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

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Abstract
Background: Genetic risk scores may be useful for analyzing risks for coronary artery disease (CAD). However, comparisons between restricted and genome‐wide scores have been underexplored, particularly for individuals at increased risk by one score but not the other. Here, we compared restricted polygenic risk scores with 181 high‐confidence genetic variants (PRS 181 ) and genome‐wide risk scores that encompass 6.6 million single‐nucleotide polymorphisms (GRS 6.6M ). Methods: Data were from the RS (Rotterdam Study; n=11 001), MESA (Multi‐Ethnic Study of Atherosclerosis; n=2685), and the Sanford Health study (n=25 166). We analyzed score associations with CAD (prevalent and incident), age at onset, and lipid medication use. Combined use of both scores was also examined. Results: There were robust associations with CAD per SD of the scores for men (PRS 181 : hazard ratio [HR], 1.19 [95% CI, 1.13–1.26]; GRS 6.6M : HR, 1.32 [95% CI, 1.26–1.39]) and women (PRS 181 : HR, 1.24 [95% CI, 1.16–1.32]; GRS 6.6M : HR, 1.32 [95% CI, 1.25–1.40]). PRS 181 was more strongly associated with early‐onset CAD in men (β=−0.93 [95% CI, −1.36 to −0.50]) and women (β=−0.76 [95% CI, −1.31 to −0.21]). Both scores correlated with lipid medication use, but the scores were also associated with CAD among nonusers. Individuals at high risk by both scores had the highest risk and the earliest age at onset. Conclusions: PRS 181 and GRS 6.6M appear to identify different subsets of individuals. Use of both scores together may provide better association information on CAD risk and age at onset than each score alone.

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