Abstract
Background
Childhood trauma may lead to impairments in brain development and increases risk at psychiatric disorders. Evidence also suggests that childhood trauma may affect DNA methylation patterns consequently influencing gene expression (Tomassi et al., 2017). Some of this linking may be correlated with N-methyl-d-aspartate receptor (NMDAR) hypofunction, which plays a major role of central aspects of cognitive and negative features of schizophrenia (Lakhan et al., 2013). Specifically, the GRIN1 gene codes the biologically relevant NMDAR subunit involved in the synaptic plasticity which is expressed in a broad of non-neuronal cells (Hogan-Cann et al., 2016).
Aims: We investigated DNA methylation in the promoter region of GRIN1 and LINE-1 methylation in first-episode psychosis patients (FEP), their unaffected siblings and community-based controls with and without childhood trauma. We also tested for correlations between GRIN1 methylation and NR1 concentrations in peripheral blood.
Methods
This study is a part of the epidemiological investigation that estimated the incidence of psychosis and the role of environmental and biological factors in psychosis aetiology in the catchment area of Ribeirão Preto, Brazil, from 1st April 2012 to 31st March 2015. The genomic DNA was extracted from blood of 60 FEP patients, 30 of their unaffected siblings and 60 age- and sex-matched community-based controls. Diagnosis and clinical characteristics were assessed using the DSM-IV (First et al., 1997; Del-Ben et al., 2001) and history of childhood trauma was assessed using the Childhood Trauma Questionnaire (Grassi-Oliverira et al., 2006). The genomic DNA was bisulfite converted and pyrosequencing was used to determine methylation levels in three CpGs sites of the GRIN1 gene and of LINE-1, as a measure of global methylation. NR1 plasma concentrations were measured using ELISA (MyBioSource, San Diego, USA). Data were analyzed using General Linear Model with post-hoc Bonferroni correction and Pearson’s correlations.
Results
Individuals, independent of groups, who had experienced childhood trauma presented higher levels of GRIN1 methylation than those without trauma (CpG1: p=0.004; CpG3: p=0.009). Moreover, individuals with physical neglect demonstrated GRIN1 hypermethylation in comparison to individuals without trauma (CpG1: p=0.027; CpG3: p=0.006). Specifically, siblings with emotional neglect presented increased GRIN1 methylation levels at CpG1 when compared with FEP patients and controls with emotional neglect (p=0.028; p=0.001, respectively) and in relation to siblings without trauma (p=0.004). Siblings with physical neglect also showed increased GRIN1 methylation levels at CpG1 when compared to FEP patients and controls with physical neglect (p=0.010; p=0.003, respectively) and in relation to siblings without physical neglect (p=0.001). Furthermore, FEP patients with emotional neglect showed increased GRIN1 methylation at CpG3 when compared to FEP patients without emotional neglect (p=0.010). No differences were observed in the LINE-1 methylation between individuals with or without childhood trauma.
Discussion
This is the first study demonstrating the association between DNA methylation in GRIN1 and childhood trauma in FEP patients, their unaffected siblings and community-based controls. In addition, the interaction between DNA methylation changes in GRIN1 and childhood trauma may be a predict factor of susceptibility for siblings. All these findings suggest evidence for NMDAR dysfunction in response to trauma, contributing the understanding of some of the epigenetics mechanisms by which early life stress affects the glutamatergic system.
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