Restricted Versus Genome-Wide Genetic Risk Scores for Coronary Artery Disease

Area of Science:

• Cardiovascular Genetics
• Genomic Epidemiology
• Biostatistics

Background:

• Genetic risk scores (GRS) are emerging tools for coronary artery disease (CAD) risk assessment.
• Limited research exists on comparing restricted (PRS₁₈₁) versus genome-wide (GRS_6.6M) scores, especially for discordant risk profiles.

Purpose of the Study:

• To compare the performance of PRS₁₈₁ and GRS_6.6M in identifying CAD risk.
• To evaluate the combined utility of both scores for predicting CAD prevalence, incidence, age at onset, and medication use.

Main Methods:

• Utilized data from three large cohorts: Rotterdam Study (n=11,001), MESA (n=2,685), and Sanford Health (n=25,166).
• Analyzed associations between PRS₁₈₁, GRS_6.6M, and CAD outcomes, including prevalent/incident CAD, age of onset, and lipid medication use.
• Investigated the incremental value of using both PRS₁₈₁ and GRS_6.6M concurrently.

Main Results:

• Both PRS₁₈₁ and GRS_6.6M showed robust associations with CAD risk in men and women.
• PRS₁₈₁ demonstrated a stronger association with early-onset CAD in both sexes.
• Individuals identified as high risk by both scores exhibited the highest CAD risk and earliest age at onset.

Conclusions:

• PRS₁₈₁ and GRS_6.6M identify distinct subsets of individuals at risk for CAD.
• The combined application of PRS₁₈₁ and GRS_6.6M may enhance the prediction of CAD risk and age at onset compared to using individual scores.