Genetic variation in white matter hyperintensity and risk of ischemic stroke

描述(由申请人提供)：项目摘要：Natalia Rost博士是马萨诸塞州总医院(MGH)的中风神经学家，其目标是成为一名独立的研究人员，拥有遗传学、神经成像和流行病学方面的专业知识，以确定中风和其他脑血管疾病的遗传贡献。罗斯特博士的职业发展计划汇集了一支杰出的研究团队和三家领先机构的资源，其中包括麻省理工学院、弗雷明翰心脏研究(FHS)以及麻省理工学院和哈佛大学的博德研究所。Rost博士已经获得了关于急性缺血性中风患者MRI可检测到的白质高强度(WMH)体积的全基因组关联研究的初步结果。在Rosand、Wolf、DeBakker和Sorensen博士的指导下，Rost博士建议：(1)在以医院为基础的患者队列中识别与WMH相关的常见基因变异，并复制她在缺血性中风遗传学研究(ISGS)队列中的发现，这些患者拥有可用于分析的全基因组和MRI数据；(2)确定AIM 1中与WMH相关的基因变异是否与缺血性卒中病例及其匹配对照的MGH和FHS前瞻性队列中的症状性卒中风险相关，以及(3)通过建立改良的缺血性卒中临床-遗传风险预测模型，将她的研究成果转化为实用的个性化风险评估方法。这项建议的总体目标是通过汇集神经成像和基因分析的尖端方法以及拥有脑血管疾病、神经成像和复杂疾病遗传学专业知识的团队，阐明WMH风险和严重程度的共同变异在缺血性中风患者中的作用。这一明确的、有指导的、以患者为导向的研究方案，与先进的统计学、流行病学和遗传学课程的结构化教学课程相结合，将为Rost博士提供必要的技能和指导，这对她在基因组科学前沿领域发展独立的脑血管研究事业至关重要。 公共卫生相关性：尽管在预防和治疗方面取得了现代进步，但中风仍然是全球成人残疾的主要原因和第二大死亡原因。罗斯特博士提出的职业发展计划具有显著的潜力，可以促进我们对中风遗传决定因素的了解，为发现新的危险因素和开发有效的中风预防和治疗策略迈出关键的下一步。

DESCRIPTION (provided by applicant): Project Summary: Dr. Natalia Rost is a Stroke Neurologist at the Massachusetts General Hospital (MGH), whose goal is to become an indepentdent investigator with expertise in genetics, neuroimaging, and epidemiology to define genetic contribution to stroke and other cerebrovascular disease. Dr. Rost's career development plan brings together an outstanding team of investigators and the resources of three leading institutions including the MGH, the Framingham Heart Study (FHS), and the Broad Institute of MIT and Harvard. Dr. Rost has already obtained preliminary results of a genome-wide association study of MRI- detectable white matter hyperintensity (WMH) volume in patients with acute ischemic stroke. Under mentorship of Drs. Rosand, Wolf, deBakker, and Sorensen, Dr. Rost proposed: (1) to identify common genetic variants associated with WMH in a hospital-based cohort of patients with ischemic stroke and to replicate her findings in the Ischemic Stroke Genetics Study (ISGS) cohort of the patients with whole genome and MRI data available for analysis; (2) to determine whether genetic variants associated with WMH in AIM 1 are associated with risk of symptomatic stroke in the MGH and FHS prospective cohorts of ischemic stroke cases and their matched controls, and (3) to translate her research findings into an applied personalized risk assessment method by developing a modified clinical-genetic risk prediction model for ischemic stroke. The overall goal of this proposal is to elucidate the role of common variation in risk and severity of WMH in patients with ischemic stroke by bringing together cutting-edge methods for neuroimaging and genetic analysis and a team with expertise in cerebrovascular disease, neuroimaging, and complex disease genetics. This well-defined mentored patient-oriented research proposal, in concert with a structured didactic curriculum of advanced statistical, epidemiologic, and genetic coursework, will provide Dr. Rost with the skills and mentorship that are essential for her to develop an independent career in cerebrovascular research at the cutting edge of genomic science. Public Health Relevance: Despite modern advances in prevention and treatment, stroke remains the leading cause of adult disability and second leading cause of death worldwide. Dr. Rost's proposed career development plan has an outstanding potential to advance our knowledge of genetic determinants of stroke, a crucial next step toward discovery of novel risk factors and development of effective strategies for prevention and treatment of stroke.