Assessing oxidative pathway genes as risk factors for bipolar disorder.
OBJECTIVE
There is a growing body of evidence implicating oxidative stress and the glutathione system in the pathogenesis of major psychiatric illnesses, including schizophrenia and bipolar disorder. Here we investigate whether genes involved in oxidative stress regulation are associated with increased risk for bipolar disorder.


METHODS
Four candidate genes were selected a priori from two different steps in the oxidative stress pathway, specifically the synthesis of glutathione [catalytic subunit of glutamate cysteine ligase (GCLC) and regulatory subunit of glutamate cysteine ligase (GCLM)] and the removal of reactive oxygen species [superoxide dismutase 2 (SOD2) and glutathione peroxidase 3 (GPX3)]. Haplotype tagging and functional nucleotide polymorphisms were selected in each gene and tested for association with bipolar disorder under narrow (n = 240) and broad (n = 325) phenotypic models, compared to healthy controls (n = 392, comprising 166 psychiatrically assessed unaffected controls plus 226 healthy individuals).


RESULTS
Single marker association analysis did not reveal significant association with bipolar disorder; however, haplotypes in the SOD2 gene showed nominal association (global chi(2) = 8.94, p = 0.03; broad model). Interaction analysis revealed a significant interaction between SOD2 and GPX3 haplotypes, which further increases risk for bipolar disorder (odds ratio = 2.247, chi(2) = 9.526, p = 0.002, corrected p = 0.029).


CONCLUSIONS
Further characterization of the SOD2 and GPX3 interaction using larger cohorts is required to determine the role of these oxidative pathway genes as risk factors for bipolar disorder.
Fullerton
Janice M
JM
Neuroscience Research Australia, Randwick, NSW 2031, Sydney, Australia.
Tiwari
Yash
Y
Agahi
Giti
G
Heath
Anna
A
Berk
Michael
M
Mitchell
Philip B
PB
Schofield
Peter R
PR
D001714:Bipolar Disorder / Q000235:genetics*; D005787:Gene Frequency; D005796:Genes / Q000235:genetics*; D056726:Genetic Association Studies; D005838:Genotype; D005721:Glutamate-Cysteine Ligase / Q000235:genetics*; D005979:Glutathione Peroxidase / Q000235:genetics*; D006801:Humans; D010084:Oxidation-Reduction; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012307:Risk Factors; D013482:Superoxide Dismutase / Q000235:genetics*; D000099156:Superoxide Dismutase 2
D005721:Glutamate-Cysteine Ligase; D005979:Glutathione Peroxidase; D013482:Superoxide Dismutase; D000099156:Superoxide Dismutase 2; C486484:GPX3 protein, human; C546365:GCLM protein, human