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Background Oxidative stress is implicated in the neuropathology of bipolar disorder (BD). We investigated the association of single-nucleotide polymorphisms (SNPs) in the antioxidative genes superoxide dismutase 2 (SOD2) and glutathione peroxidase 3 (GPX3) with structural neuroimaging phenotypes in youth BD. Methods SOD2 rs4880 and GPX3 rs3792797 SNP genotypes, along with structural magnetic resonance imaging, were obtained from 147 youth (BD = 75; healthy controls = 72). Images were processed using FreeSurfer, yielding surface area, volume, and thickness values for regions of interest (prefrontal cortex [PFC], caudal anterior cingulate cortex, hippocampus) and for vertex-wise whole-brain analysis. Analyses controlled for age, sex, race, and intracranial volume for volume, area, and thickness analyses. Result Regions of interest analyses revealed diagnosis-by-SOD2 rs4880 interaction effects for caudal anterior cingulate cortex volume and surface area as well as PFC volume; in each case, there was lower volume/area in the BD GG genotype group vs the healthy controls GG genotype group. There was a significant BD diagnosis × GPX3 rs3793797 interaction effect for PFC surface area, where area was lower in the BD A-allele carrier group vs the other genotype groups. Vertex-wise analyses revealed significant interaction effects in frontal, temporal, and parietal regions related to smaller brain structure in the BD SOD2 rs4880 GG group and BD GPX3 rs3793797 A-allele carrier group. Conclusion We found preliminary evidence that SOD2 rs4880 and GPX3 rs3792797 are differentially associated with brain structures in youth with BD in regions that are relevant to BD. Further studies incorporating additional neuroimaging phenotypes and blood levels of oxidative stress markers are warranted.

Antioxidative Defense Genes and Brain Structure in Youth Bipolar Disorder