Population Assessments of Aggregate Genetic Risk for Dilated Cardiomyopathy

项目总结 候选人。Krishna G.Aragam，医学硕士，是内科和心脏病学委员会认证的内科医生 麻省总医院(MGH)，哈佛医学院(HMS)医学讲师， 哈佛/麻省理工学院布罗德研究所副研究员。他有科学承诺的记录，而且 生产力，并寻求在之前的临床医学、流行病学和遗传学培训的基础上扩大到 促进专注于心血管基因组医学的职业生涯。指导、培训活动，以及 环境Aragam博士将在MGH和博德研究所执行拟议的工作 帕特里克·埃利诺博士的初级指导，他是一位内科科学家，也是复杂性状遗传学的国际领导者 在指导方面有着出色的记录。联合初选导师史蒂文·卢比茨博士将提供其他 指导心血管遗传学的研究，并补充临床和医学方面的专业知识 利用电子健康记录进行流行病学分析。指导团队将包括一名高度 LUNETTA博士、林锡鸿博士、Christopher O‘Donnell博士 还有雅各布·约瑟夫。正式课程将加强多学科体验式学习的努力，以获得 具备临床信息学、高级统计遗传学、计算生物学、下一代 测序(NGS)分析、反式组学和负责任的研究行为。研究。扩张的 心肌病(DCM)是一种可遗传的心力衰竭原因，也是心脏移植的主要适应症 全世界。虽然关于扩张型心肌炎的遗传原因的研究主要集中在罕见的、大的影响 (“单基因”)突变，这些突变占转诊进行基因检测的DCM病例的40%。私人侦探将 利用多个大型数据库(Total N&>；1,000,000)和强大的表型和基因数据来识别 与扩张型心肌病相关的常见的、小影响的遗传变异，这些变异加在一起，形成了一个“多基因” 对疾病易感性。首先，PI将进行基于EHR的表型分析，以允许常见的变体 对DCM进行关联性研究和Meta分析，得出DCM多基因风险评分。第二，他会 评估人群中已建立的单基因DCM突变相关的纵向风险 队列，并进行与临床和亚临床扩张型心肌病罕见的变异关联分析。第三，他会 确定罕见的单基因突变如何与多基因风险和非遗传因素(包括 临床、生活方式和环境因素)影响疾病外显。圆满完成 拟议的研究将对扩张性心肌病的多基因基础和相关基因进行全面评估， 单基因和多基因风险对疾病发病机制的全人群贡献。最后，完成 这项提议将使PI在几个重要领域获得新技能(临床信息学、高级 统计遗传学、NGS分析、计算生物学、云计算和跨组学研究) 将有助于他转变为一名独立的内科科学家。

PROJECT SUMMARY Candidate. Krishna G. Aragam, MD MS is a board-certified physician in internal medicine and cardiology at Massachusetts General Hospital (MGH), an Instructor in Medicine at Harvard Medical School (HMS), and an affiliated researcher at the Broad Institute of Harvard/MIT. He has a track record of scientific commitment and productivity, and seeks to expand upon previous training in clinical medicine, epidemiology, and genetics to catalyze a career focused on cardiovascular genomic medicine. Mentorship, Training Activities, and Environment. Dr. Aragam will perform the proposed work at the MGH and the Broad Institute under the primary mentorship of Dr. Patrick Ellinor, a physician scientist and international leader in complex trait genetics with an outstanding track record of mentorship. Co-primary mentor Dr. Steven Lubitz will provide additional guidance with investigations in cardiovascular genetics, and complementary expertise in clinical and epidemiological analyses leveraging the electronic health record. The mentorship team will include a highly committed and accomplished Advisory Committee of Drs. Kathryn Lunetta, Xihong Lin, Christopher O’Donnell, and Jacob Joseph. Formal coursework will enhance a multi-disciplinary experiential learning effort to gain requisite skills in clinical informatics, advanced statistical genetics, computational biology, next-generation sequencing (NGS) analyses, trans-omics, and responsible research conduct. Research. Dilated cardiomyopathy (DCM) is a heritable cause of heart failure and the leading indication for heart transplantation worldwide. While studies regarding the genetic causes of DCM have focused on rare, large-effect (“monogenic”) mutations, these account for < 40% of DCM cases referred for genetic testing. The PI will leverage multiple large databases (Total N > 1,000,000) with robust phenotypic and genotypic data to identify common, small-effect genetic variants associated with DCM which, in aggregate, contribute to a “polygenic” susceptibility to disease. First, the PI will conduct EHR-based phenotyping to permit a common variant association study and meta-analysis of DCM, and then derive a DCM polygenic risk score. Second, he will assess the longitudinal risk associated with established, monogenic DCM mutations in a population-based cohort, and perform rare variant association analyses with clinical and subclinical DCM. Third, he will determine how rare, monogenic mutations interact with polygenic risk, and non-genetic factors (including clinical, lifestyle and environmental factors) to influence disease penetrance. Successful completion of the proposed studies will yield a comprehensive assessment of the polygenic basis of DCM and the relative, population-wide contributions of monogenic and polygenic risk to disease pathogenesis. Finally, completion of this proposal will allow the PI to acquire new skills in several important domains (clinical informatics, advanced statistical genetics, NGS analyses, computational biology, cloud computing, and trans-omics investigation) that will facilitate his transition to a role as an independent physician-scientist.