Antipsychotic drugs attenuate aberrant DNA methylation of DTNBP1 (dysbindin) promoter in saliva and post‐mortem brain of patients with schizophrenia and Psychotic bipolar disorder

Abstract

Due to the lack of genetic association between individual genes and schizophrenia (SCZ) pathogenesis, the current consensus is to consider both genetic and epigenetic alterations. Here, we report the examination of DNA methylation status of DTNBP1 promoter region, one of the most credible candidate genes affected in SCZ, assayed in saliva and post-mortem brain samples. The Illumina DNA methylation profiling and bisulfite sequencing of representative samples were used to identify methylation status of the DTNBP1 promoter region. Quantitative methylation specific PCR (qMSP) was employed to assess methylation of DTNBP1 promoter CpGs flanking a SP1 binding site in the saliva of SCZ patients, their first-degree relatives and control subjects (30, 15, and 30/group, respectively) as well as in post-mortem brains of patients with SCZ and bipolar disorder (BD) versus controls (35/group). qRT-PCR was used to assess DTNBP1 expression. We found DNA hypermethylation of DTNBP1 promoter in the saliva of SCZ patients (∼12.5%, P = 0.036), particularly in drug-naïve patients (∼20%, P = 0.011), and a trend toward hypermethylation in their first-degree relatives (P = 0.085) versus controls. Analysis of post-mortem brain samples revealed an inverse correlation between DTNBP1 methylation and expression, and normalization of this epigenetic change by classic antipsychotic drugs. Additionally, BD patients with psychotic depression exhibited higher degree of methylation versus other BD patients (∼80%, P = 0.025). DTNBP1 promoter DNA methylation may become a key element in a panel of biomarkers for diagnosis, prevention, or therapy in SCZ and at risk individuals pending confirmatory studies with larger sample sizes to attain a higher degree of significance.

DNA methylation as a putative mechanism for reduced dendritic spine density in the superior temporal gyrus of subjects with schizophrenia

“…57 However, DNAm alterations are observed in peripheral blood from early SZ subjects with only brief (<16 weeks) antipsychotic treatment 58 thus suggesting that not all DNAm alterations in SZ are explained by antipsychotic treatment. In some cases, SZ-associated DNAm alterations are normalized by antipsychotic drugs, 59 perhaps suggesting that the therapeutic effect of antipsychotics are mediated, in part, by affecting DNAm.…”

Differential SLC1A2 Promoter Methylation in Bipolar Disorder With or Without Addiction

“…However, changes in DNA methylation have been observed at several BD candidate gene loci such as serotonin system genes, brain-derived neurotrophic factor, and catechol- O -methyltransferase (Ghadirivasfi et al, 2011; Nohesara et al, 2011; D’Addario et al, 2012) in peripheral samples. The only study, to the best of our knowledge, conducted with peripheral samples of BD patients that reported changes in DNA methylation in the glutamatergic system is the report on increased dystrobrevin binding protein 1 (DTNB1) promoter methylation in BD patients with psychotic depression compared to other BD patients (Abdolmaleky et al, 2015; Fries et al, 2016). The DTNB1, also known as dysbindin, has been suggested to be involved in glutamatergic neurotransmission by influencing exocytotic glutamate release (Domschke et al, 2011).…”

The role of DNA methylation in the pathophysiology and treatment of bipolar disorder

“…Due to the role of glutamate in BD and psychosis, several studies have been assessing the potential role of genetic variations in the DTNBP1 gene in these disorders (Corvin et al, 2008; Joo et al, 2007; Yun et al, 2008). Accordingly, a hypermethylation of CpG sites upstream of this gene has been found in the brain of female BD patients (Mill et al, 2008), whereas a hypomethylation of its promoter has been shown in patients, especially in those who were under drug treatment (Abdolmaleky et al, 2015). Of note, methylation status was significantly lower in non-psychotic patients compared to psychotic BD or schizophrenic patients, and a correlation was found between the extent of antipsychotic drug use and DTNBP1 expression in the brains of BD patients (Abdolmaleky et al, 2015).…”

“…Accordingly, a hypermethylation of CpG sites upstream of this gene has been found in the brain of female BD patients (Mill et al, 2008), whereas a hypomethylation of its promoter has been shown in patients, especially in those who were under drug treatment (Abdolmaleky et al, 2015). Of note, methylation status was significantly lower in non-psychotic patients compared to psychotic BD or schizophrenic patients, and a correlation was found between the extent of antipsychotic drug use and DTNBP1 expression in the brains of BD patients (Abdolmaleky et al, 2015). This suggests that the overall reduction in methylation seen in BD patients might be due to drug treatment effects.…”

“…The same study also found a hypermethylation of DTNBP1 promoter in BD with psychotic depression compared to other BD patients, suggesting it as a marker of psychotic phenotype. Interestingly, even though it hasn’t been assessed in the saliva of BD patients, DTNBP1 methylation might also represent a biomarker of illness (in this case, of psychosis, since a hypermethylation was reported in saliva from schizophrenic patients) (Abdolmaleky et al, 2015). …”