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

Significance Statement Genome-wide association studies have uncovered numerous loci influencing kidney function (eGFR), but the relationship of genetic risk to kidney disease incidence or the circulating proteome is unknown. Large genome-wide association samples and recent methods allowed us to calculate a powerful genome-wide polygenic risk score (PRS) incorporating information on 1.5 million single nucleotide polymorphisms. This PRS was significantly associated with risk of CKD, ESKD, kidney failure, and AKI, and with 132 circulating plasma proteins at both midlife and older age. Contemporary kidney function markers, such as eGFR, mediate most of the associations with the plasma proteome. Background 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. Methods 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. Results 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. Conclusions 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.