Association between sodium- and potassium-activated adenosine triphosphatase alpha 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 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.
Goldstein
Inbal
I
Department of Physiology, Institute for Medical Research, The Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel.
Lerer
Elad
E
Laiba
Efrat
E
Mallet
Jacques
J
Mujaheed
Mustafa
M
Laurent
Claudine
C
Rosen
Haim
H
Ebstein
Richard P
RP
Lichtstein
David
D
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*
C488756:ATP1A3 protein, human; D020033:Protein Isoforms; C499076:ATP1A1 protein, human; C498531:ATP1A2 protein, human; D000254:Sodium-Potassium-Exchanging ATPase