title: Association between sodium- and potassium-activated adenosine triphosphatase alpha isoforms and bipolar disorders.
abstract: 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 alpha 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 alpha isoforms of Na+, K+- ATPase (ATP1A1, ATP1A2, and ATP1A3, which encode the three alpha isoforms, alpha1, alpha2, and alpha3, 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 (alpha1: rs11805078; alpha2: rs2070704, rs1016732, rs2854248, and rs2295623; alpha3: rs919390) in the three genes of Na+, K+-ATPase alpha isoforms. Haplotype analysis of the alpha2 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.
authors.affiliation: Department of Physiology, Institute for Medical Research, The Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel.
authors.forename: Inbal
authors.initials: I
authors.lastname: Goldstein
authors.forename: Elad
authors.initials: E
authors.lastname: Lerer
authors.forename: Efrat
authors.initials: E
authors.lastname: Laiba
authors.forename: Jacques
authors.initials: J
authors.lastname: Mallet
authors.forename: Mustafa
authors.initials: M
authors.lastname: Mujaheed
authors.forename: Claudine
authors.initials: C
authors.lastname: Laurent
authors.forename: Haim
authors.initials: H
authors.lastname: Rosen
authors.forename: Richard P
authors.initials: RP
authors.lastname: Ebstein
authors.forename: David
authors.initials: D
authors.lastname: Lichtstein
mesh_terms: D001714:Bipolar Disorder / Q000235:genetics*; D004252:DNA Mutational Analysis; D005192:Family Health; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008297:Male; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D020033:Protein Isoforms / Q000235:genetics*; D000254:Sodium-Potassium-Exchanging ATPase / Q000145:classification / Q000235:genetics*
chemical_list: C488756:ATP1A3 protein, human; D020033:Protein Isoforms; C499076:ATP1A1 protein, human; C498531:ATP1A2 protein, human; D000254:Sodium-Potassium-Exchanging ATPase