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
Due to the number of contributing authors, the affiliations are listed in the supplemental material.
J Am Soc Nephrol. 2017 Aug;28(8):2311-2321. doi: 10.1681/ASN.2016080892. Epub 2017 Mar 30.
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 <5.0 × 10 Of these, rs9980 at replicated in stage 2 meta-analysis (=3.1 × 10), with combined stages 1 and 2 genome-wide significance of =5.6 × 10 Transethnic meta-analysis further supported the association at rs9980 (=5.9 × 10). Additionally, rs16846053 at showed nominally, but not genome-wide, significant association in combined stages 1 and 2 meta-analysis (=6.7 × 10). 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. 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 and are expression quantitative trait loci in tissues of the central nervous system and relevant to transcriptional regulation. Thus, genetic variation in and expression and function in the central nervous system may affect the regulation of systemic water balance.
水平衡紊乱，即相对于身体电解质含量而言，全身总水量过多或过少，较为常见，分别通过血浆低钠血症或高钠血症来确定。我们对45889名欧洲血统个体（第1阶段发现）和另外17637名欧洲血统个体（第2阶段重复验证）的血浆钠浓度进行了两阶段全基因组关联研究荟萃分析，并对79506名个体（63526名欧洲血统个体、8765名亚洲印度血统个体和7215名非洲血统个体）中重复验证的单核苷酸多态性进行了跨种族荟萃分析。在第1阶段，我们在<5.0×10的水平上鉴定出8个与血浆钠浓度相关的基因座。其中，位于的rs9980在第2阶段荟萃分析中得到重复验证（=3.1×10），第1阶段和第2阶段合并后的全基因组显著性为=5.6×10。跨种族荟萃分析进一步支持了rs9980处的关联（=5.9×10）。此外，位于的rs16846053在第1阶段和第2阶段合并后的荟萃分析中显示出名义上但非全基因组显著的关联（=6.7×10）。编码一种普遍表达的转录因子，该转录因子协调细胞内对高渗应激的反应，但以前未涉及全身水平衡的调节。编码一种具有脑限制性表达模式的碳酸氢钠转运体，变体rs16846053影响一个假定的内含子NFAT5 DNA结合基序。和的主要变体是中枢神经系统组织中的表达数量性状基因座，与转录调控相关。因此，和在中枢神经系统中的表达和功能的遗传变异可能会影响全身水平衡的调节。
