NFAT5 and SLC4A10 Loci Associate with Plasma Osmolality
Authors: 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 M. , 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 S. , Pattaro Cristian , Schlessinger David , Köttgen Anna , Snieder Harold , Parsa Afshin , Cohen David M. 
Published: March 2017

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 × 10−6. Of these, rs9980 at NFAT5 replicated in stage 2 meta-analysis (P=3.1 × 10−5), with combined stages 1 and 2 genome-wide significance of P=5.6 × 10−10. Transethnic meta-analysis further supported the association at rs9980 (P=5.9 × 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 × 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 system and 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.