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Open Access | 
10.1172/JCI195624
Genetic susceptibility to kidney stone disease: unveiling pathogenesis and potential therapeutic targets
Shiwei Li,1 Xuemei Wang,1,2 and Ming Liu1
1Department of Endocrinology and Metabolism, Tianjin Medical University General Hospital, Tianjin, China.
2Department of Endocrinology and Nephrology, Tianjin Ninghe Hospital, Tianjin, China.
Address correspondence to: Ming Liu, Department of Endocrinology and Metabolism, Tianjin Medical University General Hospital, #154 Anshan Road, Heping District, Tianjin, 300052, China. Phone: 86.022.60817182; Email: mingliu@tmu.edu.cn.
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1Department of Endocrinology and Metabolism, Tianjin Medical University General Hospital, Tianjin, China.
2Department of Endocrinology and Nephrology, Tianjin Ninghe Hospital, Tianjin, China.
Address correspondence to: Ming Liu, Department of Endocrinology and Metabolism, Tianjin Medical University General Hospital, #154 Anshan Road, Heping District, Tianjin, 300052, China. Phone: 86.022.60817182; Email: mingliu@tmu.edu.cn.
Find articles by Wang, X. in: PubMed | Google Scholar
1Department of Endocrinology and Metabolism, Tianjin Medical University General Hospital, Tianjin, China.
2Department of Endocrinology and Nephrology, Tianjin Ninghe Hospital, Tianjin, China.
Address correspondence to: Ming Liu, Department of Endocrinology and Metabolism, Tianjin Medical University General Hospital, #154 Anshan Road, Heping District, Tianjin, 300052, China. Phone: 86.022.60817182; Email: mingliu@tmu.edu.cn.
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Published August 1, 2025 - More info
J Clin Invest. 2025;135(15):e195624. https://doi.org/10.1172/JCI195624.
© 2025 Li et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
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Abstract
BACKGROUND Kidney stone disease (KSD) affects approximately 10% of adults, is heritable, and is associated with mineral metabolic abnormalities.METHODS 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.RESULTS 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; P < 5.6 × 10–10). Colocalization analyses defined putative, noncoding KSD-causing variants estimated to account for 11%–19% of KSD cases in proximity to diacylglycerol kinase δ (DGKD), a CaSR signaling partner; solute carrier family 34 member 1 (SLC34A1), a renal sodium-phosphate transporter; and cytochrome P450 family 24 subfamily A member 1 (CYP24A1), which degrades 1,25-dihydroxyvitamin D. Drug target MR indicated that reducing serum calcium by 0.08 mmol/L via CASR, DGKD, or CYP24A1, or increasing serum phosphate by 0.16 mmol/L via SLC34A1 may reduce KSD relative risk by up to 90%. Furthermore, reduced DGKδ expression and KSD-associated DGKD missense variants impaired CaSR signal transduction in vitro, which was ameliorated by cinacalcet, a positive CaSR allosteric modulator.CONCLUSION DGKD-, SLC34A1-, and CYP24A1-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.FUNDING 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-0514–10091); 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’s Trust for Kidney Bladder and Prostate Research.
Authors
Catherine E. Lovegrove, Michelle Goldsworthy, Jeremy Haley, Diane Smelser, Caroline Gorvin, Fadil M. Hannan, Anubha Mahajan, Mohnish Suri, Omid Sadeghi-Alavijeh, Shabbir H. Moochhala, Daniel P. Gale, David Carey, Michael V. Holmes, Dominic Furniss, Rajesh V. Thakker, Sarah A. Howles
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From genetic variants to targeted interventions
Lovegrove and colleagues conducted one of the most comprehensive genetic studies of KSD to date, integrating GWAS data from more than 1.2 million individuals with MR, as well as data from colocalization, drug-target MR, and in vitro functional assays (11). They identified 79 independent risk signals across 71 genomic loci, markedly expanding the known genetic landscape of KSD. A key strength of this work lies in its translational focus. Rather than limiting the analysis to statistical associations, the authors followed a gene-pathway-therapy framework, exemplified by three key candidate genes: DGKD, SLC34A1, and CYP24A1 (Figure 1) (11).
Figure 1Genetic variants in DGKD, SLC34A1, and CYP24A1 and environmental factors contribute to the pathogenesis of KSD. (A) The healthy kidney maintains homeostasis of calcium and phosphate. (B) Several variants independently perturb the calcium-phosphate balance and are associated with increased susceptibility to KSD. The DGKD variant rs838717 impairs CaSR signaling via DGKδ activity, disrupting conversion of DAG to PA, a lipid mediator downstream of MAPK signaling that modulates calcium and phosphate homeostasis. This defective signaling increases calcium reabsorption in the TAL and augments phosphate excretion in the PT. Moreover, rs838717 may contribute to elevated circulating calcium and reduced phosphate levels by directly promoting PTH secretion. Cinacalcet can partially rescue the impaired CaSR signal transduction. The SLC34A1 variant rs10051765 impairs phosphate reabsorption by reducing the activity of sodium-phosphate cotransporter NPT2a in the PT, leading to increased renal phosphate excretion. The CYP24A1 variant rs6127099 decreases 24-hydroxylase activity, resulting in elevated circulating 1,25-dihydroxyvitamin D and increased renal calcium absorption. Environmental and acquired risk factors, including dietary oxalate, sodium, animal protein intake, urinary tract infection, medications, metabolic disorders, and unidentified contributors, interact with genetic susceptibility to promote lithogenesis. MAPK, mitogen-activated protein kinase; PA, phosphatidic acid; PIP2, phosphatidylinositol 4,5-bisphosphate.
DGKD encodes a diacylglycerol (DAG) kinase that modulates CaSR signaling. Functional studies have shown that the KSD-associated variant rs838717 impairs CaSR-mediated activation of MAPK pathways, resulting in decreased phosphate reabsorption in the PT and increased calcium reabsorption in the thick ascending limb (TAL) of the loop of Henle (11, 12). The authors showed this variant may also enhance parathyroid hormone (PTH) secretion, contributing to elevated serum calcium and reduced serum phosphate (11). Through direct effects on TAL calcium transport and indirect effects via PTH-mediated inhibition of proximal phosphate reabsorption, the rs838717 variant may disrupt homeostasis of calcium and phosphate and promote lithogenesis (11). SLC34A1 encodes the sodium-phosphate cotransporter NPT2a, which is essential for phosphate reabsorption in the renal PT. Lovegrove and co-authors found that the variant rs10051765 in SLC34A1 was associated with increased urinary phosphate, potentially leading to calcium phosphate supersaturation and promoting stone formation (11). CYP24A1 encodes the enzyme 24-hydroxylase, which is responsible for metabolizing active vitamin D (1,25-dihydroxyvitamin D). The variant rs6127099 in CYP24A1 was associated with reduced 24-hydroxylase activity, resulting in elevated 1,25-dihydroxyvitamin D3 and subsequently contributing to increasing serum calcium, which occurs in conditions linked to increased KSD (11).
MR and colocalization analyses have been used to infer causal relationships between imbalances in serum minerals and the risk of KSD (13–15). By leveraging independent genetic variants as instrumental variables, Lovegrove et al. present evidence that even modest, genetically mediated changes in serum calcium or phosphate levels can substantially alter the risk of kidney stone formation. Specially, MR analysis suggests that a one SD increase in serum calcium mediated via DGKD variants confers more than a four-fold increase in KSD risk (11). These mechanistic hypotheses are further supported by colocalization and expression quantitative trait locus (eQTL) analyses and are reinforced by MR studies that suggest a causal link between gene expression levels and KSD risk. While these findings require cautious interpretation due to the complexity of calcium homeostasis, they provide a framework for understanding how common genetic variation cumulatively influences disease susceptibility (11).
Notably, the work by Lovegrove et al. parallels and complements a contemporaneous trans-ancestry GWAS by Cao et al., recently published in Nature Communications (16), which aimed to elucidate the genetic architecture of KSD. Methodologically, Cao et al. conducted cross-population GWAS meta-analyses and validated polygenic risk scores (PRSs) across multiple ancestries, improving generalizability but introducing potential limitations related to diagnostic heterogeneity and differences in linkage disequilibrium structure (16). In contrast, Lovegrove et al. focused primarily on European ancestry cohorts, which limits ethnic generalizability but offers greater mechanistic depth through MR, colocalization, and functional validation (11). These two studies considerably expanded the list of KSD-associated loci and identified shared genes, including SLC34A1 and CYP24A1. However, each study also uncovered distinct associations: Lovegrove et al. highlighted variants in DGKD (11), whereas Cao et al. identified novel loci such as TRIOBP by leveraging fine-mapping across European and East Asian populations (16). These complementary approaches underscore the value of integrating population-scale discovery with functional genomics to advance the understanding of KSD.
Beyond mechanistic insights, drug-target MR simulations that modeled the effects of enhancing or inhibiting activity at these risk loci provide a preclinical rationale for therapeutic development. Importantly, these analyses indicate that modulation of serum calcium via CASR, DGKD, or CYP24A1, or increased phosphate reabsorption via SLC34A1, could reduce the risk of KSD by as much as 90% (10). Specifically, cinacalcet, a clinically approved CaSR agonist (17), partially rescued impaired CaSR signaling caused by DGKD variants in genetically susceptible individuals (11). Similarly, targeting the vitamin D pathway, for example, through inhibitors of vitamin D synthesis, may be beneficial in individuals carrying high-risk CYP24A1 variants (10). These scenarios underscore the translational potential of the gene-pathway-therapy paradigm and may promote a shift from conventional management, which has focused largely on symptom control and general lifestyle modifications, to more targeted intervention based on genetic susceptibilities.
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ISSN: 0021-9738 (print), 1558-8238 (online)