Polygenic risk scores for cardiovascular risk prediction: moving towards implementation into clinical practice?

SCORE2 10-year absolute risk of (fatal and non-fatal) cardiovascular events in populations at low CVD risk (top). The example illustrates clinical risk by SCORE2 in a 56-year-old woman (left) and man (right) with similar clinical risk factors. The clinical risk is 5% in the woman and 9% in the man (i.e. both are at intermediate risk). Both are also at high genetic risk corresponding to the upper 10(th) percentile of the polygenic risk score distribution, equating to a polygenic risk score factor (=odds ratio for CVD) of 1.72. The total risk score is clinical risk by SCORE2 multiplied by the polygenic risk score factor (bottom). For the woman the total score is 9%, remaining at intermediate cardiovascular risk, whereas the total score for the man is 16%, reclassifying him to high cardiovascular risk. Thus men are more likely than women to be reclassified to higher risk when including a polygenic risk score, most probably due to the underestimation of absolute risk in young individuals and women by SCORE2. This may limit this model from fully capturing the lifelong genetic exposure to increased cardiovascular risk in these subgroups. CVD, cardiovascular disease; PRS, polygenic risk score.