ERICH-GENE

项目总结/摘要 中风是美国第三大死亡原因和成人残疾的主要原因。更 成年人每年受中风的影响超过阿尔茨海默病、多发性硬化症、肌萎缩侧索硬化症 或帕金森氏症。脑出血（ICH）是卒中中最严重的亚型。一个 据估计，40-50%的ICH受害者将死亡，超过80%的幸存者仍然残疾。ICH患者 与其他形式的脑小血管病（CSVD）有共同的组织病理学特征， 脑淀粉样血管病。CSVD是进行性神经功能下降的关键组成部分， 阿尔茨海默病和血管性痴呆，近一半的ICH幸存者在4年内发展为痴呆。 我们的研究人员以前曾合作发表了最大的ICH全基因组关联研究 约1500例病例，确定了新的遗传因素，这些因素后来在CSVD中得到了复制。 表型包括白色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。 脑出血的种族/种族差异（ERICH）研究最初招募了3000多例病例 在白色、黑人和西班牙裔病例中，自发性出血的发生率相同。研究设计开始 根据ICH的种族特异性和非特异性风险因素可能存在的理念， ERICH出版物支持这一点。我们建议联合收割机将世界各地的其他ICH病例合并， 最大限度地发挥我们的研究能力，以确定跨种族的新遗传变异。我们已经确定了 21，000例已完成基因分型或有样本可用于评估ICH遗传风险的病例。 然而，关键的第一步是进行仔细的表型协调，特别是在位置， 对患者进行临床、组织病理学和遗传学分层的出血。不同的研究使用 不同的位置定义，如果不统一，将因病例错误分类而限制研究效力。我们有 先前在我们的两个中心进行了ICH病例状态和位置的表型协调， 超过5，000例病例来自3项NIH资助的研究。我们打算利用现有数据完成案件的统一， 并将协调扩展到相关的成像CSVD表型和临床结局。接下来，我们将联合收割机 基因组数据，以创建多基因风险评分（PRS），对个体ICH的累积遗传风险进行分层 水平，这可能提供了一个短期的机会，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，在NINDS支持下建立的可自由访问的在线协作资源。 如果成功，我们将通过位置和CSVD神经影像学确定ICH的风险因素、亚型 功能，这将是有价值的目标，合理的治疗发展。我们还将建立PRS， ICH风险和结局，作为根据ICH风险对个体进行分层并提供结局预后信息的工具。

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.