Decreased DNA methylation at promoters and gene-specific neuronal hypermethylation in the prefrontal cortex of patients with bipolar disorder.
Miki BundoJunko UedaYutaka NakachiKiyoto KasaiTadafumi KatoKazuya IwamotoPublished in: Molecular psychiatry (2021)
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. 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 GO 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 mood stabilizers. 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, suggesting the therapeutic effects of mood stabilizers. Among the DMRs, 12 overlapped with loci identified in a genome-wide association study (GWAS) of BD. We also found significant enrichment of neuronal DMRs in the loci reported in another GWAS of BD. Finally, we performed qPCR of 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.
Keyphrases
- bipolar disorder
- dna methylation
- genome wide
- genome wide association study
- major depressive disorder
- prefrontal cortex
- gene expression
- copy number
- end stage renal disease
- ejection fraction
- single cell
- newly diagnosed
- prognostic factors
- chronic kidney disease
- peritoneal dialysis
- sleep quality
- stem cells
- spinal cord
- high glucose
- mental health
- cell therapy
- induced apoptosis
- healthcare
- emergency department
- oxidative stress
- spinal cord injury
- mesenchymal stem cells
- endothelial cells
- drug induced
- adverse drug
- patient reported outcomes
- electronic health record
- blood brain barrier
- cell cycle arrest
- cell proliferation
- resting state
- brain injury
- functional connectivity