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

• 批准号: 10689056
• 负责人: Krishna G Aragam
• 金额: $ 16.96万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 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/10689056
• 关键词: Active Learning; Advisory Committees; Alcohol consumption; Atrial Fibrillation; Board Certification; Body mass index; Cardiac; Cardiology; Cardiovascular system; Circulation; 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; 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 Factors; Role; Scientist; Structure; Testing; Training; Training Activity; Variant; Veterans; Work; 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; risk mitigation; skills; sudden cardiac death

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.

项目总结

项目成果

Association of Habitual Alcohol Intake With Risk of Cardiovascular Disease.

• DOI: 10.1001/jamanetworkopen.2022.3849
• 发表时间: 2022-03-01
• 期刊: JAMA network open
• 影响因子: 13.8
• 作者: Biddinger KJ;Emdin CA;Haas ME;Wang M;Hindy G;Ellinor PT;Kathiresan S;Khera AV;Aragam KG
• 通讯作者: Aragam KG