Genome-wide polygenic score withAPOL1risk genotypes predicts chronic kidney disease across major continental ancestries

Abstract

Introduction: Chronic kidney disease (CKD) is a common complex condition associated with significant morbidity and mortality in the US and worldwide. Early detection is critical for effective prevention of kidney disease progression. Polygenic prediction of CKD could enhance screening and prevention of kidney disease progression, but this approach has not been optimized for risk prediction in ancestrally diverse populations. Methods: We developed and validated a genome-wide polygenic score (GPS) for CKD defined by estimated glomerular filtration rate (eGFR) <60 mL/min/1.73m2 using common variant association statistics from GWAS for eGFR combined with information on APOL1 risk genotypes. The score was designed to ensure transferability across major continental ancestries, genotyping platforms, imputation panels, and phenotyping strategies, and was tested following ClinGen guidelines. The polygenic component of the score was developed and optimized using 28,047 cases and 251,772 controls (70% of UK Biobank participants of European ancestry), while the weights for APOL1 effects were derived based on UK Biobank participants of African ancestry (967 cases and 6,191 controls). We tested the performance of the score in 15 independent testing cohorts, including 3 cohorts of European ancestry (total 23,364 cases and 117,883 controls), 6 cohorts of African ancestry (4,268 cases and 10,276 controls), 4 cohorts of Asian ancestry (1,030 cases and 9,896 controls), and 2 Hispanic/Latinx cohorts (1,492 cases and 2,984 controls). Results: We demonstrated the risk score transferability with reproducible performance across all independent testing cohorts. In the meta-analyses, disease odds ratios per standard deviation of the score were estimated at 1.49 (95%CI: 1.47-1.50, P<1.0E-300) for European, 1.32 (95%CI: 1.26-1.38, P=1.8E-33) for African, 1.59 (95%CI: 1.52-1.67, P=1.3E-30) for Asian, and 1.42 (95%CI: 1.33-1.51, P=4.1E-14) for Latinx cohorts. The top 2% cutoff of the GPS was associated with nearly 3-fold increased risk of CKD across all major ancestral groups, the degree of risk that is equivalent to a positive family history of kidney disease. In African-ancestry cohorts, APOL1 risk genotype and the polygenic risk components of the GPS had additive effects on the risk of CKD with no significant interactions. We also observed that individuals of African ancestry had a significantly higher polygenic risk score for CKD compared to other populations, even without accounting for APOL1 variants. Conclusions: By combining APOL1 risk genotypes with the available GWAS for renal function, we designed, optimized, and validated a GPS predictive of CKD across four major continental ancestries. With the upper tail of the GPS distribution associated with disease risk equivalent to a positive family history, this score could be used for clinically meaningful risk stratification.

A Polygenic Score for Reduced Kidney Function and Adverse Outcomes in a Chronic Kidney Disease Cohort

“…12 , Khan et al . 13 ) in the general population, little is known about the relationship of an eGFR PGS to adverse outcomes in persons with already diagnosed moderate CKD, a novel aspect addressed in this study. In agreement with our findings, a previous population-based study by Yu et al .…”

“…While various studies focused primarily on the association of an eGFR PGS with clinical outcomes or the prediction of the presence of CKD (e.g. Yun et al 12 , Khan et al 13 ) in the general population, little is known about the relationship of an eGFR PGS to adverse outcomes in persons with already diagnosed moderate CKD, a novel aspect addressed in this study. In agreement with our findings, a previous population-based study by Yu et al 8 reported significant positive association of a similarly developed eGFR PGS with incident CKD and KF.…”

“…The limited use of PGS for risk prediction has been pointed out by Wald et al previously. 15 While several studies concluded that eGFR PGS were suitable for prediction of the presence of CKD 8,13 , they did not evaluate prediction of incident outcomes, although these are two important separate aspects in PGS validity according to Torkamani et al 16 A previous population-based prospective study of incident CKD 8 on the other hand did not report on risk prediction. Thus, evidence around the predictive ability of an eGFR PGS for adverse outcomes among CKD patients is lacking, a knowledge gap filled by our study.…”

“…previously. 15 While several studies concluded that eGFR PGS were suitable for prediction of the presence of CKD 8,13 , they did not evaluate prediction of incident outcomes, although these are two important separate aspects in PGS validity according to Torkamani et al . 16 A previous population-based prospective study of incident CKD 8 on the other hand did not report on risk prediction.…”

APOL1 and APOL1-Associated Kidney Disease: A Common Disease, an Unusual Disease Gene – Proceedings of the Henry Shavelle Professorship

“…Clinical studies aiming to efficiently recruit appropriate subjects naturally focus on Black, African, and African-American populations, as well as other specific populations known to have significant recent west African ancestry. It may prove to be the case that other variants related to ancestry may affect the severity of APOL1-associated kidney disease, but the individual effects of these variants, if they exist, are small [97]. G1 and G2 behave differently from G0 in a variety of model systems that allow APOL1 genotypes to be isolated as the only variable [98].…”