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Population Assessments of Aggregate Genetic Risk for Dilated Cardiomyopathy

扩张型心肌病总体遗传风险的人群评估

基本信息

批准号：
10459589
负责人：
Krishna G Aragam
金额：
$ 16.87万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-15 至 2026-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10459589
关键词：
Active Learning Advisory Committees Alcohol consumption Atrial Fibrillation Blood Circulation Body mass index Cardiac Cardiology Cardiovascular system Classification Clinical Clinical Data Clinical Informatics Clinical Medicine Clinical assessments Cloud Computing Complex Complex Genetic Trait Computational Biology Coupled Data Databases Development Dilated Cardiomyopathy Disease Drug Targeting Early identification Electronic Health Record Environment Environmental Risk Factor Epidemiology General Hospitals General Population Genes Genetic Genetic Determinism Genetic Predisposition to Disease Genetic Risk Genomic medicine Genomics Genotype Healthcare Heart Transplantation Heart failure Heritability Individual Institutes Internal Medicine International Investigation Joints Link Massachusetts Mediating Medical Genetics Medicine Mentors Mentorship Meta-Analysis Mutation Myocardial Infarction Onset of illness Outcome Participant Pathogenesis Patients Penetrance Perinatal Phenotype Physicians Population Population Genetics Positioning Attribute Predictive Value Predisposition Productivity Prognosis Research Research Personnel Risk Risk Assessment Risk Factors Role Scientist Structure Testing Time Training Training Activity Variant Veterans Work base biobank cardiac magnetic resonance imaging career clinical practice clinical risk cohort connectin disease-causing mutation exome sequencing genetic analysis genetic epidemiology genetic testing genetic variant genome wide association study heart imaging improved inherited cardiomyopathy instructor lifestyle factors loss of function mutation medical schools multidisciplinary mutation carrier next generation sequencing non-genetic novel novel therapeutics phenotypic data polygenic risk score population based prognostication programs prospective rare variant responsible research conduct skills sudden cardiac death

项目摘要

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.

项目摘要候选人克里希纳湾Aragam，MD MS是内科和心脏病学的委员会认证医生，马萨诸塞州总医院（MGH），哈佛医学院（HMS）医学讲师，以及他是哈佛/麻省理工学院布罗德研究所的附属研究员。他有着科学承诺的记录，生产力，并寻求扩大在临床医学，流行病学和遗传学以前的培训，催化专注于心血管基因组医学的职业生涯。指导、培训活动和环境Aragam博士将在MGH和Broad研究所开展拟议的工作，帕特里克·埃莉诺博士的主要指导，帕特里克·埃莉诺博士是一位医生科学家和复杂性状遗传学领域的国际领导者有着出色的指导记录共同主要导师史蒂芬卢比茨博士将提供额外的心血管遗传学研究的指导，以及临床和利用电子健康记录进行流行病学分析。导师团队将包括一个高度由Kathryn Lunetta、Xihong Lin、Christopher奥唐纳、雅各布·约瑟夫正式的课程将加强多学科的体验式学习，临床信息学，先进的统计遗传学，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。Research.扩张型心肌病（DCM）是心力衰竭的遗传原因，也是心脏移植的主要指征国际吧虽然关于DCM遗传原因的研究主要集中在罕见的，大作用的，在一些实施例中，DCM（“单基因”）突变占被转介进行基因检测的DCM病例的< 40%。PI将利用多个大型数据库（总N > 1，000，000）和强大的表型和基因型数据，与DCM相关的常见的小效应遗传变异，其总体上有助于“多基因” 对疾病的易感性。首先，PI将进行基于EHR的表型分析，以允许常见变异 DCM的关联研究和荟萃分析，然后得出DCM多基因风险评分。第二，他将在基于人群的研究中评估与已确定的单基因DCM突变相关的纵向风险队列，并与临床和亚临床DCM进行罕见变异相关性分析。第三，他将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）影响疾病的发病率。成功完成所提出的研究将产生对DCM的多基因基础和相对的，单基因和多基因风险对疾病发病机制的人群贡献。最后，完成这一建议将使主要研究者在几个重要领域（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），这将有助于他转变为一个独立的物理学家和科学家。