Insights into Renal Protein Handling Through GWAS of the Human Urine Proteome

The kidneys are an important determinant of circulating protein levels that retain plasma proteins at the glomerular filter and reclaim filtered proteins from urine. While genetic determinants of the circulating proteome have been extensively studied, studies of the urine proteome are lacking. We performed genome-wide association studies (GWAS) of 9 million common genetic variants for each of 2,868 proteins quantified using antibody-based technology from the urine of 1,246 persons. We identified associations between urine protein levels and at least one significant (P<1.7E-11) variant at 174 loci. Index variants were mostly (153/174) located near their encoding cis-gene and enriched for protein-altering variants. Comparative analysis with plasma levels of the respective protein revealed a shared genetic basis at 122 loci, suggesting that their levels in urine provide a readout for systemic processes. Conversely, 38 loci showed urine-specific genetic signals. Variants in CUBN and LRP2, encoding the major receptor complex for tubular protein reabsorption from renal ultrafiltrate, were associated with >20 urine proteins each and shared with urine albumin, a known CUBN ligand. Integration with molecular and clinical data suggested many functional relationships, linking genetically driven changes in urine protein levels to differential gene expression, metabolite levels, and/or risk of disease. For example, genotypes at variants in the PSCA locus were perfectly predicted by urine PSCA levels and associated with PSCA expression and diseases of PSCA-expressing tissues, including bladder cancer and urinary tract infections, demonstrating potential clinical utility of urine protein levels. These findings are accessible through a convenient web application, and establish a comprehensive genetic framework for kidney protein handling to facilitate clinical and experimental investigations.