ERICH-GENE

项目摘要/摘要 在美国，中风是第三大致死原因，也是成人致残的首要原因。更多 成年人每年受中风的影响比阿尔茨海默病、多发性硬化症、肌萎缩侧索硬化症要多 或者帕金森氏症。脑出血(ICH)是中风最严重的亚型。一个 据估计，40%-50%的非物质文化遗产受害者将死亡，80%以上的幸存者仍然残疾。脑溢血患者 与其他形式的脑部小血管疾病(CSVD)的组织病理学特征相同，由 高血压和脑淀粉样血管病。CSVD是进行性神经功能衰退的关键组成部分 阿尔茨海默病和血管性痴呆症，近一半的脑出血幸存者在4年内患上痴呆症。 我们的研究人员此前曾合作发表了最大的脑出血全基因组关联研究 在大约1500例病例中，发现了后来在CSVD中复制的新的遗传因素 表型包括白质高信号和小血管卒中。随着样本量的增加，我们将 发现脑出血的其他危险因素，并通过这些机制，阿尔茨海默氏症和血管性痴呆。 脑出血的民族/种族变异(ERICH)研究最初招募了3000多例患者 在白人、黑人和西班牙裔病例中，自发性出血的威力相同。研究设计开始 其理念是，种族特有的和非特有的非脑血管意外危险因素可能存在，而且有许多 埃里希的出版物支持这一点。我们建议将来自世界各地的更多非物质文化遗产病例结合起来 最大限度地发挥我们研究的力量，以确定跨种族的新基因变异。我们已经确认了超过 21,000例已完成基因分型或已有样本可用于评估脑出血的遗传风险。 然而，关键的第一步是进行仔细的表型协调，特别是在定位 在临床、组织病理学和遗传学上对患者进行分层的出血。不同的研究使用了 不同的地点定义，如果不协调，将由于案例错误分类而限制研究权力。我们有 之前在我们的两个中心进行了表型协调，包括ICH病例状态和地点 美国国立卫生研究院资助的3项研究共5000例。我们打算利用现有数据完成案件的协调， 并扩大对相关成像CSVD表型和临床结果的协调。接下来，我们将结合 创建多基因风险评分(PR)的基因组数据，用于对个体的ICH累积遗传风险进行分层 水平，这可能提供一个近期机会，以利用基因组关联数据，以改善临床护理。 最后，我们将通过脑血管疾病最大限度地分享所有关联结果和表型 知识门户，一个可自由访问的在线协作资源，由NINDS支持建立。 如果成功，我们将确定脑出血的危险因素，按部位和跨CSVD神经成像的亚型 特征，这将是有价值的合理治疗开发的目标。我们还将为 ICH风险和结果，作为一种工具，根据ICH风险对个体进行分层并提供关于结果的预后信息。

Project Summary/Abstract Stroke is the third leading cause of death and the leading cause of adult disability in the United States. More adults are affected by stroke each year than Alzheimer’s disease, multiple sclerosis, amyotrophic lateral sclerosis or Parkinson’s disease. Intracerebral hemorrhage (ICH) represents the most severe subtype of stroke. An estimated 40-50% of ICH victims will die and more than 80% of survivors remain disabled. Patients with ICH share histopathological features with other forms of cerebral small vessel disease (CSVD) caused by hypertension and cerebral amyloid angiopathy. CSVD is a key component of progressive neurologic decline in Alzheimer’s disease and vascular dementia, and nearly half of ICH survivors develop dementia within 4 years. Our investigators have previously collaborated to publish the largest genome wide association study of ICH with ~1500 cases, which identified novel genetic factors that have since gone on to be replicated in CSVD phenotypes including white matter hyperintensity and small vessel stroke. With greater sample size, we will uncover additional risk factors for ICH and through those mechanisms, Alzheimer’s and vascular dementias. The Ethnic/Racial Variations of Intracerebral Hemorrhage (ERICH) study originally recruited over 3000 cases of spontaneous hemorrhage with equal power among white, black and Hispanic cases. The study design begins with the philosophy that both ethnicity-specific and non-specific risk factors for ICH may exist, and numerous ERICH publications support this. We propose to combine additional ICH cases from around the world to maximize the power of our study to identify novel genetic variants across ethnicities. We have identified over 21,000 cases that have either completed genotyping or have samples available to assess genetic risk of ICH. However, the critical first step is to perform careful phenotype harmonization, specifically in location of hemorrhage which stratifies patients clinically, histopathologically, and genetically. Different studies have used different location definitions which if not harmonized will limit study power due to case misclassification. We have previously performed phenotype harmonization across our two centers for both ICH case status and location in >5,000 cases across 3 NIH-funded studies. We intend to complete harmonization on cases with available data, and expand harmonization to related imaging CSVD phenotypes and clinical outcomes. Next, we will combine genomic data to create polygenic risk scores (PRS) to stratify cumulative genetic risk of ICH at the individual level, which may provide a near-term opportunity to leverage genomic association data to improve clinical care. Finally, we will maximally share all association results and phentoypes through the Cerebrovascular Disease Knowledge Portal, a freely-accessible on-line collaborative resource established with NINDS support. If successful, we will have identified risk factors for ICH, subtypes by location and across CSVD neuroimaging features, which will be valuable as targets for rational therapeutic development. We will also have built PRS for ICH risk and outcome, as a tool to stratify individuals by ICH risk and provide prognostic information on outcomes.