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Original Investigation
February 18, 2020

Predictive Accuracy of a Polygenic Risk Score Compared With a Clinical Risk Score for Incident Coronary Heart Disease

Author Affiliations
  • 1Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee
  • 2Department of Biomedical Informatics, Vanderbilt University, Nashville, Tennessee
  • 3Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Department of Pediatrics, Torrance, California
  • 4Department of Pharmacology, Vanderbilt University, Nashville, Tennessee
  • 5Vanderbilt O'Brien Center for Kidney Disease, Vanderbilt University Medical Center, Nashville, Tennessee
  • 6Departments of Medicine, Epidemiology and Health Services, University of Washington School of Public Health; and Kaiser Permanente Washington Health Research Institute, Seattle, Washington
  • 7Department of Public Health Sciences, Center for Public Health Genomics, Charlottesville, Virginia
  • 8Department of Medicine, Johns Hopkins University, Baltimore, Maryland
  • 9Department of Epidemiology, Johns Hopkins University, Baltimore, Maryland
  • 10Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Department of Medicine, Torrance, California12
  • 11Beth Israel Deaconess Medical Center, Division of Cardiovascular Medicine, Boston, Massachusetts
  • 12Department of Internal Medicine, University of Texas Southwestern Medical Center
JAMA. 2020;323(7):627-635. doi:10.1001/jama.2019.21782
Key Points

Question  Does a polygenic predictor of coronary heart disease (CHD) that incorporates millions of common single-nucleotide polymorphisms (SNPs) improve risk stratification compared with a guideline-based risk equation?

Findings  In a retrospective cohort study that included 7237 middle-aged participants of European ancestry free of clinical CHD at baseline, a polygenic risk score added to the 2013 American College of Cardiology and American Heart Association pooled cohort equations did not significantly improve discriminative accuracy (measured by C statistic), calibration (comparing observed vs expected event probabilities), or net reclassification improvement (using a 10-year risk threshold of 7.5%).

Meaning  Addition of a polygenic risk score to a clinical risk score for incident CHD may not provide important information in a white middle-aged population.


Importance  Polygenic risk scores comprising millions of single-nucleotide polymorphisms (SNPs) could be useful for population-wide coronary heart disease (CHD) screening.

Objective  To determine whether a polygenic risk score improves prediction of CHD compared with a guideline-recommended clinical risk equation.

Design, Setting, and Participants  A retrospective cohort study of the predictive accuracy of a previously validated polygenic risk score was assessed among 4847 adults of white European ancestry, aged 45 through 79 years, participating in the Atherosclerosis Risk in Communities (ARIC) study and 2390 participating in the Multi-Ethnic Study of Atherosclerosis (MESA) from 1996 through December 31, 2015, the final day of follow-up. The performance of the polygenic risk score was compared with that of the 2013 American College of Cardiology and American Heart Association pooled cohort equations.

Exposures  Genetic risk was computed for each participant by summing the product of the weights and allele dosage across 6 630 149 SNPs. Weights were based on an international genome-wide association study.

Main Outcomes and Measures  Prediction of 10-year first CHD events (including myocardial infarctions, fatal coronary events, silent infarctions, revascularization procedures, or resuscitated cardiac arrest) assessed using measures of model discrimination, calibration, and net reclassification improvement (NRI).

Results  The study population included 4847 adults from the ARIC study (mean [SD] age, 62.9 [5.6] years; 56.4% women) and 2390 adults from the MESA cohort (mean [SD] age, 61.8 [9.6] years; 52.2% women). Incident CHD events occurred in 696 participants (14.4%) and 227 participants (9.5%), respectively, over median follow-up of 15.5 years (interquartile range [IQR], 6.3 years) and 14.2 (IQR, 2.5 years) years. The polygenic risk score was significantly associated with 10-year CHD incidence in ARIC with hazard ratios per SD increment of 1.24 (95% CI, 1.15 to 1.34) and in MESA, 1.38 (95% CI, 1.21 to 1.58). Addition of the polygenic risk score to the pooled cohort equations did not significantly increase the C statistic in either cohort (ARIC, change in C statistic, −0.001; 95% CI, −0.009 to 0.006; MESA, 0.021; 95% CI, −0.0004 to 0.043). At the 10-year risk threshold of 7.5%, the addition of the polygenic risk score to the pooled cohort equations did not provide significant improvement in reclassification in either ARIC (NRI, 0.018, 95% CI, −0.012 to 0.036) or MESA (NRI, 0.001, 95% CI, −0.038 to 0.076). The polygenic risk score did not significantly improve calibration in either cohort.

Conclusions and Relevance  In this analysis of 2 cohorts of US adults, the polygenic risk score was associated with incident coronary heart disease events but did not significantly improve discrimination, calibration, or risk reclassification compared with conventional predictors. These findings suggest that a polygenic risk score may not enhance risk prediction in a general, white middle-aged population.