and Loci Associate with Plasma Osmolality.

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.