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Kidney stone disease (nephrolithiasis) is a major clinical and economic health burden with a heritability of ~45–60%. We present genome-wide association studies in British and Japanese populations and a trans-ethnic meta-analysis that include 12,123 cases and 417,378 controls, and identify 20 nephrolithiasis-associated loci, seven of which are previously unreported. A CYP24A1 locus is predicted to affect vitamin D metabolism and five loci, DGKD, DGKH, WDR72, GPIC1, and BCR, are predicted to influence calcium-sensing receptor (CaSR) signaling. In a validation cohort of only nephrolithiasis patients, the CYP24A1-associated locus correlates with serum calcium concentration and a number of nephrolithiasis episodes while the DGKD-associated locus correlates with urinary calcium excretion. In vitro, DGKD knockdown impairs CaSR-signal transduction, an effect rectified with the calcimimetic cinacalcet. Our findings indicate that studies of genotype-guided precision-medicine approaches, including withholding vitamin D supplementation and targeting vitamin D activation or CaSR-signaling pathways in patients with recurrent kidney stones, are warranted., Kidney stones form in the presence of overabundance of crystal-forming substances such as Ca2+ and oxalate. Here, the authors report genome-wide association analyses for kidney stone disease, report seven previously unknown loci and find that some of these loci also associate with Ca2+ concentration and excretion.

BACKGROUND Kidney stone disease (nephrolithiasis) is a major clinical and economic health burden with a multifactorial etiology and heritability of ~45-60%. To identify common genetic variants associated with nephrolithiasis we performed genome-wide association studies (GWAS) and meta-analysis in British and Japanese populations. METHODS GWAS and trans-ethnic meta-analysis of 12,123 kidney stone cases and 416,928 controls was performed. Genotype-phenotype correlations were established in a validation cohort of kidney stone patients. Biological pathways were studied in vitro in HEK293 cells. RESULTS Twenty loci associated with nephrolithiasis were identified, ten of which are novel. One such locus is associated with CYP24A1 and is predicted to affect vitamin D metabolism. Five loci, DGKD, DGKH, WDR72, GPIC1, and BCR, are predicted to influence calcium-sensing receptor (CaSR) signaling. The CYP24A1-associated locus, correlated with serum calcium concentration and number of kidney stone episodes in a validation cohort of nephrolithiasis patients. In addition, the DGKD-associated locus correlated with urinary calcium excretion in the validation cohort. Moreover, DGKD knockdown was shown to impair CaSR-signal transduction in vitro, an effect that was rectified by the calcimimetic cinacalcet, thereby supporting the role of DGKD in CaSR signaling. CONCLUSIONS Our study identified ten novel loci associated with kidney stone disease; six loci are predicted to influence calcium-sensing receptor and vitamin D metabolism pathways. These findings indicate that genotyping may help to inform risk of incident kidney stone disease prior to vitamin D supplementation and facilitate precision-medicine approaches, by targeting CaSR signaling or vitamin D activation pathways in patients with recurrent kidney stones.