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. 2021 Dec:5:100038.
doi: 10.1016/j.bionps.2021.100038. Epub 2021 Jun 24.

Gene Expression Of Methylation Cycle And Related Genes In Lymphocytes And Brain Of Patients With Schizophrenia And Non-Psychotic Controls

Henry Sershen  1   2 , Alessandro Guidotti  3 , James Auta  3 , Jenny Drnevich  4 , Dennis R Grayson  3 , Marin Veldic  5 , Jordan Meyers  6 , Mary Youseff  7 , Adrian Zhubi  3 , Keturah Faurot  8 , Renrong Wu  9 , Jingping Zhao  9 , Hua Jin  10 , Abel Lajtha  1   2 , John M Davis  3 , Robert C Smith #  1   2
Affiliations

Gene Expression Of Methylation Cycle And Related Genes In Lymphocytes And Brain Of Patients With Schizophrenia And Non-Psychotic Controls

Henry Sershen et al. Biomark Neuropsychiatry. 2021 Dec.

Abstract

Some of the biochemical abnormalities underlying schizophrenia, involve differences in methylation and methylating enzymes, as well as other related target genes. We present results of a study of differences in mRNA expression in peripheral blood lymphocytes (PBLs) and post-mortem brains of chronic schizophrenics (CSZ) and non-psychotic controls (NPC), emphasizing the differential effects of sex and antipsychotic drug treatment on mRNA findings. We studied mRNA expression in lymphocytes of 61 CSZ and 49 NPC subjects using qPCR assays with TaqMan probes to assess levels of DNMT, TET, GABAergic, NR3C1, BDNF mRNAs, and several additional targets identified in a recent RNA sequence analysis. In parallel we studied DNMT1 and GAD67 in samples of brain tissues from 19 CSZ, 26 NPC. In PBLs DNMT1 and DNMT3A mRNA levels were significantly higher in male CSZ vs NPC. No significant differences were detected in females. The GAD1, NR3C1 and CNTNAP2 mRNA levels were significantly higher in CSZ than NPC. In CSZ patients treated with clozapine, GAD-1 related, CNTNAP2, and IMPA2 mRNAs were significantly higher than in CSZ subjects not treated with clozapine. Differences between CSZ vs NPC in these mRNAs was primarily attributable to the clozapine treatment. In the brain samples, DNMT1 was significantly higher and GAD67 was significantly lower in CSZ than in NPC, but there were no significant sex differences in diagnostic effects. These findings highlight the importance of considering sex and drug treatment effects in assessing the substantive significance of differences in mRNAs between CSZ and NPC.

Keywords: DNMTs; GABAergic; epigenetics; lymphocyte vs brain; mRNA biomarkers; schizophrenia.

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Conflict of interest statement

Conflict of Interest: The authors report no conflicts of interest potentially related to the research reported in this paper.

Figures

Figure 1.
Figure 1.. Effects of Clozapine on Difference Between Schizophrenics (CSZ) and Controls (NPC)
‘A’ significance of difference CSZ On Clozapine vs. NPC, ‘B’ significance of difference CSZ On Clozapine vs CSZ No-Clozapine ***P<.001, ** P<.01. (A) GAD1 (log), Univariate GLM- Overall Group Effect: F= 24.32, df=2,64, P<.001 (B) IMPA2 (square root), Univariate GLM Overall Group effect: F= 9.223, df=2,66, P<.001 (C) GAD67, non-parametric Kruskal-Wallis test, Test Statistic 16.71, df=2, P<.001. Pairwise Comparisons tested (with Bonferroni corrections) CSZ On Clozapine vs NPC standardized test statistic=3.772, P<.001, CSZ On Clozapine vs CSZ No Clozapine standardized test statistic =3.774, P<.001. (D) CNTNAP2, non-parametric Kruskal-Wallis test, Test Statistic 18.06, df=2, P<.001. Pairwise Comparisons tested (with Bonferroni corrections) CSZ On Clozapine vs NPC standardized test statistic=4.218, P<.001, CSZ On Clozapine vs CSZ No Clozapine standardized test statistic =3.240, P=.004. No AP = No antipsychotic medication.
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