BACKGROUND AND AIMSWe tested the association of polygenic risk scores (PRS) for low-density lipoprotein cholesterol (LDL-C) and coronary artery disease (CAD) with LDL-C and risk of ischemic heart disease (IHD) in the Danish general population. METHODSWe included a total of 21,485 individuals from the Copenhagen General Population Study and Copenhagen City Heart Study. For everyone, an LDL-PRS and CAD-PRS was calculated, each based on >400,000 variants. We also genotyped four rare variants in LDLR or APOB known to cause familial hypercholesterolemia (FH). RESULTSHeterozygous carriers of FH-causing variants in APOB or LDLR had a mean LDL-C of 5.40 and 6.09 mmol/L, respectively, and an odds ratio for IHD of 2.27 (95% CI 1.43-3.51) when compared to non-carriers. The LDL-PRS explained 13.8% of the total variation in LDL-C in the cohort. Individuals in the lowest and highest 1% of the LDL-PRS had a mean LDL-C of 2.49 and 4.75 mmol/L, respectively. Compared to those in the middle 20-80%, those in the lowest and highest 1% of the LDL-PRS had odds ratios for IHD of 0.58 (95% CI, 0.38-0.88) and 1.83 (95% CI, 1.33-2.53). The corresponding odds ratios for the CAD-PRS were 0.61 (95% CI, 0.41-0.92) and 2.06 (95% CI, 1.49-2.85). CONCLUSIONSThe top 1% of the LDL-PRS and CAD-PRS conferred effects on LDL-C and risk of IHD that were comparable to those seen for carriers of rare FH-causing variants in APOB or LDLR. These results highlight the potential value of implementing such PRS clinically.