Methylation in OTX2 and related genes, maltreatment, and depression in children

Abstract

Through unbiased transcriptomics and multiple molecular tools, transient downregulation of the Orthodenticle homeobox 2 (OTX2) gene was recently causatively associated with the development of depressive-like behaviors in a mouse model of early life stress. The analyses presented in this manuscript test the translational applicability of these findings by examining peripheral markers of methylation of OTX2 and OTX2-regulated genes in relation to measures of depression and resting-state functional connectivity data collected as part of a larger study examining risk and resilience in maltreated children. The sample included 157 children between the ages of 8 and 15 years (χ = 11.4, SD = 1.9). DNA specimens were derived from saliva samples and processed using the Illumina 450 K beadchip. A subset of children (N = 47) with DNA specimens also had resting-state functional MRI data. After controlling for demographic factors, cell heterogeneity, and three principal components, maltreatment history and methylation in OTX2 significantly predicted depression in the children. In terms of the imaging data, increased OTX2 methylation was found to be associated with increased functional connectivity between the right vmPFC and bilateral regions of the medial frontal cortex and the cingulate, including the subcallosal gyrus, frontal pole, and paracingulate gyrus-key structures implicated in depression. Mouse models of early stress hold significant promise in helping to unravel the mechanisms by which child adversity confers risk for psychopathology, with data presented in this manuscript supporting a potential role for OTX2 and OTX2-related (e.g., WNT1, PAX6) genes in the pathophysiology of stress-related depressive disorders in children.

Bridging Basic and Clinical Research in Early Life Adversity, DNA Methylation, and Major Depressive Disorder

“…More recently, the Illumina 450K BeadChip array was used by the same group in another study of ELA and MDD that sought to predict differential DNA methylation in maltreated children. In this study (Kaufman et al, 2018), methylation of the Orthodenticle homeobox 2 ( OTX2 ) gene significantly predicted depression in saliva samples of maltreated children compared to controls (Table 1) (Kaufman et al, 2018).…”

“…Imaging data revealed that methylation of OTX2 is associated with increased functional connectivity between the ventromedial prefrontal cortex and structures of the medial frontal cortex that have been implicated in MDD- such as the paracingulate gyrus, frontal pole, and subcallosal gyrus (Table 1) (Kaufman et al, 2018).…”

Understanding and Predicting Antidepressant Response: Using Animal Models to Move Toward Precision Psychiatry

“…Focusing on response to antidepressant treatment, we could identify response-associated transcript profiles in peripheral blood samples of mice, predicting antidepressant treatment response with an accuracy of almost 80% in a patient population ( 26 ). Those and other ( 39 , 40 ) examples of translational studies are encouraging. Importantly, for any translational approach in psychiatry, the research questions originating from the daily clinical situation (i.e., Why does one patient respond to the antidepressant, whereas another does not?…”

Gene Expression Changes in the Ventral Tegmental Area of Male Mice with Alternative Social Behavior Experience in Chronic Agonistic Interactions

“…Its transient knockdown in the VTA increased stress susceptibility, and its overexpression was associated with reverse effects [ 44 ]. The role for the OTX2 gene was confirmed in the study of stress-related depressive disorder pathophysiology in children [ 45 ]. Otx2 is involved in the regulation of the number of VTA neurons with efficient dopamine uptake [ 46 ] and is considered one of the genes with a key role in midbrain dopaminergic neuron development and the regulation of their survival and physiology [ 47 ].…”