NFAT5 and SLC4A10 loci associate with plasma osmolality

Carsten A. Böger, Mathias Gorski, Gearoid M. McMahon, Huichun Xu, Yen Pei C. Chang, Peter J. Van Der Most, Gerjan Navis, Ilja M. Nolte, Martin H. De Borst, Weihua Zhang, Benjamin Lehne, Marie Loh, Sian Tsung Tan, Eric Boerwinkle, Morgan E. Grams, Peggy Sekula, Man Li, Beth Wilmot, James G. Moon, Paul ScheetFrancesco Cucca, Xiangjun Xiao, Leo Pekka Lyytikäinen, Graciela Delgado, Tanja B. Grammer, Marcus E. Kleber, Sanaz Sedaghat, Fernando Rivadeneira, Tanguy Corre, Zoltan Kutalik, Sven Bergmann, Carrie M. Nielson, Priya Srikanth, Alexander Teumer, Martina Müller-Nurasyid, Anne Catharina Brockhaus, Arne Pfeufer, Wolfgang Rathmann, Annette Peters, Martha Matsumoto, Mariza De Andrade, Elizabeth J. Atkinson, Cassianne Robinson-Cohen, Ian H. De Boer, Shih Jen Hwang, Iris M. Heid, Martin Gögele, Maria Pina Concas, Toshiko Tanaka, Stefania Bandinelli, Mike A. Nalls, Andrew Singleton, Salman M. Tajuddin, Adebowale Adeyemo, Jie Zhou, Ayo Doumatey, Shannon McWeeney, Joanne Murabito, Nora Franceschini, Michael Flessner, Michael Shlipak, James G. Wilson, Guanjie Chen, Charles N. Rotimi, Alan B. Zonderman, Michele K. Evans, Luigi Ferrucci, Olivier Devuyst, Mario Pirastu, Alan Shuldiner, Andrew A. Hicks, Peter Paul Pramstaller, Bryan Kestenbaum, Sharon L.R. Kardia, Stephen T. Turner, Lifelines Cohort Study, Tamara Ellefson Briske, Christian Gieger, Konstantin Strauch, Christa Meisinger, Thomas Meitinger, Uwe Völker, Matthias Nauck, Henry Völzke, Peter Vollenweider, Murielle Bochud, Gerard Waeber, Mika Kähönen, Terho Lehtimäki, Winfried März, Abbas Dehghan, Oscar H. Franco, Andre G. Uitterlinden, Albert Hofman, Herman A. Taylor, John C. Chambers, Jaspal S. Kooner, Caroline S. Fox, Robert Hitzemann, Eric S. Orwoll, Cristian Pattaro, David Schlessinger, Anna Köttgen, Harold Snieder, Afshin Parsa, David M. Cohen

Research output: Contribution to journalArticle

8 Scopus citations

Abstract

Disorders of water balance, an excess or deficit of total body water relative to body electrolyte content, are common and ascertained by plasma hypo- or hypernatremia, respectively. We performed a two-stage genome-wide association study meta-analysis on plasma sodium concentration in 45,889 individuals of European descent (stage 1 discovery) and 17,637 additional individuals of European descent (stage 2 replication), and a transethnic meta-analysis of replicated single-nucleotide polymorphisms in 79,506 individuals (63,526 individuals of European descent, 8765 individuals of Asian Indian descent, and 7215 individuals of African descent). In stage 1, we identified eight loci associated with plasma sodium concentration at P<5.0 x 10-6. Of these, rs9980 at NFAT5 replicated in stage 2 meta-analysis (P=3.1 3 x 10-5), with combined stages 1 and 2 genomewide significance of P=5.6 x 10-10. Transethnic meta-analysis further supported the association at rs9980 (P=5.9 x 10-12). Additionally, rs16846053 at SLC4A10 showed nominally, but not genome-wide, significant association in combined stages 1 and 2 meta-analysis (P=6.7 x 10-8). NFAT5 encodes a ubiquitously expressed transcription factor that coordinates the intracellular response to hypertonic stress but was not previously implicated in the regulation of systemic water balance. SLC4A10 encodes a sodium bicarbonate transporter with a brain-restricted expression pattern, and variant rs16846053 affects a putative intronic NFAT5 DNA binding motif. The lead variants for NFAT5 and SLC4A10 are cis expression quantitative trait loci in tissues of the central nervous systemand relevant to transcriptional regulation. Thus, genetic variation in NFAT5 and SLC4A10 expression and function in the central nervous system may affect the regulation of systemic water balance.

Original languageEnglish (US)
Pages (from-to)2311-2321
Number of pages11
JournalJournal of the American Society of Nephrology
Volume28
Issue number8
DOIs
StatePublished - Aug 2017

ASJC Scopus subject areas

  • Nephrology

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    Böger, C. A., Gorski, M., McMahon, G. M., Xu, H., Chang, Y. P. C., Van Der Most, P. J., Navis, G., Nolte, I. M., De Borst, M. H., Zhang, W., Lehne, B., Loh, M., Tan, S. T., Boerwinkle, E., Grams, M. E., Sekula, P., Li, M., Wilmot, B., Moon, J. G., ... Cohen, D. M. (2017). NFAT5 and SLC4A10 loci associate with plasma osmolality. Journal of the American Society of Nephrology, 28(8), 2311-2321. https://doi.org/10.1681/ASN.2016080892