Pitfalls of predicting age-related traits by polygenic risk scores

Polygenic risk scores (PRS) are a method increasingly used to capture the combined effect of genome-wide significant variants and those which individually do not show genome-wide significant association but are likely to contribute to the risk of developing diseases. However, their practical use incurs complications and inconsistencies that so far limit their clinical applicability. The aims of the present review are to discuss the PRS for age-related diseases and to highlight pitfalls and limitations of PRS prediction accuracy due to ageing and mortality effects. We argue that the PRS is widely used but the individual's PRS values differ substantially depending on the number of genetic variants included, the discovery GWAS and the method employed to generate them. Moreover, for neurodegenerative disorders, although an individual's genetics do not change with age, the actual score depends on the age of the sample used in the discovery GWAS and is likely to reflect the individual's disease risk at this particular age. Improvement of PRS prediction accuracy for neurodegenerative disorders will come from two sides, both the precision of clinical diagnoses, and a careful attention to the age distribution in the underlying samples and validation of the prediction in longitudinal studies.