Genetic Variants Predisposing to Increased Risk of Kidney Stone Disease

Kidney stones (KS) are common, heritable, and associated with mineral metabolism abnormalities. We used Mendelian randomization and colocalization to identify variants predicted to increase KS risk via increased serum calcium or decreased serum phosphate (odds ratios for genomic regions=4.30–13.83 per 1 standard deviation alteration) that account for 11–19% of KS due to reduced calcium–sensing receptor (CaSR)–signal transduction, increased urinary phosphate excretion, and impaired 1,25-dihydroxyvitamin D inactivation via diacylglycerol kinase delta ( DGKD ), solute carrier family 34 member 1 ( SLC34A1 ), and cytochrome P450 family 24 subfamily A member 1 ( CYP24A1 ), respectively. In silico analyses revealed that targeting CASR , DGKD , or CYP24A1 to decrease serum calcium, or SLC34A1 to increase serum phosphate may reduce KS risk, and in vitro studies demonstrated that positive CaSR-allosteric modulation ameliorates CaSR-signal transduction impaired by reduced DGKδ expression or KS-associated DGKD missense variants. These studies suggest that genotyping individuals with KS may facilitate personalized risk stratification and pharmacomodulation.### Competing Interest StatementM.V.H. is an employee of 23andMe, Inc. and holds stock in 23andMe, Inc. RVT has received grants from Novo Nordisk, GSK, NPS Pharma, BMS and Novartis for unrelated projects. D.G. reports fees for consulting and presenting from Novartis, Alexion, Calliditas, Sanofi, Britannia, and Travere This study is partly funded by the National Institute for Health Research (N.I.H.R) Oxford Biomedical Research Centre (NF SI 0514 10091). The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care.### Funding StatementWork was supported by OHSRC (part of Oxford Hispitals Charity) and grants from Kidney Research UK (RP 030 20180306) to S.A.H., M.G., and D.F., The Urology Foundation to S.A.H., and M.G., National Institute for Health Research (N.I.H.R) Oxford Biomedical Research Centre to R.V.T (NF SI 0514 10091), S.A.H, and D.F., and the Wellcome Trust to S.A.H, and M.G. (204826/z/16/z), and R.V.T. (106995/z/15/z). C.E.L. is an M.R.C. Clinical Research Training Fellow (MR/W03168X/1). S.A.H. is a Wellcome Trust Clinical Career Development Fellow. C.M.G is a Sir Henry Dale Fellow jointly funded by the Wellcome Trust and the Royal Society (224155/Z/21/Z). O.S.A. is funded by an MRC Clinical Research Training Fellowship (MR/S021329/1). D.G. is supported by St Peters Trust for Kidney Bladder and Prostate Research.### Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:UK Biobank has approval from the North West Multi Centre Research Ethics Committee (11/NW/0382). Ethical approval for the 100,000 genomes (100KGP) was granted by the Cambridge South Research Ethics Committee for the East of England (REC Ref14/EE/1112). Additional informed consent was obtained from 100KGP participants using protocols approved by Multicenter Research Ethics Committee (MREC/02/2/93). Participants from the DiscovEHR cohort provided written informed consent for participation in the MyCode Community Health Initiative, an institutional review board approved project (Protocol 2006 0258) that allows for genetic analysis and linking to information from the electronic health records. The research included in this publication was reviewed and determined to be exempt by the Geisinger IRB, #2023 1786. All participants gave written informed consent. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.YesAll data produced in the present study are available upon reasonable request to the authors