Decreased DNA methylation at promoters and gene-specific neuronal hypermethylation in the prefrontal cortex of patients with bipolar disorder

Abstract

Bipolar disorder (BD) is a severe mental disorder characterized by repeated mood swings. Although genetic factors are collectively associated with the etiology of BD, the underlying molecular mechanisms, particularly how environmental factors affect the brain, remain largely unknown. We performed promoter-wide DNA methylation analysis of neuronal and nonneuronal nuclei in the prefrontal cortex of patients with BD (N=34) and controls (N=35). We found decreased DNA methylation at promoters in both cell types in the BD patients compared to the controls. Gene Ontology (GO) analysis of differentially methylated region (DMR)-associated genes revealed enrichment of molecular motor-related genes in neurons, chemokines in both cell types, and ion channel- and transporter-related genes in nonneurons. Detailed analysis further revealed that growth cone- and dendrite-related genes, including NTRK2 and GRIN1, were hypermethylated in neurons of BD patients. To assess the effect of medication, neuroblastoma cells were cultured under therapeutic concentrations of three different mood stabilizers (lithium, valproate, and carbamazepine). We observed that up to 37.9% of DMRs detected in BD overlapped with mood stabilizer-induced DMRs. Interestingly, mood stabilizer-induced DMRs showed the opposite direction of changes in DMRs in BD, suggesting the therapeutic effects of mood stabilizers on DNA methylation. Among the DMRs, 12 overlapped with loci identified by a previous genome-wide association study of BD. Finally, we performed qPCR analysis of 10 DNA methylation-related genes and found that DNMT3B was overexpressed in BD. The cell type-specific DMRs identified in this study will be useful for understanding the pathophysiology of BD.

Cross-Disorder Analysis of Genic and Regulatory Copy Number Variations in Bipolar Disorder, Schizophrenia, and Autism Spectrum Disorder

“…The results of gene set analysis implicated chromatin modification and organization in BD pathogenesis. Consistent with this, changes in histone modification and DNA methylation were detected in postmortem brain tissue from patients with BD (54,55). The involvement of chromatin modification is suggested based on the clinical efficacy of the mood stabilizer valproic acid.…”

Life cycle patterns of professional performance from Go world champions

“…Epigenetic dysregulations including DNA methylation alterations were observed in brain tissues of BD patients, and mood stabilizers such as valproate also affect DNA methylation. 7 Considering that the present patient responded to valproate, epigenetic dysregulation caused by MBD5 deletion may have been mitigated by the epigenetic effect of valproate.In conclusion, we report a new BD patient with MBD5 deletion. This case report strengthens the evidence for a link between MBD5 and BD.…”

Case report of a female with bipolar disorder and MBD5 deletion

“…Epigenetic dysregulations including DNA methylation alterations were observed in brain tissues of BD patients, and mood stabilizers such as valproate also affect DNA methylation. 7 Considering that the present patient responded to valproate, epigenetic dysregulation caused by MBD5 deletion may have been mitigated by the epigenetic effect of valproate.…”