Elsevier

Journal of Psychiatric Research

Volume 92, September 2017, Pages 24-30
Journal of Psychiatric Research

Gene expression in blood of children and adolescents: Mediation between childhood maltreatment and major depressive disorder

https://doi.org/10.1016/j.jpsychires.2017.03.015Get rights and content

Abstract

Investigating major depressive disorder (MDD) in childhood and adolescence can help reveal the relative contributions of genetic and environmental factors to MDD, since early stages of disease have less influence of illness exposure. Thus, we investigated the mRNA expression of 12 genes related to the hypothalamic–pituitary–adrenal (HPA) axis, inflammation, neurodevelopment and neurotransmission in the blood of children and adolescents with MDD and tested whether a history of childhood maltreatment (CM) affects MDD through gene expression. Whole-blood mRNA levels of 12 genes were compared among 20 children and adolescents with MDD diagnosis (MDD group), 49 participants without MDD diagnosis but with high levels of depressive symptoms (DS group), and 61 healthy controls (HC group). The differentially expressed genes were inserted in a mediation model in which CM, MDD, and gene expression were, respectively, the independent variable, outcome, and intermediary variable. NR3C1, TNF, TNFR1 and IL1B were expressed at significantly lower levels in the MDD group than in the other groups. CM history did not exert a significant direct effect on MDD. However, an indirect effect of the aggregate expression of the 4 genes mediated the relationship between CM and MDD. In the largest study investigating gene expression in children with MDD, we demonstrated that NR3C1, TNF, TNFR1 and IL1B expression levels are related to MDD and conjunctly mediate the effect of CM history on the risk of developing MDD. This supports a role of glucocorticoids and inflammation as potential effectors of environmental stress in MDD.

Introduction

Major Depressive Disorder (MDD) is a complex psychiatric disorder. Genetic factors contribute up to 40% of MDD risk and are complemented largely by individual-specific environmental exposure to adverse life events (Kendler et al., 2006). Exposure to early adverse life events, including childhood maltreatment (CM), substantially increases risk for several psychiatric disorders in both children and adults (Dvir et al., 2014, Salum et al., 2016). Among mood disorders, CM has been also associated to MDD worse clinical and treatment outcomes (Nanni et al., 2012). Thus, a better understanding of the biological mechanisms by which CM confers MDD risk might shed light on novel ways to prevent and treat MDD.

Hyperactivity of the HPA axis is a consistent finding in MDD (Pariante and Lightman, 2008). Several studies have described a reduced function, or resistance, of glucocorticoid receptor (GR), encoded by NR3C1 gene, in patients with MDD (Pariante, 2004, Pariante and Miller, 2001). A second biological system involved in MDD etiology is inflammation (Miller et al., 2009). mRNA levels of proinflammatory cytokines, including tumor necrosis factor-α (TNF-α) and interleukin (IL)-1β, are higher in MDD patients than in controls (Cattaneo et al., 2013, Tsao et al., 2006). Moreover, proinflammatory cytokine system activation might function in the aforementioned HPA-axis hyperactivity, since considerable data show that TNF-α induces GR resistance (Himmerich et al., 2008, Lang and Borgwardt, 2013). Other potential mechanisms that might contribute to MDD pathogenesis are disturbances of neurodevelopment; this hypothesis is based on clinical evidence that MDD might be related to structural abnormalities in various brain regions (Frodl and O'Keane, 2013, Zhao et al., 2014). Moreover, studies suggest that other neurotransmitter systems, in addition to the monoamine neurotransmission, contribute to the pathophysiological mechanisms of mood disorders (Kendell et al., 2005). Glutamatergic abnormalities have been implicated in the pathophysiology of MDD and it has been reported an increase of glutamate levels in serum/plasma of MDD patients compared to controls (Kim et al., 1982, Kucukibrahimoglu et al., 2009).

A useful method to investigate the pathogenesis of this disorder is the use of peripheral blood to measure the expression levels of genes. As there is a clear association between the immune system and MDD, the development of the disorder might be associated with some systemic alterations (Miller et al., 2009), which can be captured by gene expression in blood. Moreover, it has observed that the correlation between transcripts present in whole blood and brain tissues was around 0.5, showing that transcriptome in blood is neither perfectly correlated nor uncorrelated with that in many brain regions (Sullivan et al., 2006). Furthermore, peripheral blood is an accessible tissue that, via low-invasive procedures, can be used to evaluate several biomarkers, for example mRNA levels or proteins, using quantitative techniques.

The mRNA levels in blood of MDD-associated genes have been widely reported to differ between MDD patients and healthy controls (see (Hepgul et al., 2013) for review). A recent study in a larger cohort of depressed patients has found 129 genes associated with current MDD, that were enriched for IL-6-signaling and natural killer cell pathways (Jansen et al., 2016). However, some findings have not been replicated. Several factors could underlie the inconsistency, such as gender and age, as well as the clinical heterogeneity of MDD itself (Flint and Kendler, 2014, Pietschmann et al., 2003). These findings might be related to the effects of illness duration, number of recurrent episodes, ongoing or previous medication and lifestyle factors. In this context, studies focused on investigating gene expression in children and adolescents with MDD, a group with potentially shorter illness exposure (Mitchell and Goldstein, 2014), might overcome the aforementioned limitations and help further elucidate the mechanisms underlying early MDD.

In this study, we had two main goals: 1) to compare mRNA levels of 12 genes related to HPA axis (NR3C1 and FKBP5), inflammation (TNF, TNFR1, TNFR2 and IL1B), neurodevelopment (DISC1, PDE4B and QKI) and neurotransmission (SLC1A4, GLUL and COMT) in blood of children and adolescents with: a) MDD (MDD group); b) high levels of depressive symptoms but without MDD (DS group); and c) healthy controls (HC group); 2) to employ a mediation model to verify if childhood maltreatment history, an environmental stressor trait that influences MDD risk, affects MDD through the expression of genes, specifically the differentially expressed genes (DEGs) from Aim 1. To our knowledge, this is the first study to test a mediation model of CM history, gene expression and MDD in children and adolescents from a non-medicated community sample. Furthermore, this is the largest study to examine gene expression in blood of children with MDD.

Section snippets

Study procedures

We selected a subsample from a large prospective community school-based study in Brazil, the High Risk Cohort Study for Psychiatric Disorders. The cohort characteristics and study design are detailed elsewhere (Supplementary and (Salum et al., 2015)). Briefly, baseline assessment was performed in multiple visits including a household parent interview (n = 2512) and, on a separate visit, collection of blood samples to assess peripheral biomarkers (n = 625). In the household parent interview,

Results

We analyzed the mRNA levels of 12 candidate genes in 20 children with MDD, 49 children without MDD but with high levels of depressive symptoms and 61 controls. The characteristics of the participants in this study are given in Table 1. The groups did not differ regarding gender frequencies and mean age. However, we have found differences in site. Children from MDD and DS groups were more frequent in Porto Alegre than Sao Paulo. As expected, both MDD and DS groups showed increased CM history

Discussion

We have found that NR3C1, TNF, TNFR1 and IL1B were downregulated in blood of MDD group compared to DS and HC groups. There were no differences of mRNA levels between DS and HC groups. To our knowledge, only two studies have evaluated mRNA levels of candidate genes in the peripheral blood of children and early adolescents with depression (Pajer et al., 2012, Pandey et al., 2010), but they investigated the expression of different genes. Moreover, we have found that CM history did not impact MDD

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    These authors contributed equally to this work.

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