M4. Epigeneticly Related mRNA Levels in Lymphocytes of Schizophrenic and Nonpsychotic Controls

Abstract

Background: Epigenetic dysregulation may be involved in the underlying molecular deficits in schizophrenia (SZ). Previous research by our group has show hypermethylation of GABAergic promoter gene in and increases in DNMT1 and DNMT3A in post mortem brain samples of patients with SZ. We have also shown that difference sin DNMT1 and other epigenetically related enzymes are also found in the lymphocytes of living patients with chronic schizophrenia (CSZ). We now report preliminary results on epigenetic related mRNA’s in lymphocytes on a larger sample of CSZ. Methods: CSZ (n = 29) and nonpsychotic controls (NPC) (n = 31) subjects had a blood sample (60–80 cc) drawn, and lymphocyte pellet extracted by Ficoll gradient procedure. qPCR assays were used to measure epigenetically related mRNA’s—DNMT1, DMNT3A, TET1, TET2, TET3, BDNF, NR3C (glucocorticoid receptor).We also assayed several immunological related mRNA (which appeared as strong hits from RNA sequence analysis) T-Cell Surface Glycoprotein CD4, CCR1 (C-C motif chemokine receptor 1), FPRL3 (Formyl Peptide Receptor). Assays were performed using Taqman probes with B-Actin as housekeeping gene. Patients were also evaluated with psychopathology with PANSS, for cognitive function with MATRICS, and for odor identification and discrimination with Sniff and Sticks smell test. Results: In this sample CSZ showed significantly higher DMNT3A (P = .048) than NPC Male CSZ showed significantly higher DNMT1 than NPC (P = .014), but the total sample there was a trend but no significant difference in DNMT1. Compared to NPC, CSZ subjects showed significantly higher levels of GABAergic enzymes measured by the GAD1 probe (which assays GAD67 and GAD25 mRNA) (P = .030), higher levels of glucocorticoid receptor measured by the NRC3 probe (P = .006), and significantly lower levels of FRPRL3(P = .039). Higher levels FPRL3 and CD4 were moderately correlated with PANSS positive symptoms in CSZ (FRPL3 r = +.43 P = .019, CD4 r = +.37 P = .054) and these correlations were slightly stronger in male CSZ. Higher DNMT1 and DNMT3A levels in lymphocytes of CSZ correlated negatively with scores n MATRICs battery (DNMT1—attention/vigilance—r = −.41, P = .031, working memory r = −.37, P = .048, composite score r = −.36, P = .063). Conclusion: CSZ demonstrate differences in epigenetically related mRNA’s in their lymphocytes. In CSZ higher levels of DNMT were related to poorer cognitive performance and higher levels of immunological related mRNA to greater positive symptom scores. Some potential differences to our previously published results may be related to differences in mRNA’s measured by the Taqman probes and earlier research with specifically generated sequence probes.