{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T18:21:24Z","timestamp":1790878884978,"version":"4.1.0"},"reference-count":86,"publisher":"American Society for Clinical Investigation","issue":"15","license":[{"start":{"date-parts":[[2025,8,1]],"date-time":"2025-08-01T00:00:00Z","timestamp":1754006400000},"content-version":"vor","delay-in-days":78,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"OHSRC","award":["NA"],"award-info":[{"award-number":["NA"]}]},{"DOI":"10.13039\/501100000291","name":"Kidney Research UK","doi-asserted-by":"crossref","award":["(RP_030_20180306)"],"award-info":[{"award-number":["(RP_030_20180306)"]}],"id":[{"id":"10.13039\/501100000291","id-type":"DOI","asserted-by":"crossref"}]},{"name":"The Urology Foundation","award":["NA"],"award-info":[{"award-number":["NA"]}]},{"name":"National Institute for Health Research (N.I.H.R) Oxford Biomedical Research Centre","award":["NF-SI-0514\u201310091"],"award-info":[{"award-number":["NF-SI-0514\u201310091"]}]},{"DOI":"10.13039\/100010269","name":"Wellcome Trust","doi-asserted-by":"crossref","award":["204826\/z\/16\/z,106995\/z\/15\/z"],"award-info":[{"award-number":["204826\/z\/16\/z,106995\/z\/15\/z"]}],"id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Medical Research Council","award":["MR\/W03168X\/1,MR\/S021329\/1"],"award-info":[{"award-number":["MR\/W03168X\/1,MR\/S021329\/1"]}]},{"DOI":"10.13039\/501100000388","name":"St Peter\u2019s Trust for Kidney Bladder and Prostate Research","doi-asserted-by":"crossref","award":["NA"],"award-info":[{"award-number":["NA"]}],"id":[{"id":"10.13039\/501100000388","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Wellcome Trust and the Royal Society","award":["224155\/Z\/21\/Z"],"award-info":[{"award-number":["224155\/Z\/21\/Z"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,8,1]]},"abstract":"<jats:sec>\n                    <jats:title>BACKGROUND<\/jats:title>\n                    <jats:p>Kidney stone disease (KSD) affects approximately 10% of adults, is heritable, and is associated with mineral metabolic abnormalities.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS<\/jats:title>\n                    <jats:p>Genetic variants and pathways increasing KSD risk via calcium and phosphate homeostasis were ascertained using GWAS, region-specific Mendelian randomization (MR), and genetic colocalization. The utility of pathway modulation was estimated via drug target MR, and the effects of variants on calcium-sensing receptor (CaSR) signaling were characterized.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS<\/jats:title>\n                    <jats:p>\n                      Seventy-nine independent KSD-associated genetic signals at 71 loci were identified. MR identified 3 loci affecting KSD risk via increased serum calcium or decreased serum phosphate concentrations (ORs for genomic regions = 4.30, 11.42, and 13.83 per 1 SD alteration;\n                      <jats:italic>P<\/jats:italic>\n                      &lt; 5.6 \u00d7 10\n                      <jats:sup>\u201310<\/jats:sup>\n                      ). Colocalization analyses defined putative, noncoding KSD-causing variants estimated to account for 11%\u201319% of KSD cases in proximity to diacylglycerol kinase \u03b4 (\n                      <jats:italic>DGKD<\/jats:italic>\n                      ), a CaSR signaling partner; solute carrier family 34 member 1 (\n                      <jats:italic>SLC34A1<\/jats:italic>\n                      ), a renal sodium-phosphate transporter; and cytochrome P450 family 24 subfamily A member 1 (\n                      <jats:italic>CYP24A1<\/jats:italic>\n                      )\n                      <jats:italic>,<\/jats:italic>\n                      which degrades 1,25-dihydroxyvitamin D. Drug target MR indicated that reducing serum calcium by 0.08 mmol\/L via\n                      <jats:italic>CASR<\/jats:italic>\n                      ,\n                      <jats:italic>DGKD<\/jats:italic>\n                      , or\n                      <jats:italic>CYP24A1<\/jats:italic>\n                      , or increasing serum phosphate by 0.16 mmol\/L via\n                      <jats:italic>SLC34A1<\/jats:italic>\n                      may reduce KSD relative risk by up to 90%. Furthermore, reduced DGK\u03b4 expression and KSD-associated\n                      <jats:italic>DGKD<\/jats:italic>\n                      missense variants impaired CaSR signal transduction in vitro, which was ameliorated by cinacalcet, a positive CaSR allosteric modulator.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSION<\/jats:title>\n                    <jats:p>\n                      <jats:italic>DGKD<\/jats:italic>\n                      -,\n                      <jats:italic>SLC34A1<\/jats:italic>\n                      -, and\n                      <jats:italic>CYP24A1<\/jats:italic>\n                      -associated variants linked to reduced CaSR signal transduction, increased urinary phosphate excretion, and impaired 1,25-dihydroxyvitamin D inactivation, respectively, are common causes of KSD. Genotyping patients with KSD may facilitate personalized KSD risk stratification and targeted pharmacomodulation of associated pathways to prevent KSD.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>FUNDING<\/jats:title>\n                    <jats:p>Oxfordshire Health Services Research Committee (OHSRC, part of Oxford Hospitals Charity); Kidney Research UK (RP_030_20180306); The Urology Foundation; National Institute for Health Research (NIHR) Oxford Biomedical Research Centre (NF-SI-0514\u201310091); Wellcome Trust (204826\/z\/16\/z and 106995\/z\/15\/z); Medical Research Council (MRC) Clinical Research Training Fellowships (MR\/W03168X\/1 and MR\/S021329\/1); Wellcome Trust Clinical Career Development Fellowship; Sir Henry Dale Fellowship, with joint funding by the Wellcome Trust and the Royal Society (224155\/Z\/21\/Z); St. Peter\u2019s Trust for Kidney Bladder and Prostate Research.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1172\/jci186915","type":"journal-article","created":{"date-parts":[[2025,5,15]],"date-time":"2025-05-15T12:00:32Z","timestamp":1747310432000},"source":"Crossref","is-referenced-by-count":17,"title":["Genetic variants predisposing to an increased risk of kidney stone disease"],"prefix":"10.1172","volume":"135","author":[{"given":"Catherine E.","family":"Lovegrove","sequence":"first","affiliation":[{"name":"Nuffield Department of Surgical Sciences, University of Oxford, Oxford, United Kingdom."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michelle","family":"Goldsworthy","sequence":"additional","affiliation":[{"name":"Nuffield Department of Surgical Sciences, University of Oxford, Oxford, United Kingdom."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeremy","family":"Haley","sequence":"additional","affiliation":[{"name":"Department of Genomic Health, Geisinger Medical Center, Danville, Pennsylvania, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diane","family":"Smelser","sequence":"additional","affiliation":[{"name":"Department of Genomic Health, Geisinger Medical Center, Danville, Pennsylvania, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1361-9174","authenticated-orcid":true,"given":"Caroline","family":"Gorvin","sequence":"additional","affiliation":[{"name":"Institute of Metabolism and Systems Research and Centre of Membrane Proteins and Receptors (COMPARE), University of Birmingham, Birmingham, United Kingdom."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fadil M.","family":"Hannan","sequence":"additional","affiliation":[{"name":"Nuffield Department of Surgical Sciences, University of Oxford, Oxford, United Kingdom."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anubha","family":"Mahajan","sequence":"additional","affiliation":[{"name":"Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohnish","family":"Suri","sequence":"additional","affiliation":[{"name":"Nottingham University Hospitals NHS Trust, Nottingham, United Kingdom, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Omid","family":"Sadeghi-Alavijeh","sequence":"additional","affiliation":[{"name":"UCL Department of Renal Medicine, University College London, London, United Kindom."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shabbir H.","family":"Moochhala","sequence":"additional","affiliation":[{"name":"UCL Department of Renal Medicine, University College London, London, United Kindom."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9170-1579","authenticated-orcid":true,"given":"Daniel P.","family":"Gale","sequence":"additional","affiliation":[{"name":"UCL Department of Renal Medicine, University College London, London, United Kindom."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Carey","sequence":"additional","affiliation":[{"name":"Department of Genomic Health, Geisinger Medical Center, Danville, Pennsylvania, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6617-0879","authenticated-orcid":true,"given":"Michael V.","family":"Holmes","sequence":"additional","affiliation":[{"name":"Medical Research Council, Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dominic","family":"Furniss","sequence":"additional","affiliation":[{"name":"Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, United Kingdom."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1438-3220","authenticated-orcid":true,"given":"Rajesh V.","family":"Thakker","sequence":"additional","affiliation":[{"name":"Academic Endocrine Unit, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom."},{"name":"National Institute for Health Research Oxford Biomedical Research Centre, Oxford, United Kingdom."},{"name":"Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine, Queen Mary University of London, London, United Kingdom."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah A.","family":"Howles","sequence":"additional","affiliation":[{"name":"Nuffield Department of Surgical Sciences, University of Oxford, Oxford, United Kingdom."},{"name":"National Institute for Health Research Oxford Biomedical Research Centre, Oxford, United Kingdom."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"232","published-online":{"date-parts":[[2025,5,15]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/j.euf.2020.08.011"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ekir.2018.11.017"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1016\/j.nephro.2020.02.003"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2016050576"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1038\/nrneph.2011.211"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1007\/s40620-016-0329-y"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.0000000000000238"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-022-05473-8"},{"key":"B9","doi-asserted-by":"crossref","unstructured":"Lovegrove C, et al. Data accompanying \u201cGenetic variants predisposing to increased risk of kidney stone disease.\u201dhttps:\/\/portal.sds.ox.ac.uk\/articles\/dataset\/Data_accompanying_b_Genetic_variants_predisposing_to_increased_risk_of_kidney_stone_disease_b_\/26968825\/2 Updated February 2, 2025. Accessed May 15, 2025","DOI":"10.1172\/JCI186915"},{"key":"B10","unstructured":"Hannan F, Mahajan A. Summary statistics for mineral metabolism GWAS. https:\/\/portal.sds.ox.ac.uk\/articles\/dataset\/Summary_statistics_for_mineral_metabolism_GWAS\/23735709 Updated August 8, 2023. Accessed May 15, 2025"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1004383"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1002\/sim.7221"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2016010069"},{"key":"B14","unstructured":"R: A language and environment for statistical computing. Version 4.5.0. R Foundation for Statistical Computing; 2025. https:\/\/www.R-project.org\/"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2014101025"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1007\/s13353-017-0397-2"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-13145-x"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(93)90617-Y"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199610103351505"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms8975"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1103864"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1021\/bi101261x"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1016\/j.str.2007.12.017"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(95)90219-8"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M115.648717"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1016\/j.chembiol.2017.06.007"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1111\/bju.15250"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1007\/s00223-015-0052-z"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2796.2006.01684.x"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1007\/s00467-010-1547-5"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2010-1306"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1210\/jc.85.5.2042"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2265.1996.750891.x"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1093\/ndt\/gfu065"},{"key":"B35","unstructured":"Reddy M, et al. Renal calculi as a presenting feature in a patient with familial hypocalciuric hypercalcaemia (FHH). Paper presented at: Society for Endocrinology BES 2012; March 19\u201322, 2012; Harrowgate, United Kingdom. https:\/\/www.endocrine-abstracts.org\/ea\/0028\/ea0028p80 Accessed May 15, 2025"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-12399-9"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1016\/j.mayocpiqo.2019.08.007"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2265.2011.04059.x"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1172\/JCI17038"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1042\/EBC20200041"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1016\/j.kint.2023.06.019"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1038\/ki.2008.320"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1016\/j.ekir.2024.08.013"},{"issue":"1 pt 2","key":"B44","first-page":"186","article-title":"Localization of parathyroid hormone\/parathyroid hormone-related peptide receptor mRNA in kidney","volume":"270","author":"Lee","year":"1996","journal-title":"Am J Physiol"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pmed.1001779"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-018-0144-6"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-018-0579-z"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.21105\/joss.00731"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3406"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3211"},{"key":"B51","unstructured":"Wellcome Sanger Institute. HapMap 3. https:\/\/www.sanger.ac.uk\/resources\/downloads\/human\/hapmap3.html Accessed July 5, 2023"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1038\/nature15393"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.1038\/ng.2213"},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2010.11.011"},{"key":"B55"},{"key":"B56","unstructured":"FinnGen. FinnGen: Documentation of R12 release. https:\/\/finngen.gitbook.io\/documentation\/ Updated December 2024. Accessed September 26, 2024"},{"key":"B57","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btq340"},{"key":"B58","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pcbi.1004219"},{"key":"B59","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0506580102"},{"key":"B60","doi-asserted-by":"publisher","DOI":"10.1016\/j.cels.2015.12.004"},{"key":"B61","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btr260"},{"key":"B62","doi-asserted-by":"publisher","DOI":"10.1007\/s11154-020-09613-1"},{"key":"B63","doi-asserted-by":"publisher","DOI":"10.1210\/endrev\/bnad009"},{"key":"B64","doi-asserted-by":"publisher","DOI":"10.1007\/s10654-018-0424-6"},{"key":"B65","doi-asserted-by":"publisher","DOI":"10.1002\/gepi.22506"},{"key":"B66","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1007081"},{"key":"B67","doi-asserted-by":"publisher","DOI":"10.1093\/ije\/dyt179"},{"key":"B68","doi-asserted-by":"publisher","DOI":"10.1002\/gepi.21998"},{"key":"B69","unstructured":"Bias and Type 1 error rate for Mendelian randomization with sample overlap. https:\/\/sb452.shinyapps.io\/overlap\/ Accessed May 2, 2025"},{"key":"B70","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-021-00945-5"},{"key":"B71","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkaa840"},{"key":"B72","doi-asserted-by":"publisher","DOI":"10.1126\/science.aaf6814"},{"key":"B73","unstructured":"National Heart, Lung, and Blood Institute. TOPMed Imputation Server. https:\/\/imputation.biodatacatalyst.nhlbi.nih.gov\/ Accessed May 2, 2025"},{"key":"B74","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2018.03.012"},{"key":"B75","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2014.10.005"},{"key":"B76","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1300253"},{"key":"B77","doi-asserted-by":"publisher","DOI":"10.1038\/ng.2492"},{"key":"B78","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkab1061"},{"key":"B79","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-021-03819-2"},{"key":"B80","unstructured":"The PyMOL Molecular Graphics System. Version 1.8. Schr\u00f6dinger; 2015. https:\/\/www.pymol.org\/"},{"key":"B81","unstructured":"The AxPyMOL Molecular Graphics Plugin for Microsoft PowerPoint. Version 2.5.2. Schrodinger; 2015. https:\/\/www.pymol.org\/ax.html?"},{"key":"B82","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btaa849"},{"key":"B83","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2105-13-S4-S2"},{"key":"B84","doi-asserted-by":"publisher","DOI":"10.1038\/ng.610"},{"key":"B85","doi-asserted-by":"publisher","DOI":"10.1093\/ije\/dyq151"},{"key":"B86","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkac993"}],"container-title":["Journal of Clinical Investigation"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.jci.org\/articles\/view\/186915\/files\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T17:15:41Z","timestamp":1779210941000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.jci.org\/articles\/view\/186915"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,5,15]]},"references-count":86,"journal-issue":{"issue":"15","published-online":{"date-parts":[[2025,6,12]]},"published-print":{"date-parts":[[2025,8,1]]}},"alternative-id":["10.1172\/JCI186915"],"URL":"https:\/\/doi.org\/10.1172\/jci186915","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2024.06.07.24308490","asserted-by":"object"}]},"ISSN":["1558-8238"],"issn-type":[{"value":"1558-8238","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,5,15]]},"article-number":"e186915"}}