Single-Ancestry versus Multi-Ancestry Polygenic Risk Scores for CKD in Black American Populations

Abstract

Key Points The predictive performance of an African ancestry–specific polygenic risk score (PRS) was comparable to a European ancestry–derived PRS for kidney traits.However, multi-ancestry PRSs outperform single-ancestry PRSs in Black American populations.Predictive accuracy of PRSs for CKD was improved with the use of race-free eGFR. Background CKD is a risk factor of cardiovascular disease and early death. Recently, polygenic risk scores (PRSs) have been developed to quantify risk for CKD. However, African ancestry populations are underrepresented in both CKD genetic studies and PRS development overall. Moreover, European ancestry–derived PRSs demonstrate diminished predictive performance in African ancestry populations. Methods This study aimed to develop a PRS for CKD in Black American populations. We obtained score weights from a meta-analysis of genome-wide association studies for eGFR in the Million Veteran Program and Reasons for Geographic and Racial Differences in Stroke Study to develop an eGFR PRS. We optimized the PRS risk model in a cohort of participants from the Hypertension Genetic Epidemiology Network. Validation was performed in subsets of Black participants of the Trans-Omics in Precision Medicine Consortium and Genetics of Hypertension Associated Treatment Study. Results The prevalence of CKD—defined as stage 3 or higher—was associated with the PRS as a continuous predictor (odds ratio [95% confidence interval]: 1.35 [1.08 to 1.68]) and in a threshold-dependent manner. Furthermore, including APOL1 risk status—a putative variant for CKD with higher prevalence among those of sub-Saharan African descent—improved the score's accuracy. PRS associations were robust to sensitivity analyses accounting for traditional CKD risk factors, as well as CKD classification based on prior eGFR equations. Compared with previously published PRS, the predictive performance of our PRS was comparable with a European ancestry–derived PRS for kidney traits. However, single-ancestry PRSs were less predictive than multi-ancestry–derived PRSs. Conclusions In this study, we developed a PRS that was significantly associated with CKD with improved predictive accuracy when including APOL1 risk status. However, PRS generated from multi-ancestry populations outperformed single-ancestry PRS in our study.