AbstractOxidative stress is associated with white matter diffusion metrics in adults with bipolar disorder (BD). We examined the association of single-nucleotide polymorphisms in the oxidative stress system, superoxide dismutase-2 (SOD2) rs4880 and glutathione peroxidase-3 (GPX3) rs3792797 with fractional anisotropy (FA) and radial diffusivity (RD) in youth with BD. Participants included 104 youth (age 17.5 ± 1.7 years; 58 BD, 46 healthy controls). Saliva samples were obtained for genotyping, and diffusion tensor imaging was acquired. Voxel-wise whole-brain white matter diffusion analyses controlled for age, sex, and race. There were significant diagnosis-by-SOD2 rs4880 interaction effects for FA and RD in major white matter tracts. Within BD, the group with two copies of the G-allele (GG) showed lower FA and higher RD than A-allele carriers. Whereas within the control group, the GG group showed higher FA and lower RD than A-allele carriers. Additionally, FA was higher and RD was lower within the control GG group compared to the BD GG group. No significant findings were observed for GPX3 rs3793797. The current study revealed that, within matter tracts known to differ in BD, associations of SOD2 rs4880 GG genotype with both FA and RD differed between BD vs healthy control youth. The SOD2 enzyme encoded by the G-allele, has higher antioxidant capacity than the enzyme encoded by the A-allele. We speculate that the current findings of lower FA and higher RD of the BD GG group compared to the other groups reflects attenuation of the salutary antioxidant effects of GG genotype on white matter integrity in youth with BD, in part due to predisposition to oxidative stress. Future studies incorporating other genetic markers and oxidative stress biomarkers are warranted.