Chunk #24 — Limitations and misunderstandings of clinical, translational, and research applications of PRS — Uneven common variant risk contributions across the phenotypic spectrum
High predicted genetic risk for the same disease across individuals does not necessarily correspond to homogeneously dysregulated biology—instead, disease-relevant pathways may be affected in different ways in individuals with similarly high polygenic risk. Importantly for precision medicine, schizophrenia patients with high common and rare variant risk have inherited different rates of variants in known and predicted gene targets of antipsychotic drugs, likely contributing to the variable treatment responses among patients (63). This and other work highlights the eventual utility of genomic medicine for predicting treatment trajectories (63–66), while cautioning that in the absence of more granular pathway insights, heterogeneous biological perturbations can limit the utility of PRS analyses jointly with other clinical and experimental tools (67). Further, the pervasiveness, ease of use, and potentially unrecognized limitations of PRS warns of issues reminiscent of the candidate gene era, in which well-characterized phenomena are repeatedly studied while unknown biology remains undiscovered (68).
