Nephrolithiasis is a major clinical and economic health burden. We performed a genome-wide association study in British and Japanese nephrolithiasis populations and identified twenty nephrolithiasis-associated loci, five of which (DGKD, DGKH, WDR72, GPIC1 and BCR) were predicted to influence calcium-sensing receptor (CaSR) signalling. Gain-of-function CaSR-signalling pathway mutations cause enhanced signalling via intracellular calcium ([Ca2+]i) and MAPK pathways and result in autosomal dominant hypocalcaemia (ADH), with hypercalciuria, and we hypothesised that these CaSR-related loci may cause enhanced CaSR-signal transduction and an attenuated ADH-phenotype. We have previously reported the DGKD-associated locus to correlate with urinary calcium excretion but not serum calcium concentrations, and we therefore investigated the effects of DGKD knockdown on CaSR-signal transduction in vitro. MAPK responses of HEK-CaSR-SRE and HEK-CaSR cells, treated with scrambled or DGKD targeted siRNA, to alterations in extracellular calcium concentration [Ca2+]e, as assessed by SRE-reporter and ERK-phosphorylation (pERK) assays, respectively, were significantly decreased in DGKD-knockdown cells (DGKD-KD) compared to wildtype (WT) (SRE maximal response DGKD-KD=5.28 fold change, 95% confidence interval (CI)=4.775.79 vs. WT=7.20 fold change, 95% CI=6.46-7.93, P=0.0065, pERK maximal response DGKD-KD=24.77, 95% CI=22.16-27.38 vs. WT= 39.46 fold change, 95% CI=34.07-44.84, P=0.0056). Cinacalcet rectified attenuated SRE responses (DGKD-KD+5nM cinacalcet, maximal response=7.62 fold change, 95% CI=5.989.27). However, [Ca2+]i responses to [Ca2+]e alterations were unaffected when HEK-CaSR-NFAT and HEK-CaSR cells were treated with scrambled or DGKD targeted siRNA and assessed by NFAT-reporter and Fluo-4 calcium assays, respectively. Our results suggest that the DGKD increased-risk allele associates with relatively increased DGKD expression that enhances CaSR-mediated signalling via the MAPK pathway but not [Ca2+]i. This biased signalling may provide an explanation for the correlation of the DGKD-associated locus with urinary calcium excretion but not serum calcium concentration. Our findings suggest that the development of biased calcilytics may provide a therapeutic approach to reduce urinary calcium excretion in hypercalciuric patients.