Population Assessments of Aggregate Genetic Risk for Dilated Cardiomyopathy

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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.