Chronic kidney disease (CKD) is a common complex condition associated with high morbidity and mortality. Polygenic prediction could enhance CKD screening and prevention; however, this approach has not been optimized for ancestrally diverse populations. By combining APOL1 risk genotypes with genome-wide association studies (GWAS) of kidney function, we designed, optimized and validated a genome-wide polygenic score (GPS) for CKD. The new GPS was tested in 15 independent cohorts, including 3 cohorts of European ancestry (n = 97,050), 6 cohorts of African ancestry (n = 14,544), 4 cohorts of Asian ancestry (n = 8,625) and 2 admixed Latinx cohorts (n = 3,625). We demonstrated score transferability with reproducible performance across all tested cohorts. The top 2% of the GPS was associated with nearly threefold increased risk of CKD across ancestries. In African ancestry cohorts, the APOL1 risk genotype and polygenic component of the GPS had additive effects on the risk of CKD.
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The final formulation of the GPS for CKD along with the standardized metrics of performance have been deposited in the PGS catalog at https://www.pgscatalog.org/publication/PGP000269/. The UKBB genotype and phenotype data are available through the UKBB web portal at https://www.ukbiobank.ac.uk/. The eMERGE-III imputed genotype and phenotype data are available through the database of Genotypes and Phenotypes (dbGAP) under accession no. phs001584.v2.p2. The BioMe genotype datasets used in this study were generated by Regeneron and are not publicly available. However, the data will be made available for the purposes of replicating the results by contacting the corresponding author and through appropriate collaboration and/or data sharing agreements. The WPC and REGARDS imputed genotype and phenotype data are available through dbGAP under accession nos. phs000708.v1.p1 and phs002719.v1.p1, respectively. The GenHAT cohort is also available on dbGAP under accession no. phs002716.v1.p1. The HyperGEN cohort has been sequenced by the TOPMed consortium; WGS data along with phenotype data are available through dbGAP under accession no. phs001293.v3.p1. Minimum testing datasets with the GPS, CKD outcome, and a set of essential clinical covariates for each cohort are also available when consistent with the consent given by the participants and can be requested directly from the corresponding author with a 2–4-week response time frame. Because these datasets contain clinical data, access to them may require a data use agreement.
The CKD phenotype software is available from the Phenotype Knowledge Database at https://phekb.org/phenotype/chronic-kidney-disease. The CKD GPS score equation is available through the PGS catalog at https://www.pgscatalog.org/publication/PGP000269/ and through our laboratory website at http://www.columbiamedicine.org/divisions/kiryluk/study_GPS_CKD.php.
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This work was funded by the National Human Genome Research Institute eMERGE-IV grant nos. 2U01HG008680-05, 1U01HG011167-01 and 1U01HG011176-01. Additional sources of funding included grant nos. UG3DK114926 (K.K.), RC2DK116690 (K.K.), R01LM013061 (C.W., K.K.), K25DK128563 (A.K.), UL1TR001873 (A.K., K.K.), R01HL151855 (J.B.M.) and UM1DK078616 (J.B.M.). The parent REGARDS study was supported by cooperative agreement no. U01NS041588 cofunded by the National Institute of Neurological Disorders and Stroke and the National Institute on Aging, the National Institutes of Health (NIH) and the Department of Health and Human Services. The HyperGEN (R01HL055673), GenHAT (R01HL123782) and WPC (R01HL092173, K24HL133373) studies were all supported by the NHLBI. Parts of this study were conducted using the UKBB resource under UKBB project no. 41849. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.
The authors declare no competing interests.
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Extended Data Fig. 1 Distribution of risk allele frequencies (RAF) and their effect sizes for the variants included in the GPS.
Distribution of risk allele frequencies (RAF) and their effect sizes for the variants included in the GPS (a) comparison of RAF distributions for the risk variants included in the CKD GPS demonstrates higher frequency of rare (RAF < 0.01) and common (RAF > 0.99) risk alleles in African compared to European genomes (based on 1000 G reference populations); this may be explained by the exclusion of variants with MAF < 0.01 in European discovery GWAS; (b) highly skewed effect size (weight) distribution for the variants included in the GPS for CKD; (c) Distribution of RAF difference (AFR-EUR) demonstrating higher average frequency of risk alleles in African genomes (mean RAF difference = 0.002) and a slight rightward shift of the RAF difference distribution from the expected mean of 0; (d) Mean RAF difference (AFR-EUR) as a function of effect size binned into three categories (high, intermediate, and low) based on the observed distribution of effects sizes in panel b, demonstrating that the risk alleles with larger effect size have higher average frequency in African compared to European genomes. EUR: European (N = 503) and AFR: African (N = 661). The bars represent 95% confidence intervals around the mean RAF difference estimate for each bin; two-sided P-values were calculated using t-test.
Extended Data Fig. 2 Risk score distributions in eMERGE-III (N = 22,453) and UKBB (N = 77,584) validation datasets.
Risk score distributions in eMERGE-III (N = 22,453) and UKBB (N = 77,584) validation datasets: (a) the distribution of raw polygenic score without APOL1 in UKBB by ancestry; (b) the distribution of ancestry-adjusted polygenic score (method 1: mean-adjusted) in UKBB by ancestry; (c) the distribution of ancestry-adjusted polygenic score (method 2: mean and variance-adjusted) in UKBB by ancestry. Panels (d), (e) and (f) show the same analyses for the eMERGE-III dataset, respectively.
Extended Data Fig. 3 Final GPS calibration analysis in eMERGE-III cohorts combined (N = 22,453).
Final GPS calibration analysis in eMERGE-III cohorts combined (N = 22,453): predicted risk (X-axis) as a function of the observed risk (Y-axis) in the multiethnic eMERGE-III dataset after ancestry adjustment with (a) method 1 and (b) method 2. The bars represent 95% confidence intervals.
Extended Data Fig. 4 Distributions of the raw (non-standardized) genome-wide polygenic score (GPS) by Yu et al. in the eMERGE-III validation datasets by ancestry.
Distributions of the raw (non-standardized) genome-wide polygenic score (GPS) by Yu et al. in the eMERGE-III validation datasets by ancestry.
Extended Data Fig. 5 PCA projections of the study participants from the UKBB (top) and eMERGE-III (bottom) against the 1000 G reference populations.
PCA projections of the study participants from the UKBB (top) and eMERGE-III (bottom) against the 1000 G reference populations: (a) UKBB (N = 77,584) and (b) eMERGE-III (N = 22,453) participants plotted against the reference 1000 G populations (N = 2,504); (b, e) plotted by self-reported race/ethnicity; and (c, f) plotted by final ancestry group assignment. X-axis: PC1; Y-axis: PC2; AFR: African; AMR: Admixed American; EAS: East Asian; EUR: European; and SAS: South Asian.
Supplementary Tables 1–11.
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Khan, A., Turchin, M.C., Patki, A. et al. Genome-wide polygenic score to predict chronic kidney disease across ancestries. Nat Med 28, 1412–1420 (2022). https://doi.org/10.1038/s41591-022-01869-1
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