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Clinical Research and Public HealthIn-Press PreviewEndocrinologyGeneticsNephrology Open Access | 10.1172/JCI186915

Genetic variants predisposing to increased risk of kidney stone disease

Catherine E. Lovegrove,1 Michelle Goldsworthy,1 Jeremy Haley,2 Diane Smelser,2 Caroline Gorvin,3 Fadil M. Hannan,4 Anubha Mahajan,5 Mohnish Suri,6 Omid Sadeghi-Alavijeh,7 Shabbir H. Moochhala,7 Daniel P. Gale,7 David Carey,2 Michael V. Holmes,8 Dominic Furniss,9 Rajesh V. Thakker,10 and Sarah A. Howles1

1Nuffield Department of Surgical Sciences, University of Oxford, Oxford, United Kingdom

2Department of Genomic Health, Geisinger Medical Center, Danville, United States of America

3Institute of Metabolism and Systems Research and Centre of Membrane Protein, University of Birmingham, Birmingham, United Kingdom

4Nuffield Department of Women’s and Reproductive Health, University of Oxford, Oxford, United Kingdom

5Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom

6Nottingham University Hospitals NHS Trust, Nottingham, United Kingdom

7UCL Department of Renal Medicine, University College London, London, United Kingdom

8Medical Research Council, Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom

9Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Scien, University of Oxford, Oxford, United Kingdom

10Academic Endocrine Unit, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom

Find articles by Lovegrove, C. in: PubMed | Google Scholar

1Nuffield Department of Surgical Sciences, University of Oxford, Oxford, United Kingdom

2Department of Genomic Health, Geisinger Medical Center, Danville, United States of America

3Institute of Metabolism and Systems Research and Centre of Membrane Protein, University of Birmingham, Birmingham, United Kingdom

4Nuffield Department of Women’s and Reproductive Health, University of Oxford, Oxford, United Kingdom

5Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom

6Nottingham University Hospitals NHS Trust, Nottingham, United Kingdom

7UCL Department of Renal Medicine, University College London, London, United Kingdom

8Medical Research Council, Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom

9Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Scien, University of Oxford, Oxford, United Kingdom

10Academic Endocrine Unit, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom

Find articles by Goldsworthy, M. in: PubMed | Google Scholar

1Nuffield Department of Surgical Sciences, University of Oxford, Oxford, United Kingdom

2Department of Genomic Health, Geisinger Medical Center, Danville, United States of America

3Institute of Metabolism and Systems Research and Centre of Membrane Protein, University of Birmingham, Birmingham, United Kingdom

4Nuffield Department of Women’s and Reproductive Health, University of Oxford, Oxford, United Kingdom

5Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom

6Nottingham University Hospitals NHS Trust, Nottingham, United Kingdom

7UCL Department of Renal Medicine, University College London, London, United Kingdom

8Medical Research Council, Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom

9Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Scien, University of Oxford, Oxford, United Kingdom

10Academic Endocrine Unit, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom

Find articles by Haley, J. in: PubMed | Google Scholar

1Nuffield Department of Surgical Sciences, University of Oxford, Oxford, United Kingdom

2Department of Genomic Health, Geisinger Medical Center, Danville, United States of America

3Institute of Metabolism and Systems Research and Centre of Membrane Protein, University of Birmingham, Birmingham, United Kingdom

4Nuffield Department of Women’s and Reproductive Health, University of Oxford, Oxford, United Kingdom

5Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom

6Nottingham University Hospitals NHS Trust, Nottingham, United Kingdom

7UCL Department of Renal Medicine, University College London, London, United Kingdom

8Medical Research Council, Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom

9Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Scien, University of Oxford, Oxford, United Kingdom

10Academic Endocrine Unit, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom

Find articles by Smelser, D. in: PubMed | Google Scholar

1Nuffield Department of Surgical Sciences, University of Oxford, Oxford, United Kingdom

2Department of Genomic Health, Geisinger Medical Center, Danville, United States of America

3Institute of Metabolism and Systems Research and Centre of Membrane Protein, University of Birmingham, Birmingham, United Kingdom

4Nuffield Department of Women’s and Reproductive Health, University of Oxford, Oxford, United Kingdom

5Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom

6Nottingham University Hospitals NHS Trust, Nottingham, United Kingdom

7UCL Department of Renal Medicine, University College London, London, United Kingdom

8Medical Research Council, Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom

9Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Scien, University of Oxford, Oxford, United Kingdom

10Academic Endocrine Unit, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom

Find articles by Gorvin, C. in: PubMed | Google Scholar |

1Nuffield Department of Surgical Sciences, University of Oxford, Oxford, United Kingdom

2Department of Genomic Health, Geisinger Medical Center, Danville, United States of America

3Institute of Metabolism and Systems Research and Centre of Membrane Protein, University of Birmingham, Birmingham, United Kingdom

4Nuffield Department of Women’s and Reproductive Health, University of Oxford, Oxford, United Kingdom

5Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom

6Nottingham University Hospitals NHS Trust, Nottingham, United Kingdom

7UCL Department of Renal Medicine, University College London, London, United Kingdom

8Medical Research Council, Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom

9Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Scien, University of Oxford, Oxford, United Kingdom

10Academic Endocrine Unit, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom

Find articles by Hannan, F. in: PubMed | Google Scholar

1Nuffield Department of Surgical Sciences, University of Oxford, Oxford, United Kingdom

2Department of Genomic Health, Geisinger Medical Center, Danville, United States of America

3Institute of Metabolism and Systems Research and Centre of Membrane Protein, University of Birmingham, Birmingham, United Kingdom

4Nuffield Department of Women’s and Reproductive Health, University of Oxford, Oxford, United Kingdom

5Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom

6Nottingham University Hospitals NHS Trust, Nottingham, United Kingdom

7UCL Department of Renal Medicine, University College London, London, United Kingdom

8Medical Research Council, Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom

9Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Scien, University of Oxford, Oxford, United Kingdom

10Academic Endocrine Unit, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom

Find articles by Mahajan, A. in: PubMed | Google Scholar

1Nuffield Department of Surgical Sciences, University of Oxford, Oxford, United Kingdom

2Department of Genomic Health, Geisinger Medical Center, Danville, United States of America

3Institute of Metabolism and Systems Research and Centre of Membrane Protein, University of Birmingham, Birmingham, United Kingdom

4Nuffield Department of Women’s and Reproductive Health, University of Oxford, Oxford, United Kingdom

5Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom

6Nottingham University Hospitals NHS Trust, Nottingham, United Kingdom

7UCL Department of Renal Medicine, University College London, London, United Kingdom

8Medical Research Council, Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom

9Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Scien, University of Oxford, Oxford, United Kingdom

10Academic Endocrine Unit, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom

Find articles by Suri, M. in: PubMed | Google Scholar

1Nuffield Department of Surgical Sciences, University of Oxford, Oxford, United Kingdom

2Department of Genomic Health, Geisinger Medical Center, Danville, United States of America

3Institute of Metabolism and Systems Research and Centre of Membrane Protein, University of Birmingham, Birmingham, United Kingdom

4Nuffield Department of Women’s and Reproductive Health, University of Oxford, Oxford, United Kingdom

5Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom

6Nottingham University Hospitals NHS Trust, Nottingham, United Kingdom

7UCL Department of Renal Medicine, University College London, London, United Kingdom

8Medical Research Council, Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom

9Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Scien, University of Oxford, Oxford, United Kingdom

10Academic Endocrine Unit, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom

Find articles by Sadeghi-Alavijeh, O. in: PubMed | Google Scholar

1Nuffield Department of Surgical Sciences, University of Oxford, Oxford, United Kingdom

2Department of Genomic Health, Geisinger Medical Center, Danville, United States of America

3Institute of Metabolism and Systems Research and Centre of Membrane Protein, University of Birmingham, Birmingham, United Kingdom

4Nuffield Department of Women’s and Reproductive Health, University of Oxford, Oxford, United Kingdom

5Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom

6Nottingham University Hospitals NHS Trust, Nottingham, United Kingdom

7UCL Department of Renal Medicine, University College London, London, United Kingdom

8Medical Research Council, Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom

9Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Scien, University of Oxford, Oxford, United Kingdom

10Academic Endocrine Unit, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom

Find articles by Moochhala, S. in: PubMed | Google Scholar

1Nuffield Department of Surgical Sciences, University of Oxford, Oxford, United Kingdom

2Department of Genomic Health, Geisinger Medical Center, Danville, United States of America

3Institute of Metabolism and Systems Research and Centre of Membrane Protein, University of Birmingham, Birmingham, United Kingdom

4Nuffield Department of Women’s and Reproductive Health, University of Oxford, Oxford, United Kingdom

5Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom

6Nottingham University Hospitals NHS Trust, Nottingham, United Kingdom

7UCL Department of Renal Medicine, University College London, London, United Kingdom

8Medical Research Council, Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom

9Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Scien, University of Oxford, Oxford, United Kingdom

10Academic Endocrine Unit, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom

Find articles by Gale, D. in: PubMed | Google Scholar |

1Nuffield Department of Surgical Sciences, University of Oxford, Oxford, United Kingdom

2Department of Genomic Health, Geisinger Medical Center, Danville, United States of America

3Institute of Metabolism and Systems Research and Centre of Membrane Protein, University of Birmingham, Birmingham, United Kingdom

4Nuffield Department of Women’s and Reproductive Health, University of Oxford, Oxford, United Kingdom

5Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom

6Nottingham University Hospitals NHS Trust, Nottingham, United Kingdom

7UCL Department of Renal Medicine, University College London, London, United Kingdom

8Medical Research Council, Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom

9Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Scien, University of Oxford, Oxford, United Kingdom

10Academic Endocrine Unit, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom

Find articles by Carey, D. in: PubMed | Google Scholar

1Nuffield Department of Surgical Sciences, University of Oxford, Oxford, United Kingdom

2Department of Genomic Health, Geisinger Medical Center, Danville, United States of America

3Institute of Metabolism and Systems Research and Centre of Membrane Protein, University of Birmingham, Birmingham, United Kingdom

4Nuffield Department of Women’s and Reproductive Health, University of Oxford, Oxford, United Kingdom

5Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom

6Nottingham University Hospitals NHS Trust, Nottingham, United Kingdom

7UCL Department of Renal Medicine, University College London, London, United Kingdom

8Medical Research Council, Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom

9Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Scien, University of Oxford, Oxford, United Kingdom

10Academic Endocrine Unit, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom

Find articles by Holmes, M. in: PubMed | Google Scholar |

1Nuffield Department of Surgical Sciences, University of Oxford, Oxford, United Kingdom

2Department of Genomic Health, Geisinger Medical Center, Danville, United States of America

3Institute of Metabolism and Systems Research and Centre of Membrane Protein, University of Birmingham, Birmingham, United Kingdom

4Nuffield Department of Women’s and Reproductive Health, University of Oxford, Oxford, United Kingdom

5Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom

6Nottingham University Hospitals NHS Trust, Nottingham, United Kingdom

7UCL Department of Renal Medicine, University College London, London, United Kingdom

8Medical Research Council, Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom

9Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Scien, University of Oxford, Oxford, United Kingdom

10Academic Endocrine Unit, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom

Find articles by Furniss, D. in: PubMed | Google Scholar

1Nuffield Department of Surgical Sciences, University of Oxford, Oxford, United Kingdom

2Department of Genomic Health, Geisinger Medical Center, Danville, United States of America

3Institute of Metabolism and Systems Research and Centre of Membrane Protein, University of Birmingham, Birmingham, United Kingdom

4Nuffield Department of Women’s and Reproductive Health, University of Oxford, Oxford, United Kingdom

5Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom

6Nottingham University Hospitals NHS Trust, Nottingham, United Kingdom

7UCL Department of Renal Medicine, University College London, London, United Kingdom

8Medical Research Council, Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom

9Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Scien, University of Oxford, Oxford, United Kingdom

10Academic Endocrine Unit, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom

Find articles by Thakker, R. in: PubMed | Google Scholar |

1Nuffield Department of Surgical Sciences, University of Oxford, Oxford, United Kingdom

2Department of Genomic Health, Geisinger Medical Center, Danville, United States of America

3Institute of Metabolism and Systems Research and Centre of Membrane Protein, University of Birmingham, Birmingham, United Kingdom

4Nuffield Department of Women’s and Reproductive Health, University of Oxford, Oxford, United Kingdom

5Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom

6Nottingham University Hospitals NHS Trust, Nottingham, United Kingdom

7UCL Department of Renal Medicine, University College London, London, United Kingdom

8Medical Research Council, Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom

9Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Scien, University of Oxford, Oxford, United Kingdom

10Academic Endocrine Unit, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom

Find articles by Howles, S. in: PubMed | Google Scholar

Published May 15, 2025 - More info

J Clin Invest. https://doi.org/10.1172/JCI186915.
Copyright © 2025, Lovegrove 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/.
Published May 15, 2025 - Version history
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Abstract

BACKGROUND. Kidney stone disease (KSD) affects ~10% of adults, is heritable, and associated with mineral metabolic abnormalities.

METHODS. Genetic variants and pathways increasing KSD risk via calcium and phosphate homeostasis were ascertained using genome-wide association analyses, region-specific Mendelian randomization (MR), and genetic colocalization. Utility of pathway modulation was estimated via drug-target MR, and effects of variants on calcium-sensing receptor (CaSR)-signaling characterized.

RESULTS. Seventy-nine independent KSD-associated genetic signals at 71 loci were identified. MR identified three loci affecting KSD risk via increased serum calcium or decreased serum phosphate concentrations (odds ratios for genomic regions=4.30, 11.42, and 13.83 per 1 standard deviation alteration; p<5.6x10-10). Colocalization analyses defined putative, non-coding KSD-causing variants estimated to account for 11-19% of KSD cases in proximity to diacylglycerol kinase delta (DGKD), a CaSR-signalling 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 0.08mmol/L via CASR, DGKD, or CYP24A1, or increasing serum phosphate by 0.16mmol/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 personalised KSD-risk stratification and targeted pharmacomodulation of associated pathways to prevent KSD.

Graphical Abstract
graphical abstract
Supplemental material

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View calcium and phosphate GWAS variants

View Results of serum calcium Mendelian randomization and colocalisation analyses with kdiney stone disease

View Results of serum phosphate Mendelian randomization and colocalisation analyses with kdiney stone disease

View PHEWAS from Open Gene Targets

Version history
  • Version 1 (May 15, 2025): In-Press Preview
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