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Development and Validation of a Clinical Polygenic Risk Report in U.S.-Based Health Systems for 8 Cardiovascular

Anika Misra1, Amanda Jowell2, Sara Haidermota1

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This summary is machine-generated.

Integrated polygenic risk scores (PRS) effectively stratify inherited cardiovascular risk for 8 conditions. These scores are now clinically available, offering a new tool for personalized risk assessment and management.

Keywords:
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Area of Science:

  • Genetics and Genomics
  • Cardiovascular Medicine
  • Personalized Medicine

Background:

  • Polygenic risk scores (PRS) are crucial for stratifying inherited cardiovascular disease risk.
  • Clinical implementation pathways for PRS require further development and validation.

Purpose of the Study:

  • To develop and validate integrated PRS for 8 distinct cardiovascular conditions.
  • To establish a framework for the clinical reporting of integrated PRS.

Main Methods:

  • Utilized genotype and clinical data from 245,394 participants in the All of Us Research Program.
  • Combined publicly available PRS for 8 cardiovascular traits using the PRSmix elastic-net approach.
  • Externally validated integrated PRS in 53,306 Mass General Brigham Biobank participants.

Main Results:

  • Integrated PRS demonstrated robust discrimination and calibration across 8 cardiovascular traits in external validation.
  • High genetic risk (top 10-20% PRS) showed significantly elevated odds ratios for all 8 conditions compared to average risk.
  • Incorporating integrated PRS improved risk classification in clinical models and associated with incident cardiovascular outcomes.

Conclusions:

  • Integrated PRS provide an implementable framework for genetic risk reporting and are now a clinically orderable test.
  • Further prospective validation studies are recommended to fully establish the clinical utility of integrated PRS.