Accuracy of Polygenic Risk Score Tests for Cardiovascular Health
Polygenic risk score (PRS) tests for cardiovascular health have limited accuracy and should be considered screening tools rather than diagnostic tests, with significant limitations in their predictive value for individual patients. 1
Understanding PRS Accuracy for Cardiovascular Disease
Polygenic risk scores aggregate thousands of genetic variants to estimate an individual's genetic predisposition to cardiovascular disease. However, their accuracy has several important limitations:
Probabilistic Nature of Prediction
- PRS provides a risk assessment rather than a binary disease/no-disease prediction 1
- Even in coronary artery disease (CAD), one of the most predictive PRS applications:
- Over 50% of individuals in the highest risk decile (top 10%) never develop CAD
- 16% of individuals in the lowest risk decile still develop CAD 1
- Disease risk varies across the lifespan, with age and environmental factors significantly influencing outcomes beyond genetic factors
Population-Specific Limitations
- Most PRS models are based on genome-wide association studies (GWAS) conducted primarily in European populations 1
- Decreased predictive accuracy occurs when applied to non-European populations due to:
- Differences in linkage disequilibrium patterns
- Variations in allele frequencies
- Demographic and environmental differences 1
- This creates significant health equity concerns and limits clinical utility in diverse populations
Interaction with Other Risk Factors
- PRS accuracy is affected by:
- Environmental interactions
- Presence of single-gene variants with large phenotypic effects
- Genetic admixture
- Age of the individual 1
- A low-risk PRS result may provide false reassurance if monogenic factors are present 1
Current Evidence on PRS Performance
Recent research provides mixed evidence on PRS performance for cardiovascular disease:
- A 2023 scoping review found that PRS performance for coronary artery disease, hypertension, and cerebrovascular disease was similar to or superior to traditional risk factors 2
- A 2024 study showed that adding a CVD-PRS to clinical risk scores (QRISK2) improved identification of individuals who later developed major cardiovascular events by 11.7%, with stronger improvements (47.7%) in younger individuals (40-54 years) 3
- Another 2024 study on peripheral artery disease found that adding PRS to clinical models improved risk reclassification but did not significantly improve the area under the curve (AUC) 4
- However, a 2022 study examining long-term CHD risk found that despite statistically significant associations between PRS and 30-year CHD risk, adding PRS to traditional risk factor models only marginally improved prediction in young adults and showed no improvement in midlife adults 5
Clinical Application Considerations
When considering PRS for cardiovascular health assessment:
- PRS should be viewed as a screening tool, not a diagnostic test 1
- PRS results should be integrated with traditional risk factors for optimal risk assessment
- Isolated PRS testing is inappropriate when monogenic etiology is known or suspected 1
- Currently, there are limited evidence-based guidelines for PRS-based medical management 1
- PRS may be most beneficial when:
Common Pitfalls to Avoid
- Misinterpreting PRS as a definitive predictor of disease development
- Applying PRS derived from one population to individuals from different ancestral backgrounds
- Overlooking monogenic causes of cardiovascular disease by relying solely on PRS
- Failing to consider age, environmental factors, and lifestyle influences alongside genetic risk
- Using PRS results to make clinical decisions without established evidence-based guidelines
PRS testing for cardiovascular health continues to evolve, with improving accuracy as methods develop and more diverse populations are included in reference databases. However, current limitations in accuracy and clinical utility should be carefully considered when interpreting results.