Genetic variation in white matter hyperintensity and risk of ischemic stroke

项目简介：Natalia Rost博士是麻省总医院（MGH）的中风神经科医生，她的目标是成为一名具有遗传学、神经影像学和流行病学专业知识的独立研究者，以确定遗传对中风和其他脑血管疾病的影响。Rost博士的职业发展计划汇集了一个杰出的研究团队和三个领先机构的资源，包括MGH，弗雷明汉心脏研究（FHS）和麻省理工学院和哈佛大学的Broad研究所。Rost博士已经获得了急性缺血性中风患者MRI检测白质高强度（WMH）体积全基因组关联研究的初步结果。在博士的指导下。Rosand, Wolf， deBakker和Sorensen博士提出：(1)在医院缺血性卒中患者队列中确定与WMH相关的常见遗传变异，并在缺血性卒中遗传学研究（ISGS）患者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AIM 1中与WMH相关的遗传变异是否与缺血性卒中患者的MGH和FHS前瞻性队列及其匹配对照的症状性卒中风险相关。(3)通过建立改进的缺血性卒中临床-遗传风险预测模型，将她的研究成果转化为一种应用的个性化风险评估方法。本提案的总体目标是通过将神经影像学和遗传分析的前沿方法与脑血管疾病、神经影像学和复杂疾病遗传学的专业团队结合起来，阐明缺血性卒中患者WMH风险和严重程度的共同变异的作用。这一明确的以患者为导向的指导研究计划，与高级统计、流行病学和遗传课程的结构化教学课程相结合，将为Rost博士提供技能和指导，这对她在基因组科学的前沿发展脑血管研究的独立职业生涯至关重要。

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.