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 Scheet & 86 others Francesco 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 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 Orwoll, Cristian Pattaro, David Schlessinger, Anna Köttgen, Harold Snieder, Afshin Parsa, David Cohen

Research output: Contribution to journalArticle

4 Citations (Scopus)

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 1 2017

Fingerprint

Osmolar Concentration
Meta-Analysis
Water
Sodium
Hypernatremia
Nerve Tissue
Nucleotide Motifs
Sodium Bicarbonate
Hyponatremia
Body Water
Quantitative Trait Loci
Genome-Wide Association Study
Osmotic Pressure
Electrolytes
Single Nucleotide Polymorphism
Transcription Factors
Central Nervous System
Genome
Brain

ASJC Scopus subject areas

  • Nephrology

Cite this

Böger, C. A., Gorski, M., McMahon, G. M., Xu, H., Chang, Y. P. C., Van Der Most, P. J., ... Cohen, D. (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

NFAT5 and SLC4A10 loci associate with plasma osmolality. / Böger, Carsten A.; Gorski, Mathias; McMahon, Gearoid M.; Xu, Huichun; Chang, Yen Pei C.; Van Der Most, Peter J.; Navis, Gerjan; Nolte, Ilja M.; De Borst, Martin H.; Zhang, Weihua; Lehne, Benjamin; Loh, Marie; Tan, Sian Tsung; Boerwinkle, Eric; Grams, Morgan E.; Sekula, Peggy; Li, Man; Wilmot, Beth; Moon, James G.; Scheet, Paul; Cucca, Francesco; Xiao, Xiangjun; Lyytikäinen, Leo Pekka; Delgado, Graciela; Grammer, Tanja B.; Kleber, Marcus E.; Sedaghat, Sanaz; Rivadeneira, Fernando; Corre, Tanguy; Kutalik, Zoltan; Bergmann, Sven; Nielson, Carrie; Srikanth, Priya; Teumer, Alexander; Müller-Nurasyid, Martina; Brockhaus, Anne Catharina; Pfeufer, Arne; Rathmann, Wolfgang; Peters, Annette; Matsumoto, Martha; De Andrade, Mariza; Atkinson, Elizabeth J.; Robinson-Cohen, Cassianne; De Boer, Ian H.; Hwang, Shih Jen; Heid, Iris M.; Gögele, Martin; Concas, Maria Pina; Tanaka, Toshiko; Bandinelli, Stefania; Nalls, Mike A.; Singleton, Andrew; Tajuddin, Salman M.; Adeyemo, Adebowale; Zhou, Jie; Doumatey, Ayo; McWeeney, Shannon; Murabito, Joanne; Franceschini, Nora; Flessner, Michael; Shlipak, Michael; Wilson, James G.; Chen, Guanjie; Rotimi, Charles N.; Zonderman, Alan B.; Evans, Michele K.; Ferrucci, Luigi; Devuyst, Olivier; Pirastu, Mario; Shuldiner, Alan; Hicks, Andrew A.; Pramstaller, Peter Paul; Kestenbaum, Bryan; Kardia, Sharon L.R.; Turner, Stephen T.; Study, Lifelines Cohort; Briske, Tamara Ellefson; Gieger, Christian; Strauch, Konstantin; Meisinger, Christa; Meitinger, Thomas; Völker, Uwe; Nauck, Matthias; Völzke, Henry; Vollenweider, Peter; Bochud, Murielle; Waeber, Gerard; Kähönen, Mika; Lehtimäki, Terho; März, Winfried; Dehghan, Abbas; Franco, Oscar H.; Uitterlinden, Andre G.; Hofman, Albert; Taylor, Herman A.; Chambers, John C.; Kooner, Jaspal S.; Fox, Caroline S.; Hitzemann, Robert; Orwoll, Eric; Pattaro, Cristian; Schlessinger, David; Köttgen, Anna; Snieder, Harold; Parsa, Afshin; Cohen, David.

In: Journal of the American Society of Nephrology, Vol. 28, No. 8, 01.08.2017, p. 2311-2321.

Research output: Contribution to journalArticle

Böger, CA, Gorski, M, McMahon, GM, Xu, H, Chang, YPC, Van Der Most, PJ, Navis, G, Nolte, IM, De Borst, MH, Zhang, W, Lehne, B, Loh, M, Tan, ST, Boerwinkle, E, Grams, ME, Sekula, P, Li, M, Wilmot, B, Moon, JG, Scheet, P, Cucca, F, Xiao, X, Lyytikäinen, LP, Delgado, G, Grammer, TB, Kleber, ME, Sedaghat, S, Rivadeneira, F, Corre, T, Kutalik, Z, Bergmann, S, Nielson, C, Srikanth, P, Teumer, A, Müller-Nurasyid, M, Brockhaus, AC, Pfeufer, A, Rathmann, W, Peters, A, Matsumoto, M, De Andrade, M, Atkinson, EJ, Robinson-Cohen, C, De Boer, IH, Hwang, SJ, Heid, IM, Gögele, M, Concas, MP, Tanaka, T, Bandinelli, S, Nalls, MA, Singleton, A, Tajuddin, SM, Adeyemo, A, Zhou, J, Doumatey, A, McWeeney, S, Murabito, J, Franceschini, N, Flessner, M, Shlipak, M, Wilson, JG, Chen, G, Rotimi, CN, Zonderman, AB, Evans, MK, Ferrucci, L, Devuyst, O, Pirastu, M, Shuldiner, A, Hicks, AA, Pramstaller, PP, Kestenbaum, B, Kardia, SLR, Turner, ST, Study, LC, Briske, TE, Gieger, C, Strauch, K, Meisinger, C, Meitinger, T, Völker, U, Nauck, M, Völzke, H, Vollenweider, P, Bochud, M, Waeber, G, Kähönen, M, Lehtimäki, T, März, W, Dehghan, A, Franco, OH, Uitterlinden, AG, Hofman, A, Taylor, HA, Chambers, JC, Kooner, JS, Fox, CS, Hitzemann, R, Orwoll, E, Pattaro, C, Schlessinger, D, Köttgen, A, Snieder, H, Parsa, A & Cohen, D 2017, 'NFAT5 and SLC4A10 loci associate with plasma osmolality', Journal of the American Society of Nephrology, vol. 28, no. 8, pp. 2311-2321. https://doi.org/10.1681/ASN.2016080892
Böger CA, Gorski M, McMahon GM, Xu H, Chang YPC, Van Der Most PJ et al. NFAT5 and SLC4A10 loci associate with plasma osmolality. Journal of the American Society of Nephrology. 2017 Aug 1;28(8):2311-2321. https://doi.org/10.1681/ASN.2016080892
Böger, Carsten A. ; Gorski, Mathias ; McMahon, Gearoid M. ; Xu, Huichun ; Chang, Yen Pei C. ; Van Der Most, Peter J. ; Navis, Gerjan ; Nolte, Ilja M. ; De Borst, Martin H. ; Zhang, Weihua ; Lehne, Benjamin ; Loh, Marie ; Tan, Sian Tsung ; Boerwinkle, Eric ; Grams, Morgan E. ; Sekula, Peggy ; Li, Man ; Wilmot, Beth ; Moon, James G. ; Scheet, Paul ; Cucca, Francesco ; Xiao, Xiangjun ; Lyytikäinen, Leo Pekka ; Delgado, Graciela ; Grammer, Tanja B. ; Kleber, Marcus E. ; Sedaghat, Sanaz ; Rivadeneira, Fernando ; Corre, Tanguy ; Kutalik, Zoltan ; Bergmann, Sven ; Nielson, Carrie ; Srikanth, Priya ; Teumer, Alexander ; Müller-Nurasyid, Martina ; Brockhaus, Anne Catharina ; Pfeufer, Arne ; Rathmann, Wolfgang ; Peters, Annette ; Matsumoto, Martha ; De Andrade, Mariza ; Atkinson, Elizabeth J. ; Robinson-Cohen, Cassianne ; De Boer, Ian H. ; Hwang, Shih Jen ; Heid, Iris M. ; Gögele, Martin ; Concas, Maria Pina ; Tanaka, Toshiko ; Bandinelli, Stefania ; Nalls, Mike A. ; Singleton, Andrew ; Tajuddin, Salman M. ; Adeyemo, Adebowale ; Zhou, Jie ; Doumatey, Ayo ; McWeeney, Shannon ; Murabito, Joanne ; Franceschini, Nora ; Flessner, Michael ; Shlipak, Michael ; Wilson, James G. ; Chen, Guanjie ; Rotimi, Charles N. ; Zonderman, Alan B. ; Evans, Michele K. ; Ferrucci, Luigi ; Devuyst, Olivier ; Pirastu, Mario ; Shuldiner, Alan ; Hicks, Andrew A. ; Pramstaller, Peter Paul ; Kestenbaum, Bryan ; Kardia, Sharon L.R. ; Turner, Stephen T. ; Study, Lifelines Cohort ; Briske, Tamara Ellefson ; Gieger, Christian ; Strauch, Konstantin ; Meisinger, Christa ; Meitinger, Thomas ; Völker, Uwe ; Nauck, Matthias ; Völzke, Henry ; Vollenweider, Peter ; Bochud, Murielle ; Waeber, Gerard ; Kähönen, Mika ; Lehtimäki, Terho ; März, Winfried ; Dehghan, Abbas ; Franco, Oscar H. ; Uitterlinden, Andre G. ; Hofman, Albert ; Taylor, Herman A. ; Chambers, John C. ; Kooner, Jaspal S. ; Fox, Caroline S. ; Hitzemann, Robert ; Orwoll, Eric ; Pattaro, Cristian ; Schlessinger, David ; Köttgen, Anna ; Snieder, Harold ; Parsa, Afshin ; Cohen, David. / NFAT5 and SLC4A10 loci associate with plasma osmolality. In: Journal of the American Society of Nephrology. 2017 ; Vol. 28, No. 8. pp. 2311-2321.
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title = "NFAT5 and SLC4A10 loci associate with plasma osmolality",
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.",
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T1 - NFAT5 and SLC4A10 loci associate with plasma osmolality

AU - Böger, Carsten A.

AU - Gorski, Mathias

AU - McMahon, Gearoid M.

AU - Xu, Huichun

AU - Chang, Yen Pei C.

AU - Van Der Most, Peter J.

AU - Navis, Gerjan

AU - Nolte, Ilja M.

AU - De Borst, Martin H.

AU - Zhang, Weihua

AU - Lehne, Benjamin

AU - Loh, Marie

AU - Tan, Sian Tsung

AU - Boerwinkle, Eric

AU - Grams, Morgan E.

AU - Sekula, Peggy

AU - Li, Man

AU - Wilmot, Beth

AU - Moon, James G.

AU - Scheet, Paul

AU - Cucca, Francesco

AU - Xiao, Xiangjun

AU - Lyytikäinen, Leo Pekka

AU - Delgado, Graciela

AU - Grammer, Tanja B.

AU - Kleber, Marcus E.

AU - Sedaghat, Sanaz

AU - Rivadeneira, Fernando

AU - Corre, Tanguy

AU - Kutalik, Zoltan

AU - Bergmann, Sven

AU - Nielson, Carrie

AU - Srikanth, Priya

AU - Teumer, Alexander

AU - Müller-Nurasyid, Martina

AU - Brockhaus, Anne Catharina

AU - Pfeufer, Arne

AU - Rathmann, Wolfgang

AU - Peters, Annette

AU - Matsumoto, Martha

AU - De Andrade, Mariza

AU - Atkinson, Elizabeth J.

AU - Robinson-Cohen, Cassianne

AU - De Boer, Ian H.

AU - Hwang, Shih Jen

AU - Heid, Iris M.

AU - Gögele, Martin

AU - Concas, Maria Pina

AU - Tanaka, Toshiko

AU - Bandinelli, Stefania

AU - Nalls, Mike A.

AU - Singleton, Andrew

AU - Tajuddin, Salman M.

AU - Adeyemo, Adebowale

AU - Zhou, Jie

AU - Doumatey, Ayo

AU - McWeeney, Shannon

AU - Murabito, Joanne

AU - Franceschini, Nora

AU - Flessner, Michael

AU - Shlipak, Michael

AU - Wilson, James G.

AU - Chen, Guanjie

AU - Rotimi, Charles N.

AU - Zonderman, Alan B.

AU - Evans, Michele K.

AU - Ferrucci, Luigi

AU - Devuyst, Olivier

AU - Pirastu, Mario

AU - Shuldiner, Alan

AU - Hicks, Andrew A.

AU - Pramstaller, Peter Paul

AU - Kestenbaum, Bryan

AU - Kardia, Sharon L.R.

AU - Turner, Stephen T.

AU - Study, Lifelines Cohort

AU - Briske, Tamara Ellefson

AU - Gieger, Christian

AU - Strauch, Konstantin

AU - Meisinger, Christa

AU - Meitinger, Thomas

AU - Völker, Uwe

AU - Nauck, Matthias

AU - Völzke, Henry

AU - Vollenweider, Peter

AU - Bochud, Murielle

AU - Waeber, Gerard

AU - Kähönen, Mika

AU - Lehtimäki, Terho

AU - März, Winfried

AU - Dehghan, Abbas

AU - Franco, Oscar H.

AU - Uitterlinden, Andre G.

AU - Hofman, Albert

AU - Taylor, Herman A.

AU - Chambers, John C.

AU - Kooner, Jaspal S.

AU - Fox, Caroline S.

AU - Hitzemann, Robert

AU - Orwoll, Eric

AU - Pattaro, Cristian

AU - Schlessinger, David

AU - Köttgen, Anna

AU - Snieder, Harold

AU - Parsa, Afshin

AU - Cohen, David

PY - 2017/8/1

Y1 - 2017/8/1

N2 - 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.

AB - 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.

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DO - 10.1681/ASN.2016080892

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JF - Journal of the American Society of Nephrology : JASN

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