Assessing agreement between different polygenic risk scores in the UK Biobank

Abstract

1.Polygenic risk scores (PRS) are proposed to be used in clinical and research settings for risk stratification. However, there are limited investigations on how different PRS diverge from each other for risk prediction of individuals. We compared two recently published PRS for each of three conditions, breast cancer, hypertension and dementia, to assess the stability of running these algorithms for risk prediction in a single large population. We used imputed genotyping data from the UK Biobank (UKB) prospective cohort, limited to the White British subset. We found that: O_LIOnly 65%-79% of SNPs in the first PRS were represented in the more recent PRS for all three diseases, after having taken linkage disequilibrium (LD) into account (R2 >0.8). C_LIO_LIAlthough the difference in the area under the received operator curve (AUC) obtained using the two PRS is hardly appreciable for all three diseases, there were large differences in individual risk prediction between the two PRS. C_LI We found substantial discordance between different PRS for the same disease, indicating that individuals could receive different medical advice depending on which PRS is used to assess their genetic susceptibility. It is desirable to resolve this uncertainty before using PRS for risk stratification in clinical settings.