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Circulation. 2018 Nov 11. doi: 10.1161/CIRCULATIONAHA.118.035658. [Epub ahead of print]

Whole Genome Sequencing to Characterize Monogenic and Polygenic Contributions in Patients Hospitalized with Early-Onset Myocardial Infarction.

Author information

Cardiology, Massachutsetts General Hospital, Boston, MA.
Cardiovascular Disease Initiative, The Broad Institute of MIT and Harvard, Cambridge, MA.
Computational Biology & Bioinformatics Program, Yale School of Medicine, New Haven, CT.
Center for Human Genetics Research, Massachusetts General Hospital, Boston, MA.
Medical and Population Genetics, Broad Institute, Cambridge, MA.
Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA.
Chronic Disease Epidemiology, Yale School of Public Health, New Haven, CT.
Dept of Emergency Medicine, Yale University, New Haven, CT.
CORE, Yale New Haven Hospital Center for Outcomes Research and Evaluation, New Haven, CT.
Emergency Medicine, Dept of Emergency Med, Yale Univ Sch of Med; Ctr for Outcomes Res and Evaluation (CORE), New Haven, CT.
Cardiovascular Research, Saint Luke's Mid America Heart Institute, Kansas City, MO.
Pediatrics, Los Angeles Biomedical Research Inst, CA.
Cardiovascular Health Research Unit, University of Washington & Group Health Research Inst, Group Health Cooperative, Seattle, WA.
Public Health Sciences, University of Virginia, Richmond, VA.
Cardiology/Medicine, Johns Hopkins University, Baltimore, MD.
Pediatrics, UCLA Medical Center at Harbor, Torrance, CA.
Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA.
Pediatrics, Lo Angeles Biomedical Research Instiute, Torrance, CA.
Department of Internal Medicine, Yale School of Medicine & Yale School of Public Health, New Haven, CT.
Massachusetts General Hospital, Boston, MA.



The relative prevalence and clinical importance of monogenic mutations related to familial hypercholesterolemia and of high polygenic score (cumulative impact of many common variants) pathways for early-onset myocardial infarction remain uncertain. Whole genome sequencing enables simultaneous ascertainment of both monogenic mutations and polygenic score for each individual.


We performed deep-coverage whole genome sequencing of 2,081 patients from four racial subgroups hospitalized in the U.S. with early-onset myocardial infarction (age ≤ 55 years) recruited using a 2:1 female to male enrollment design. We compared these genomes with 3,761 population-based controls. We first identified individuals with a rare, monogenic mutation related to familial hypercholesterolemia. Second, we calculated a recently developed polygenic score of 6.6 million common DNA variants to quantify the cumulative susceptibility conferred by common variants. We defined high polygenic score as the top 5% of the control distribution, as this cutoff has been previously shown to confer similar risk to familial hypercholesterolemia mutations.


Mean age of the 2,081 patients presenting with early-onset myocardial infarction was 48 years and 66% were female. A familial hypercholesterolemia mutation was present in 36 (1.7%) of these patients and associated with a 3.8-fold (95%CI 2.1 - 6.8; p < 0.001) increased odds of myocardial infarction. 359 (17.3%) of the patients with early-onset myocardial infarction carried a high polygenic score, associated with a 3.7-fold (95%CI 3.1 - 4.6; p < 0.001) increased odds. Mean estimated untreated LDL cholesterol was 206 mg/dl in those with a familial hypercholesterolemia mutation, 132 mg/dl in those with high polygenic score, and 122 mg/dl in those in the remainder of the population. Although associated with increased risk in all racial groups, high polygenic score demonstrated the strongest association in white participants (pheterogeneity = 0.008).


Both familial hypercholesterolemia mutations and high polygenic score are associated with a more than three-fold increased odds of early-onset myocardial infarction. However, high polygenic score cannot be reliably identified on the basis of elevated LDL cholesterol and has a ten-fold higher prevalence among patients presenting with early-onset myocardial infarction.


URL: Unique identifier: NCT00597922.


polygenic risk score

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