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.
Nature communications. 2019 Nov 15*** epublish ***
Sarah A Howles, Akira Wiberg, Michelle Goldsworthy, Asha L Bayliss, Anna K Gluck, Michael Ng, Emily Grout, Chizu Tanikawa, Yoichiro Kamatani, Chikashi Terao, Atsushi Takahashi, Michiaki Kubo, Koichi Matsuda, Rajesh V Thakker, Benjamin W Turney, Dominic Furniss
Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK. ., Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK., Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK., Academic Endocrine Unit, Radcliffe Department of Medicine, University of Oxford, Oxford, UK., Laboratory of Genome Technology, Human Genome Centre, University of Tokyo, Tokyo, Japan., RIKEN Centre for Integrative Medical Sciences, Yokohama, Kanagawa, Japan., Laboratory of Clinical Genome Sequencing, Department of Computational Biology and Medical Sciences, University of Tokyo, Tokyo, Japan.