Population Assessments of Aggregate Genetic Risk for Dilated Cardiomyopathy

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.

Grant Number: 5K08HL153937-05
NIH Institute/Center: NIH
Principal Investigator: Krishna Aragam