A Genome-Wide Association Study of Ischemic Brain Vascular Injury

描述（由申请人提供）：据世界卫生组织统计，全世界每年有1500万人患中风。其中，500万人死亡，另有500万人终身残疾，给家庭、社区和政府带来沉重负担。虽然急性缺血性脑卒中患者的症状和体征是很容易识别的“冰山一角”，但人们普遍认为，缺血性脑血管疾病的有害影响远在临床症状出现之前就开始了。事实上，通过磁共振成像（MRI）检测到的缺血性脑血管异常，包括白质高信号（WMH）和无症状脑梗死（SBI），在中年开始的无症状人群中很常见。两者都与随后缺血性卒中的风险增加密切且独立相关，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。基因组科学的进步为通过全基因组连锁不平衡定位来鉴定缺血性脑血管损伤基因提供了新的机会。该研究代表了一项合作努力，利用现有标本、先前收集的全基因组单核苷酸多态性（snp）基因型数据、高质量表型数据和最先进的分析方法，在临床和亚临床阶段识别和复制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（ARIC）研究，这是一项前瞻性研究，研究15,792名年龄在45-64岁的非洲裔美国人和欧裔美国人的基线，以调查心血管疾病的病因和自然病史及其危险因素。收集的906,600个snp的基因型数据可用于整个队列的全基因组关联分析，这些数据将用于临床缺血性卒中和亚临床缺血性脑血管损伤的全基因组关联分析，这些损伤是由MRI上出现的wmh或sbi定义的。通过对弗雷明汉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的荟萃分析，以及其他队列的后续基因分型和关联分析，包括与卒中风险和结局研究（GASROS）和动脉硬化遗传网络（GENOA），将有助于结果的复制。本研究为在临床和亚临床阶段鉴定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鉴定缺血性脑血管损伤基因提供了新的机会。该研究代表了一项合作努力，利用现有标本、先前收集的全基因组单核苷酸多态性（snp）基因型数据、高质量表型数据和最先进的分析方法，在临床和亚临床阶段识别和复制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.