Identification of Acer2 as a First Susceptibility Gene for Lithium-Induced Nephrogenic Diabetes Insipidus in Mice

Authors

Theun de Groot
Lena K Ebert
Birgitte Mønster Christensen
Karolina Andralojc
Lydie Cheval
Alain Doucet
Cungui Mao
Ruben Baumgarten
Benjamin E. Low, The Jackson LaboratoryFollow
Roger Sandhoff
Michael V. Wiles, The Jackson LaboratoryFollow
Peter M T Deen
Ron Korstanje, The Jackson LaboratoryFollow

Document Type

Article

Publication Date

12-2019

JAX Source

J Am Soc Nephrol 2019 Dec; 30(12):2322-2336

Volume

30

Issue

12

First Page

2322

Last Page

2336

ISSN

1533-3450

PMID

31558682

DOI

https://doi.org/10.1681/ASN.2018050549

Abstract

BACKGROUND: Lithium, mainstay treatment for bipolar disorder, causes nephrogenic diabetes insipidus and hypercalcemia in about 20% and 10% of patients, respectively, and may lead to acidosis. These adverse effects develop in only a subset of patients treated with lithium, suggesting genetic factors play a role.

METHODS: To identify susceptibility genes for lithium-induced adverse effects, we performed a genome-wide association study in mice, which develop such effects faster than humans. On day 8 and 10 after assigning female mice from 29 different inbred strains to normal chow or lithium diet (40 mmol/kg), we housed the animals for 48 hours in metabolic cages for urine collection. We also collected blood samples.

RESULTS: In 17 strains, lithium treatment significantly elevated urine production, whereas the other 12 strains were not affected. Increased urine production strongly correlated with lower urine osmolality and elevated water intake. Lithium caused acidosis only in one mouse strain, whereas hypercalcemia was found in four strains. Lithium effects on blood pH or ionized calcium did not correlate with effects on urine production. Using genome-wide association analyses, we identified eight gene-containing loci, including a locus containing

CONCLUSIONS: We demonstrate that genome-wide association studies in mice can be used successfully to identify susceptibility genes for development of lithium-induced adverse effects. We identified

Comments

We would like to thank Ms. Holly Savage, Mr. Thomas O’Rourke, and Ms. Rita O’Rourke (fromthe Jackson Laboratory) for their expert help.

Recommended Citation

de Groot T, Ebert L, Christensen B, Andralojc K, Cheval L, Doucet A, Mao C, Baumgarten R, Low BE, Sandhoff R, Wiles MV, Deen P, Korstanje R. Identification of Acer2 as a First Susceptibility Gene for Lithium-Induced Nephrogenic Diabetes Insipidus in Mice J Am Soc Nephrol 2019 Dec; 30(12):2322-2336