Differential SLC1A2 Promoter Methylation in Bipolar Disorder With or Without Addiction

Abstract

While downregulation of excitatory amino acid transporter 2 (EAAT2), the main transporter removing glutamate from the synapse, has been recognized in bipolar disorder (BD), the underlying mechanisms of downregulation have not been elucidated. BD is influenced by environmental factors, which may, via epigenetic modulation of gene expression, differentially affect illness presentation. This study thus focused on epigenetic DNA methylation regulation of SLC1A2, encoding for EAAT2, in BD with variable environmental influences of addiction. High resolution melting PCR (HRM-PCR) and thymine–adenine (TA) cloning with sequence analysis were conducted to examine methylation of the promoter region of the SLC1A2. DNA was isolated from blood samples drawn from BD patients (N = 150) with or without addiction to alcohol, nicotine, or food, defined as binge eating, and matched controls (N = 32). In comparison to controls, the SLC1A2 promoter region was hypermethylated in BD without addiction but was hypomethylated in BD with addiction. After adjusting for age and sex, the association of methylation levels with nicotine addiction (p = 0.0009) and binge eating (p = 0.0002) remained significant. Consistent with HRM-PCR, direct sequencing revealed increased methylation in CpG site 6 in BD, but decreased methylation in three CpG sites (6, 48, 156) in BD with alcohol and nicotine addictions. These results suggest that individual point methylation within the SLC1A2 promoter region may be modified by exogenous addiction and may have a potential for developing clinically valuable epigenetic biomarkers for BD diagnosis and monitoring.

Association of PPM1G methylation with risk-taking in alcohol use disorder

“…Future longitudinal research is warranted in order to establish the direction of causality in their relationship. Third, we did not consider the effect of some potential confounders, including heterogeneity in white blood cell composition 31 and cigarette smoking 32,33 , that may contribute to inter-individual variability in DNA methylation. In particular, since smoking can induce epigenetic modifications, the possible effect of smoking on DNA methylation should be considered in future studies.…”

Genome-wide DNA methylomic differences between dorsolateral prefrontal and temporal pole cortices of bipolar disorder

“…Future studies should include larger brain sample cohorts and balanced sample sizes between groups. Fourthly, some clinical factors known to modulate DNA methylation, such as last recorded mood state, nature of death, medications, and substance use history, could not be perfectly matched between subject groups ( Dell’Osso et al, 2014 ; Guidotti and Grayson, 2014 ; Huzayyin et al, 2014 ; Jia et al, 2017 ; Lohoff et al, 2017 ; McCullumsmith and Meador-Woodruff, 2011 ), thereby preventing statistical adjustment. Our findings might be partly attributed to these factors which were particularly complicated in BD and MDD cases.…”

Eating Disorders, Heredity and Environmental Activation: Getting Epigenetic Concepts into Practice

“…We identified no studies investigating methylation differences between patients with a primary diagnosis of BED and normal-eater controls. However, one study reported that patients who showed concurrent bipolar disorders and binge-eating had hypomethylation of the SLC1A2 gene (involved in removing glutamate from the synaptic cleft) relative to patients with bipolar disorder who displayed no binge eating [68].…”