Polygenic Risk Scores for Kidney Function and Their Associations with Circulating Proteome, and Incident Kidney Diseases

Genome-wide association studies (GWAS) have revealed numerous loci for kidney function (eGFR). The relationship between polygenic predictors of eGFR, risk of incident adverse kidney outcomes, and the plasma proteome is not known. We developed a genome-wide polygenic risk score (PRS) for eGFR by applying the LDpred algorithm to summary statistics generated from a multiethnic meta-analysis of CKDGen Consortium GWAS ( n =765,348) and UK Biobank GWAS (90% of the cohort; n =451,508), followed by best-parameter selection using the remaining 10% of UK Biobank data ( n =45,158). We then tested the association of the PRS in the Atherosclerosis Risk in Communities (ARIC) study ( n =8866) with incident CKD, ESKD, kidney failure, and AKI. We also examined associations between the PRS and 4877 plasma proteins measured at middle age and older adulthood and evaluated mediation of PRS associations by eGFR. The developed PRS showed a significant association with all outcomes. Hazard ratios per 1 SD lower PRS ranged from 1.06 (95% CI, 1.01 to 1.11) to 1.33 (95% CI, 1.28 to 1.37). The PRS was significantly associated with 132 proteins at both time points. The strongest associations were with cystatin C, collagen α -1(XV) chain, and desmocollin-2. Most proteins were higher at lower kidney function, except for five proteins, including testican-2. Most correlations of the genetic PRS with proteins were mediated by eGFR. A PRS for eGFR is now sufficiently strong to capture risk for a spectrum of incident kidney diseases and broadly influences the plasma proteome, primarily mediated by eGFR.