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

Circulation. 2019 Mar 26;139(13):1593-1602. doi: 10.1161/CIRCULATIONAHA.118.035658.


Background: 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.

Methods: We performed deep-coverage whole-genome sequencing of 2081 patients from 4 racial subgroups hospitalized in the United States with early-onset myocardial infarction (age ≤55 years) recruited with a 2:1 female-to-male enrollment design. We compared these genomes with those of 3761 population-based control subjects. 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 because this cutoff has previously been shown to confer similar risk to that of familial hypercholesterolemia mutations.

Results: The mean age of the 2081 patients presenting with early-onset myocardial infarction was 48 years, and 66% were female. A familial hypercholesterolemia mutation was present in 36 of these patients (1.7%) and was associated with a 3.8-fold (95% CI, 2.1-6.8; P<0.001) increased odds of myocardial infarction. Of the patients with early-onset myocardial infarction, 359 (17.3%) 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 low-density lipoprotein 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 ( P for heterogeneity=0.008).

Conclusions: Both familial hypercholesterolemia mutations and high polygenic score are associated with a >3-fold increased odds of early-onset myocardial infarction. However, high polygenic score has a 10-fold higher prevalence among patients presents with early-onset myocardial infarction.

Clinical trial registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT00597922.

Keywords: genetics; humans; hypercholesterolemia; myocardial infarction; risk.

Publication types

  • Clinical Trial
  • Comparative Study
  • Multicenter Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Cholesterol, LDL / genetics
  • Female
  • Genetic Predisposition to Disease*
  • Genome, Human*
  • Humans
  • Hyperlipoproteinemia Type II / blood
  • Hyperlipoproteinemia Type II / genetics*
  • Male
  • Middle Aged
  • Multifactorial Inheritance*
  • Myocardial Infarction / blood
  • Myocardial Infarction / genetics*
  • Whole Genome Sequencing


  • Cholesterol, LDL

Associated data

  • ClinicalTrials.gov/NCT00597922