Clinical utility of polygenic risk scores: a critical 2023 appraisal

Abstract

Since their first appearance in the context of schizophrenia and bipolar disorder in 2009, polygenic risk scores (PRSs) have been described for a large number of common complex diseases. However, the clinical utility of PRSs in disease risk assessment or therapeutic decision making is likely limited because PRSs usually only account for the heritable component of a trait and ignore the etiological role of environment and lifestyle. We surveyed the current state of PRSs for various diseases, including breast cancer, diabetes, prostate cancer, coronary artery disease, and Parkinson disease, with an extra focus upon the potential improvement of clinical scores by their combination with PRSs. We observed that the diagnostic and prognostic performance of PRSs alone is consistently low, as expected. Moreover, combining a PRS with a clinical score at best led to moderate improvement of the power of either risk marker. Despite the large number of PRSs reported in the scientific literature, prospective studies of their clinical utility, particularly of the PRS-associated improvement of standard screening or therapeutic procedures, are still rare. In conclusion, the benefit to individual patients or the health care system in general of PRS-based extensions of existing diagnostic or treatment regimens is still difficult to judge.

Keywords: Clinical score; Diagnostics; Genetic risk; Heritability; Prognostics; Validation.

Fig. 1

Relationship between heritability and PRS diagnostic performance. The violin plot relates disease-specific heritability estimates to the AUC of PRSs (see Table 1). A sex-averaged heritability estimate was considered for coronary artery disease; type 2 diabetes was excluded because of its widely varying heritability estimates. The red line was derived by linear regression analysis. PRS: polygenic risk score, AUC: area under the receiver operating curve

Fig. 2

Improvement of clinical scores for breast cancer by their combination with a PRS. PRS: polygenic risk score, AUC: area under the receiver operating characteristic curve. For details on individual studies, see Supplementary Table S1. BOADICEA + risk factors (Choudhury et al. 2021) was excluded because no AUC was available. The y axis only starts at 0.5 because any smaller AUC would imply that the corresponding score is worse in assigning disease status (affected, not-affected) than flipping a coin

Fig. 3

Improvement of clinical scores, for selected diseases other than breast cancer, by their combination with a PRS. PRS: polygenic risk score, AUC: area under the receiver operating characteristic curve. For details on individual studies, see Supplementary Table S2. The y axis only starts at 0.5 because any smaller AUC would imply that the corresponding score is worse in assigning disease status (affected, not-affected) than flipping a coin