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Assessing oxidative pathway genes as risk factors for bipolar disorder
journal contributionposted on 2010-08-01, 00:00 authored by J M Fullerton, Y Tiwari, G Agahi, A Heath, Michael BerkMichael Berk, P B Mitchell, P R Schofield
OBJECTIVES: 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.
Pagination550 - 556
Publication classificationC1.1 Refereed article in a scholarly journal
Copyright notice2010, The Authors
bipolar disorderGCLglutathioneGPX3oxidative stressSOD2Gene FrequencyGenesGenetic Association StudiesGenotypeGlutamate-Cysteine LigaseGlutathione PeroxidaseHumansOxidation-ReductionPhenotypePolymorphism, Single NucleotideRisk FactorsSuperoxide DismutaseScience & TechnologyLife Sciences & BiomedicineClinical NeurologyNeurosciencesPsychiatryNeurosciences & NeurologyMOOD STABILIZING DRUGSN-ACETYL CYSTEINEGENOME SCREENSUSCEPTIBILITY LOCUSGLUTATHIONE LEVELSCATALYTIC SUBUNITDOUBLE-BLINDASSOCIATIONSCHIZOPHRENIAGLUTAMATE