Ancestry Calibration of Polygenic Risk Scores Improves Risk Stratification and Effect Estimation in African American Adults

Polygenic risk score (PRS) distributions vary across populations, complicating PRS risk assessment. We evaluated the impact of post-hoc PRS calibration according to individualized genetic ancestry estimates on PRS performance using two large multi-ethnic PRS for type 2 diabetes (T2D) (PRS _T2D ) and height (PRS _height ), in 8,841 African American (AA) individuals from the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study. We calibrated each participant’s score as a function of estimated genetic similarity to the Yoruba (GSYRI) cohort in the 1000 Genomes Project. Uncalibrated PRSs were significantly skewed by GSYRI. After calibration, 33.6% of individuals in the top decile of PRS _T2D were reclassified and performance in the top PRS _T2D decile improved from an OR of 7.97 [6.31–10.13] to 10.77 [8.41– 13.91] when compared to the lowest decile. Similarly, 55.0% of individuals in the top PRS _height decile were reclassified with GSYRI calibration. The calibrated PRS _height showed higher correlation with height (from 0.24 to 0.32, p <10 ⁻⁷ ), and increased mean height in the top PRS _height decile ( p =5.7×10 ⁻⁵ ) when compared to the uncalibrated PRS _height . Lastly, we show that evaluating uncalibrated PRS while adjusting for GSYRI in regression models can lead to inflated and unstable effect size estimates for both the PRS and GSYRI.