Evaluation of genetic associations with clinical phenotypes of kidney stone disease.

Introduction and Objective:We sought to replicate and discover genetic associations of kidney stone disease within a large-scale electronic health record (EHR) system. Methods:We performed genome-wide association studies (GWASs) for nephrolithiasis from genotyped samples of 5,571 cases and 83,692 controls. Among the significant risk variants, we performed association analyses of stone composition and first-time 24-hour urine parameters. To assess disease severity, we investigated the associations of risk variants with age at first stone diagnosis, age at first procedure, and time from first to second procedure. Results:The main GWAS analysis identified 10 significant loci, each located on chromosome 16 within coding regions of the UMOD gene, which codes for uromodulin, a urine protein with inhibitory activity for calcium crystallization. The strongest signal was from SNP 16:20359633-C-T (odds ratio [OR] 1.17, 95% CI 1.11-1.23), with the remaining significant SNPs having similar effect sizes. In subgroup GWASs by stone composition, 19 significant loci were identified, of which two loci were located in coding regions (brushite; NXPH1 , rs79970906 and rs4725104). The UMOD SNP 16:20359633-C-T was associated with differences in 24-hour excretion of urinary calcium, uric acid, phosphorus, sulfate; and the minor allele was positively associated with calcium oxalate dihydrate stone composition (p<0.05). No associations were found between UMOD variants and disease severity. Conclusions:We replicated germline variants associated with kidney stone disease risk at UMOD and reported novel variants associated with stone composition. Genetic variants of UMOD are associated with differences in 24-hour urine parameters and stone composition, but not disease severity.