Kidney stone disease (nephrolithiasis) is a major clinical and economic health burden 1,2 with a heritability of ~45-60% 3 . To identify genetic variants associated with nephrolithiasis we performed genome-wide association studies (GWAS) and meta-analysis in British and Japanese populations, including 12,123 nephrolithiasis cases and 416,928 controls. Twenty loci associated with nephrolithiasis were identified, ten of which are novel. A novel 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 nephrolithiasis patients the CYP24A1 -associated locus correlated with serum calcium concentration and number of kidney stone episodes, and the DGKD -associated locus correlated with urinary calcium excretion. Moreover, DGKD knockdown impaired CaSR-signal transduction in vitro , an effect that was rectifiable with the calcimimetic cinacalcet. Our findings indicate that genotyping may 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.