• PRS does not substitute for family history in clinical assessment. Family history is an informative marker of genetic risk and a key piece of information guiding clinical diagnosis and management. However, it is very non-specific, in terms of both individual-level risk prediction as well as disease specificity, particularly in the presence of heterotypic continuity, or variable clinical presentations at different ages across the life span 35. A predictor based on measured genotypes such as PRS should provide important information additional to family history 36, as it has for some non-psychiatric conditions 37, 38. However, some families with multiple affected members (and arguably a high genetic load toward illness) may have a low PRS 6 – in this instance, disease is likely caused by other variants not measured in the PRS, such as rare pathogenic variants or structural variants, including copy number variants or cytogenetic rearrangements.
