abnormalities detectable by magnetic resonance imaging (MRI), including white matter hyperintensities (WMH) and silent brain infarcts (SBI), are common in asymptomatic populations beginning in middle age. Both are strongly and independently associated with increased risk of subsequent ischemic stroke, and there is evidence that they may share common pathogenic mechanisms. The molecular basis of these relationships is, however, unknown. Advances in the genome sciences afford new opportunities to identify genes for ischemic brain vascular injury through genome-wide linkage disequilibrium mapping. The proposed research represents a collaborative effort to use existing specimens, previously-collected genotype data on a genome-wide collection of single nucleotide polymorphisms (SNPs), high-quality phenotypic data, and state-of-the-art analytical methods to identify and replicate genetic effects influencing ischemic brain vascular injury in the clinical and subclinical stages. The primary setting is that of the Atherosclerosis Risk In Communities (ARIC) study, a prospective study of 15,792 African-Americans and European-Americans 45-64 years of age at baseline to investigate the etiology and natural history of cardiovascular disease and its risk factors. Genotype data on a collection of 906,600 SNPs is available on the whole cohort and will be used to conduct whole genome association analyses of incident clinical ischemic stroke and subclinical ischemic brain vascular injury defined by presence on MRI of WMHs or SBIs. Replication of results will be facilitated through meta-analyses of genome-wide association data on the same phenotypes collected in the Framingham Heart Study and the Cardiovascular Health Study (CHS), as well as follow-up genotyping and association analyses in additional cohorts, including the Genes Associated with Stroke Risk and Outcomes Study (GASROS) and the Genetic Network Of Arteriosclerosis (GENOA). The proposed research provides a unique opportunity to identify novel genes influencing ischemic brain vascular injury in the clinical and subclinical stages, and to begin to unravel the molecular basis of the relationship between overt and covert brain vascular disease. PUBLIC HEALTH RELEVANCE: Advances in the genome sciences afford new opportunities to identify genes for ischemic brain vascular injury through genome-wide linkage disequilibrium mapping. The proposed research represents a collaborative effort to use existing specimens, previously-collected genotype data on a genome-wide collection of single nucleotide polymorphisms (SNPs), high-quality phenotypic data, and state-of-the-art analytical methods to identify and replicate genetic effects influencing ischemic brain vascular injury in the clinical and subclinical stages.