Association Between Sodium- and Potassium-Activated Adenosine Triphosphatase α Isoforms and Bipolar Disorders

Background: The sodium- and potassium-activated adenosine triphosphatase (Na⁺, K⁺-ATPase) is a major plasma membrane transporter for sodium and potassium. We recently suggested that bipolar disorders (BD) may be associated with alterations in brain Na⁺, K⁺-ATPase. We further conjectured that the differences in Na⁺, K⁺-ATPase in BD patients could result partially from genetic variations in Na⁺, K⁺-ATPase α isoforms. Methods: To test our hypothesis, we undertook a comprehensive study of 13 tagged single nucleotide polymorphisms (SNPs) across the three genes of the brain α isoforms of Na⁺, K⁺- ATPase (ATP1A1, ATP1A2, and ATP1A3, which encode the three α isoforms, α1, α2, and α3, respectively) identified using HapMap data and the Haploview algorithm. Altogether, 126 subjects diagnosed with BD from 118 families were genotyped (parents and affected siblings). Both individual SNPs and haplotypes were tested for association using family-based association tests as provided in the UNPHASED and PBAT set of programs. Results: Significant nominal association with BD was observed for six single SNPs (α1: rs11805078; α2: rs2070704, rs1016732, rs2854248, and rs2295623; α3: rs919390) in the three genes of Na⁺, K⁺-ATPase α isoforms. Haplotype analysis of the α2 isoform (ATP1A2 gene) showed a significant association with two loci haplotypes with BD (rs2295623: rs2070704; global p value = .0198, following a permutation test). Conclusions: This study demonstrates for the first time that genetic variations in Na⁺, K⁺-ATPase are associated with BD, suggesting a role of this enzyme in the etiology of this disease.