Genome-Wide Polygenic Score, Clinical Risk Factors, and Long-Term Trajectories of Coronary Artery Disease

Research output: Contribution to journalArticle

Abstract

OBJECTIVE: To determine the relationship of a genome-wide polygenic score for coronary artery disease (GPSCAD) with lifetime trajectories of CAD risk, directly compare its predictive capacity to traditional risk factors, and assess its interplay with the Pooled Cohort Equations (PCE) clinical risk estimator. Approach and Results: We studied GPSCAD in 28 556 middle-aged participants of the Malmö Diet and Cancer Study, of whom 4122 (14.4%) developed CAD over a median follow-up of 21.3 years. A pronounced gradient in lifetime risk of CAD was observed-16% for those in the lowest GPSCAD decile to 48% in the highest. We evaluated the discriminative capacity of the GPSCAD-as assessed by change in the C-statistic from a baseline model including age and sex-among 5685 individuals with PCE risk estimates available. The increment for the GPSCAD (+0.045, P<0.001) was higher than for any of 11 traditional risk factors (range +0.007 to +0.032). Minimal correlation was observed between GPSCAD and 10-year risk defined by the PCE (r=0.03), and addition of GPSCAD improved the C-statistic of the PCE model by 0.026. A significant gradient in lifetime risk was observed for the GPSCAD, even among individuals within a given PCE clinical risk stratum. We replicated key findings-noting strikingly consistent results-in 325 003 participants of the UK Biobank. CONCLUSIONS: GPSCAD-a risk estimator available from birth-stratifies individuals into varying trajectories of clinical risk for CAD. Implementation of GPSCAD may enable identification of high-risk individuals early in life, decades in advance of manifest risk factors or disease.

Details

Authors
Organisations
External organisations
  • Broad Institute
  • Qatar University
  • Massachusetts General Hospital
  • Harvard University
  • IBM Research Cambridge
  • Regeneron Pharmaceuticals, Inc.
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Cardiac and Cardiovascular Systems

Keywords

  • coronary artery disease, disease, genome, risk factors, statistics
Original languageEnglish
Pages (from-to)2738-2746
Number of pages9
JournalArteriosclerosis, Thrombosis, and Vascular Biology
Volume40
Issue number11
Publication statusPublished - 2020
Publication categoryResearch
Peer-reviewedYes