M78. A Preliminary Study of Neuregulin 1 Gene and Brain Glutathione

Background: Oxidative stress is thought to play a role in several neuropsychiatric diseases including schizophrenia, although the precise mechanism is unclear. Recent studies showed that a known schizophrenia candidate gene Neuregulin 1 (NRG1) may have a neuroprotective role by stimulating antioxidant synthesis and increasing glutathione (Zhang et al 2016). At least in the periphery, NRG1 is also known to modulate a key enzyme, glutathione reductase, for glutathione redox (Timolati et al 2006). Therefore, we tested the hypothesis that NRG1 may contribute to glutathione levels in the brain. Methods: In this preliminary study that included 129 Caucasians (43 schizophrenia spectrum disorder patients and 86 controls), we measured glutathione levels in the anterior cingulate/medial frontal region by 1H MRS using a very short echo time (TE) phase rotation sequence (Wijtenburg et al 2014) in a 3T scanner. Using genotype data obtained from the Omni2.5–8 Bead Chip Kit panel (Illumina), we identified a putatively functional nonsynonymous SNP rs3924999 previously found to be related to schizophrenia and performed an association analysis with glutathione. Results: This NRG1 nonsynonymous SNP was associated with the level of glutathione in the combined sample (Δ R 2 = 6.0%, t = −2.85, P = .005) after covarying out age, sex and diagnosis. Analyzing the 2 groups separately, the findings remained significant in the controls (Δ R 2 = 6.9%, t = −2.50, P = .014). The finding was not significant in the patient group (Δ R 2 = 4.5%, t = −1.39, P = .17), although the effect was in the same direction. The SNP did not deviate from Hardy-Weinberg equilibrium ( P = .71). Conclusion: Abnormal glutathione redox has been implicated in schizophrenia. Our preliminary analysis of the NRG1 effect on glutathione levels, previously only studied in peripheral systems, appears to support that a similar effect may be present in the brain. As NRG1 is a strong candidate gene for schizophrenia, further analysis of the neuregulin 1 - glutathione connection may provide new insight into the mechanism of oxidative stress dysfunction in schizophrenia.