Gene expression in blood of children and adolescents: Mediation between childhood maltreatment and major depressive disorder
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
References (51)
- et al.
DSMIH-R psychotic disorders: procedural validity of the Mini International neuropsychiatric interview (MINI). Concordance and causes for discordance with the CIDI
Eur. Psychiatry
(1998) - et al.
Interleukin-1beta and tumor necrosis factor-alpha in children with major depressive disorder or dysthymia
J. Affect. Disord.
(2004) - et al.
The genetics of major depression
Neuron
(2014) - et al.
How does the brain deal with cumulative stress? A review with focus on developmental stress, HPA axis function and hippocampal structure in humans
Neurobiol. Dis.
(2013) Developmental epidemiology of depressive disorders
Child Adolesc. Psychiatric Clin. N. Am.
(2012)- et al.
Depression, comorbidities and the TNF-alpha system
Eur. Psychiatry
(2008) - et al.
Reduced glucocorticoid Receptor alpha expression in mood disorder patients and first-degree relatives
Biol. Psychiatry
(2006) - et al.
Inflammation and its discontents: the role of cytokines in the pathophysiology of major depression
Biol. Psychiatry
(2009) - et al.
Inflammation in children and adolescents with neuropsychiatric disorders: a systematic review
J. Am. Acad. Child Adolesc. Psychiatry
(2014) - et al.
The long-term impact of the physical, emotional, and sexual abuse of children: a community study
Child Abuse Negl.
(1996)
Evaluation of neurotransmitter receptor gene expression identifies GABA receptor changes: a follow-up study in antipsychotic-naive patients with first-episode psychosis
J. Psychiatric Res.
Brain-derived neurotrophic factor gene and protein expression in pediatric and adult depressed subjects
Prog. Neuro-psychopharmacology Biol. Psychiatry
The HPA axis in major depression: classical theories and new developments
Trends Neurosci.
Glucocorticoid receptors in major depression: relevance to pathophysiology and treatment
Biol. Psychiatry
The effect of age and gender on cytokine production by human peripheral blood mononuclear cells and markers of bone metabolism
Exp. Gerontol.
The prevalence and predictors of obstructive sleep apnea in major depressive disorder, bipolar disorder and schizophrenia: a systematic review and meta-analysis
J. Affect. Disord.
Cytokines and serotonin transporter in patients with major depression
Prog. Neuro-psychopharmacology Biol. Psychiatry
Manual for the Child Behavior Checklist/4-18 and 1991 Profile
Brazilian multicentric study of psychiatric morbidity. Methodological features and prevalence estimates
Br J. Psychiatry : J. Ment. Sci.
Candidate genes expression profile associated with antidepressants response in the GENDEP study: differentiating between baseline 'predictors' and longitudinal 'targets'
Neuropsychopharmacology
Primary generalized glucocorticoid resistance and hypersensitivity
Hormone Res. Paediatr.
TNF-R1 signaling: a beautiful pathway
Science
Defining Child Maltreatment: the Interface between Policy and Research, Child Abuse, Child Development, and Social Policy
Childhood maltreatment, emotional dysregulation, and psychiatric comorbidities
Harv Rev. Psychiatry
Concurrent validity of the child behavior checklist DSM-oriented scales: correspondence with DSM diagnoses and comparison to syndrome scales
J. Psychopathol. Behav. Assess.
Cited by (25)
Inflammatory mediation of the relationship between early adversity and major depressive disorder: A systematic review
2024, Journal of Psychiatric ResearchMeta-analysis of soluble tumour necrosis factor receptors in severe mental illnesses
2023, Journal of Psychiatric ResearchMaternal early life stress is associated with pro-inflammatory processes during pregnancy
2023, Brain, Behavior, and ImmunityChildhood trauma and the plasma levels of IL-6, TNF-α are risk factors for major depressive disorder and schizophrenia in adolescents: A cross-sectional and case-control study
2022, Journal of Affective DisordersCitation Excerpt :Thus, a hypothesis was formulated by researchers and confirmed in some later researches that the pro-inflammatory phenotypes in MDD and SZ are associated with childhood trauma researchers (Cattaneoet al., 2015; Baumeister et al., 2016). Preliminary research indicated increased inflammatory markers in children and adolescents with neuropsychiatric disorders (Kaufman et al., 2001), but the data are inconsistent between adults and minors (Mitchell et al., 2014; Spindola et al., 2017). Thereby, the underlying mechanisms of MDD and SZ in children and adolescents might differ from those of adulthood disorders.
miR-218 in Adolescence Predicts and Mediates Vulnerability to Stress
2021, Biological PsychiatryCitation Excerpt :The limitation in biomarker discovery may result from the heterogeneity of the symptomatology and etiology of MDD, impact of early-life stress, different source of patient-derived samples (e.g., saliva vs. blood), difficulties in conducting well-controlled longitudinal studies, and proportion of male/female patients included in the studies. Promising approaches to solve this issue are research strategies aimed at estimating transcriptional profiles and hormone panels in blood samples from adolescents with MDD with or without experiences of negative environmental factors, such as early-life trauma (27,52–54). Genes related to the stress response or inflammation, including NR3C1, TNF, TNFR1, and IL1B, have been significantly linked to symptoms of MDD in youths (27,52,53), and DNA methylation of genes associated with neurodevelopment has been related to alterations in brain connectivity and early depressive symptoms (55,56).
- 1
These authors contributed equally to this work.