Genome-Wide Association Study of Plasma Sodium Concentrations with and without Exposure to Thiazide Diuretics

Niklas Worm Andersson^{1

2}, Xiaoping Wu^{1

2}, Frank Geller^{1

2}, Jan Wohlfahrt³, Mads Melbye^{4

5

6}, Anders Hviid^{1

7}, Michael Schwinn², Christina Mikkelsen², Joseph Dowsett², Mie Topholm Bruun^{8

9}, Bitten Aagaard¹⁰, Henrik Ullum¹¹, Christian Erikstrup^{12

13}, Daniel Fannar Gudbjartsson¹⁴, Kári Stefánsson¹⁴, Jonas Ghouse^{12

15

16}, Ole Birger Pedersen^{17

18}, Erik Sørensen², Sisse Rye Ostrowski^{2

17}, Henning Bundgaard^{17

19}, Marie Lund^{1

17

20}, Bjarke Feenstra^{1

2

21}; DBDS Genomic Consortium

Collaborators, Affiliations

Collaborators

DBDS Genomic Consortium:
Karina Banasik, Jakob Bay, Jens Kjærgaard Boldsen, Thorsten Brodersen, Søren Brunak, Alfonso Buil Demur, Lea Arregui Nordahl Christoffersen, Maria Didriksen, Khoa Manh Dinh, Joseph Dowsett, Christian Erikstrup, Bjarke Feenstra, Frank Geller, Daniel Gudbjartsson, Thomas Folkmann Hansen, Dorte Helenius Mikkelsen, Lotte Hindhede, Henrik Hjalgrim, Jakob Hjorth von Stemann, Bitten Aagaard Jensen, Andrew Joseph Schork, Kathrine Kaspersen, Bertram Dalskov Kjerulff, Mette Kongstad, Susan Mikkelsen, Christina Mikkelsen, Janna Nissen, Mette Nyegaard, Sisse Rye Ostrowski, Ole Birger Pedersen, Liam James Elgaard Quinn, Þórunn Rafnar, Palle Duun Rohde, Klaus Rostgaard, Michael Schwinn, Erik Sørensen, Kari Stefansson, Hreinn Stefánsson, Lise Wegner Thørner, Unnur Þorsteinsdóttir, Mie Topholm Bruun, Henrik Ullum, Thomas Werge, David Westergaard

Affiliations

¹ Department of Epidemiology Research, Statens Serums Institut, Copenhagen, Denmark.
² Department of Clinical Immunology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
³ Cancer Epidemiology and Surveillance, Danish Cancer Institute, Copenhagen, Denmark.
⁴ Danish Cancer Institute, Copenhagen, Denmark.
⁵ Department of Pediatrics, Stanford University School of Medicine, Stanford, California.
⁶ HUNT Center for Clinical and Molecular Epidemiology, Norwegian University of Science and Technology, Trondheim, Norway.
⁷ Pharmacovigilance Research Center, Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
⁸ Clinical Immunology Research Unit, Department of Clinical Immunology, Odense University Hospital, Odense, Denmark.
⁹ Department of Clinical Research, University of Southern Denmark, Odense, Denmark.
¹⁰ Department of Clinical Immunology, Aalborg University Hospital, Aalborg, Denmark.
¹¹ Statens Serum Institut, Copenhagen, Denmark.
¹² Department of Clinical Immunology, Aarhus University Hospital, Aarhus, Denmark.
¹³ Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.
¹⁴ deCODE Genetics, Reykjavik, Iceland.
¹⁵ Laboratory for Molecular Cardiology, Department of Cardiology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
¹⁶ Laboratory for Molecular Cardiology, Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark.
¹⁷ Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
¹⁸ Department of Clinical Immunology, Zealand University Hospital, Køge, Denmark.
¹⁹ Department of Cardiology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
²⁰ Department of Clinical Pharmacology, Copenhagen University Hospital - Bispebjerg and Frederiksberg, Copenhagen, Denmark.
²¹ Department of Biology, University of Copenhagen, Copenhagen, Denmark.

PMID: 39888683
PMCID: PMC12147972 (available on 2026-06-01)
DOI: 10.1681/ASN.0000000622

Genome-Wide Association Study of Plasma Sodium Concentrations with and without Exposure to Thiazide Diuretics

Niklas Worm Andersson et al. J Am Soc Nephrol. 2025.

. 2025 Jun 1;36(6):1014-1027.

doi: 10.1681/ASN.0000000622. Epub 2025 Jan 31.

Authors

Collaborators

DBDS Genomic Consortium:
Karina Banasik, Jakob Bay, Jens Kjærgaard Boldsen, Thorsten Brodersen, Søren Brunak, Alfonso Buil Demur, Lea Arregui Nordahl Christoffersen, Maria Didriksen, Khoa Manh Dinh, Joseph Dowsett, Christian Erikstrup, Bjarke Feenstra, Frank Geller, Daniel Gudbjartsson, Thomas Folkmann Hansen, Dorte Helenius Mikkelsen, Lotte Hindhede, Henrik Hjalgrim, Jakob Hjorth von Stemann, Bitten Aagaard Jensen, Andrew Joseph Schork, Kathrine Kaspersen, Bertram Dalskov Kjerulff, Mette Kongstad, Susan Mikkelsen, Christina Mikkelsen, Janna Nissen, Mette Nyegaard, Sisse Rye Ostrowski, Ole Birger Pedersen, Liam James Elgaard Quinn, Þórunn Rafnar, Palle Duun Rohde, Klaus Rostgaard, Michael Schwinn, Erik Sørensen, Kari Stefansson, Hreinn Stefánsson, Lise Wegner Thørner, Unnur Þorsteinsdóttir, Mie Topholm Bruun, Henrik Ullum, Thomas Werge, David Westergaard

Affiliations

¹ Department of Epidemiology Research, Statens Serums Institut, Copenhagen, Denmark.
² Department of Clinical Immunology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
³ Cancer Epidemiology and Surveillance, Danish Cancer Institute, Copenhagen, Denmark.
⁴ Danish Cancer Institute, Copenhagen, Denmark.
⁵ Department of Pediatrics, Stanford University School of Medicine, Stanford, California.
⁶ HUNT Center for Clinical and Molecular Epidemiology, Norwegian University of Science and Technology, Trondheim, Norway.
⁷ Pharmacovigilance Research Center, Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
⁸ Clinical Immunology Research Unit, Department of Clinical Immunology, Odense University Hospital, Odense, Denmark.
⁹ Department of Clinical Research, University of Southern Denmark, Odense, Denmark.
¹⁰ Department of Clinical Immunology, Aalborg University Hospital, Aalborg, Denmark.
¹¹ Statens Serum Institut, Copenhagen, Denmark.
¹² Department of Clinical Immunology, Aarhus University Hospital, Aarhus, Denmark.
¹³ Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.
¹⁴ deCODE Genetics, Reykjavik, Iceland.
¹⁵ Laboratory for Molecular Cardiology, Department of Cardiology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
¹⁶ Laboratory for Molecular Cardiology, Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark.
¹⁷ Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
¹⁸ Department of Clinical Immunology, Zealand University Hospital, Køge, Denmark.
¹⁹ Department of Cardiology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
²⁰ Department of Clinical Pharmacology, Copenhagen University Hospital - Bispebjerg and Frederiksberg, Copenhagen, Denmark.
²¹ Department of Biology, University of Copenhagen, Copenhagen, Denmark.

PMID: 39888683
PMCID: PMC12147972 (available on 2026-06-01)
DOI: 10.1681/ASN.0000000622

Abstract

Key Points:

This large-scale genetic study identified 31 loci associated with plasma sodium concentrations in individuals of European ancestry.
Tissue specificity analysis showed a significantly increased expression of sodium-associated genes in the pituitary gland.
No genetic association signals were found for the risk of hyponatremia after thiazide exposure.

Background: Abnormal plasma sodium concentration represents an imbalance of total body water relative to electrolyte content. Hyponatremia is a common and potentially severe adverse event, and thiazide diuretics constitute a leading cause of drug-induced hyponatremia.

Methods: We conducted genome-wide association study analyses of plasma sodium concentration, thiazide-induced decrease in sodium concentration, and thiazide-induced hyponatremia in a total of 188,461 individuals of European ancestry. In addition, we tested for gene–environment interaction between a polygenic score developed for plasma sodium concentration and thiazide exposure on sodium concentration and hyponatremia risk.

Results: Meta-analysis yielded 31 independent associated signals at P < 5×10⁻⁸ with plasma sodium concentrations. Subsequent tissue specificity analysis showed a significantly increased expression of sodium-associated genes in pituitary tissue (P = 4.5×10⁻⁵). No genome-wide significant loci were found for thiazide-induced sodium concentration decrease or thiazide-induced hyponatremia. A polygenic score for plasma sodium concentration was associated with 0.43 (95% confidence interval, 0.39 to 0.46) mmol/L lower plasma sodium per SD decrease, and thiazide use was associated with 0.80 (95% confidence interval, 0.72 to 0.88) mmol/L lower plasma sodium, but we observed no gene–environment interaction effect (P = 0.71).

Conclusions: These results underline the role of genetic variation in regulating plasma sodium concentration and highlight the importance of pathways involving the pituitary gland while finding no evidence of genetic predisposition for the plasma sodium–lowering effect of thiazides.

Keywords: diuretics; electrolytes; fluid, electrolyte, and acid-base disorders; hyponatremia; molecular genetics; pharmacology; water-electrolyte balance.

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Conflict of interest statement

Disclosure forms, as provided by each author, are available with the online version of the article at http://links.lww.com/JSN/F57.

References

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NNF17OC0027594/Danmarks Frie Forskningsfond, Dagmar Marshalls Fond, Gangstedfonden, Fonden til Lægevidenskabens Fremme, Snedkermester Sophus Jacobsen og Hustru Astrid Jacobsens Fond, Axel Muusfeldts Fond, Arvid Nilssons Fond, Aase og Ejnar Danielsens Fond, Novo Nordisk Foundation

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Genome-Wide Association Study of Plasma Sodium Concentrations with and without Exposure to Thiazide Diuretics

Collaborators

Affiliations

Genome-Wide Association Study of Plasma Sodium Concentrations with and without Exposure to Thiazide Diuretics

Authors

Collaborators

Affiliations

Abstract

Conflict of interest statement

References

Grants and funding

LinkOut - more resources

Full Text Sources