Genetic variation in white matter hyperintensity and risk of ischemic stroke

描述（由申请人提供）：项目摘要：娜塔莉亚罗斯特博士是马萨诸塞州总医院（MGH）的中风神经科医生，其目标是成为一名独立的研究者，具有遗传学、神经影像学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。Rost博士的职业发展计划汇集了一个优秀的研究团队和三个领先机构的资源，包括MGH，Frachial Heart Study（FHS），以及麻省理工学院和哈佛的Broad研究所。Rost博士已经获得了急性缺血性卒中患者MRI可检测到的白色高信号（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博士提出：（1）在缺血性卒中患者的医院队列中识别与WMH相关的常见遗传变异，并在缺血性卒中遗传学研究（ISGS）队列中复制她的发现，并提供全基因组和MRI数据进行分析;（2）确定与AIM 1中WMH相关的遗传变异是否与缺血性卒中病例及其匹配对照的MGH和FHS前瞻性队列中症状性卒中的风险相关，以及（3）通过开发改良的缺血性卒中临床-遗传风险预测模型，将其研究结果转化为应用的个性化风险评估方法。该提案的总体目标是通过汇集神经影像学和遗传分析的尖端方法以及具有脑血管疾病，神经影像学和复杂疾病遗传学专业知识的团队，阐明缺血性卒中患者WMH风险和严重程度的常见变异的作用。这个明确的指导以患者为导向的研究建议，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，使她能够在基因组科学的前沿发展脑血管研究的独立职业生涯。 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。Rost博士提出的职业发展计划具有突出的潜力，可以促进我们对中风遗传决定因素的了解，这是发现新的风险因素和制定预防和治疗中风的有效策略的关键一步。

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.