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

Miki Bundo,Kiyoto Kasai,Yutaka Nakachi,Tadafumi Kato,Kazuya Iwamoto,Junko Ueda

doi:10.1038/s41380-021-01079-0

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. 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.

Highlights

Bipolar disorder (BD), known as manic depressive illness, is a severe and common mental disorder characterized by repeated mood swings of depressive and manic episodes, with elevated rates of mortality [1, 2]
We found significant enrichment of neuronal differentially methylated region (DMR) in the loci reported in another Genome-wide association studies (GWAS) of BD [24]
We found that kinesin complex, microtubule, and motor molecule-related genes dominantly included neuronal DMR-associated genes, whereas chemokine activity-related and inflammationrelated genes were evenly enriched among both neuronal and nonneuronal DMR-associated genes

Summary

Introduction

Bipolar disorder (BD), known as manic depressive illness, is a severe and common mental disorder characterized by repeated mood swings of depressive and manic episodes, with elevated rates of mortality [1, 2]. Epidemiological and linkage studies suggested that BD is a highly heritable disorder caused by a complex interaction of genetic and environmental risk factors [3]. Genome-wide association studies (GWAS) revealed that BD is a polygenic disorder caused by multiple genetic risks with small effect sizes, similar to schizophrenia (SZ), and shared genetic risks with other psychiatric disorders, such as SZ and autism [4,5,6]. Comprehensive DNA methylation studies have revealed expression-linked DNA methylation changes in the cerebellum [12], accelerated aging in the hippocampus [13], loss of brain laterality associated with TGFB2 methylation [14], and methylation imbalance of synaptic function-related genes between the frontal and temporal cortices [15]. There have been no established findings that were replicated in multiple studies

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Conclusion