Epigenetic Mechanisms in the Genesis of Major Depressive Disorder

Epigenetic Mechanisms in the Genesis of Major Depressive Disorder

Major Depressive Disorder is a form of psychological disorder that is featured by the presence of low and depressed mood for at least two weeks and across most situations. The lifetime prevalence of MDD in the United States is estimated to be around 17%. Different studies have indicated that almost 40% incidences of MDD are attributed to genetic factors. Although the neurobiological and environmental etiology of MDD was appropriately elucidated, the gene-environment interactions in the genesis of MDD remained unclear. The present article explored the role of epigenetic mechanisms in the genesis of Major Depressive Disorder. The major epigenetic changes that are associated with the genesis of MDD include modification of chromatin structures, modification of histone acetylation and modified expression of respective genes. However, the article reflected that epigenetic mechanisms could not solely explain the etiology of MDD. Rather, the genesis of MDD could be viewed as interplay of different regulatory factors. The different regulatory factors include neurological, endocrine, environmental and genetic alterations. Hence, epigenetic changes might modulate the severity or symptoms of MDD.
Keywords: “Epigenetic Changes” “Major Depressive Disorder” “Suicidal tendency” “SSRIs” “DNA methylation”

Epigenetic Mechanisms in the Genesis of Major Depressive Disorder
Background
Major Depressive Disorder is a form of the psychological disorder that is featured by a plethora of symptoms.

However, the major symptom of MDD is the persistence of low mood/depressed mood for at least two weeks and across most situations. The other notable symptoms of MDD include loss of interest in activities that are perceived to be enjoyable by others, lack of energy, the feeling of fatigue and presence of idiopathic pain. Individuals affected with MDD also exhibit contrasting behaviors like anorexia or bulimia, hyperactivity or hypoactivity that are notable to others (Radley et al, 2011).
MDD is often comorbid with different psychological disorders like anxious depression, Obsessive-compulsive disorder, Panic disorder, Bipolar Disorder and Post-traumatic stress disorders. Individuals affected with MDD are at risk of committing suicide and are prone to self-harming behavior. In fact, 2% to 7% individuals affected with MDD commit suicide. On the other hand, the presence of comorbid mood disorders with MDD increase the risk of suicide to around 60%. Major Depressive Disorder stems from the interplay of different genetic, environmental, psychological and neurological factors. Moreover, a family history of depressive disorders, exposure t certain medications, major changes in life and lifestyle, history of substance abuse and presence of chronic diseases are predisposing risk factors for the genesis of MDD in an individual.
The global burden of MDD is quite high. In fact, MDD is predicted to become the second leading cause of disability by 2020. The risk of MDD is also influenced by gender. The prevalence of MDD is more in women compared to their age-matched male counterparts. The ratio of prevalence of MDD between women and men is approximately 3:1. The lifetime prevalence of MDD in the United States was estimated to be approximately 17%.
Etiology of Major Depressive Disorder
Different neurological and biochemical pathways have been implicated in the genesis of Major Depressive Disorders. The role of “Reward-Punishment” pathway and serotonergic transmission has been widely accepted as the etiology of MDD. Serotonin is a neurotransmitter in the reward pathway of our brain. The reward-punishment pathway in the brain is constituted by Ventral tegmental nucleus (VTN) and Nucleus Accumbens (NA). The reward-punishment pathway is involved with the manifestations of different emotional behaviours. This pathway is a key determinant (along with other structures of the limbic system) in influencing the mood characteristics of an individual (Benton et al., 2011). Serotonin receptors facilitate the re-uptake of serotonin from the neuronal synapses in the reward-punishment pathway of the brain. As a result, the synaptic concentrations of serotonin decrease. Increased re-uptake of serotonin by pre-synaptic neurons is strongly correlated with the genesis of MDD. The fact is supported by the mechanism of action of antidepressants. Most anti-depressants belong to the class of Selective Serotonin Re-uptake Inhibitors (SSRIs). SSRIs are recommended for the management of Major Depressive Disorder. These drugs inhibit the re-uptake of serotonin in the pre-synaptic neurons. Hence, SSRIs lead to mood elevation and reduces the symptoms associated with MDD. Bosker et al. (2011) indicated that the reward-punishment pathway could be subjected to structural and functional modifications.
.3. Purpose of the Article
Different studies have indicated that almost 40% incidences of MDD are attributed to genetic factors. Although the neurobiological and environmental etiology of MDD was elucidated; the mechanisms of gene-environment interaction in the genesis of MDD remained unclear. On the contrary, understanding the gene-environment interactions is important for assessing individual risk in the concerned individual, predicting the prognosis of the disease and for the implementation of pharmacological and psychological interventions. Hence, it was contended that there might be an epigenetic basis of MDD. In fact, different studies have elucidated the role of epigenetic mechanisms on the genesis of MDD.
Epigenetic changes refer to the stable (but reversible) alterations in the genetic information within different cells of our body. Such change alters gene expression and the associated functions of the respective genes. However, epigenetic changes do not alter the basic DNA sequence of the respective genes. The major epigenetic changes that are associated with the genesis of MDD include modification of chromatin structures, modification of histone acetylation and modified expression of respective genes (Uchida et al., 2011). The present article explored the role of epigenetic mechanisms in the genesis of Major Depressive Disorder. The present study portrayed a systematic review of the evidence-based literature.
Review of Literature
The systematic review was based on a literature search strategy. The review was based on “PRISMA guidelines for Systematic Reviews and Meta-analysis”. Evidence-based literature was retrieved by using appropriate keywords and Boolean connectors. The keywords and Boolean connectors used for selecting the appropriate articles include ” Genetic factors” or “Genetic Mechanisms” or “Epigenetic Mechanisms” AND “Genesis” or “development” or “prevalence” AND “Major Depressive Disorder” or “Depression”. The keywords and Boolean connectors were used to visit different databases for selecting the relevant articles for the proposed systematic review. The databases and websites that were visited include Pubmed Central, Cochrane Database, MEDLINE search, OVID online and Google Scholar. Google Scholar was used to validating the different articles that were selected through the other four websites.
Epigenetic mechanisms lead to alterations in the expression of different genes. However, they do not alter the genetic code of the genomic sequences. The modulations in gene expression that are associated with psychiatric disorders are achieved through two processes. The first phenomenon is “DNA methylation” and the second phenomenon is ‘Histone Acetylation”. DNA methylation indicates that the expression of a gene is silenced through modification sin the promoter region of the region. The promoter region influences the transcription of different genes that are located adjacent to it. Methylation of cytosine and guanine residues (CpG) leads to enhanced binding of “Methyl-CpG binding protein 2” (MeCP2) in the promoter region. Enhanced binding of MeCP2 to the promoter region silences the expression of adjacent genes. Epigenetic changes are also achieved through physical changes in the DNA. DNA usually remains in a tightly folded manner as nucleosomes. DNA folding is aided by histone proteins. Histone proteins could be modified by acetylation, methylation, and methylation at their amino terminal. Such modifications lead to unfolding of the DNA, which modulates epigenetic changes (Maze, Noh & Allis, 2012).
Sun et al (2013) reviewed the epigenetic changes that are associated with the genesis of depressive disorders. The authors acknowledged that heritability could not solely account for the genetic causes of depressive disorders. Such assumptions stemmed from various observations that were reported in different studies. First of all, GWAS studies failed to exhibit appropriate gene loci for the genesis of depressive disorders. Secondly, the heritability of MDD is much lower compared to the heritability of other psychiatric disorders like bipolar disorders or schizophrenia. The authors indicated that heritability rates of bipolar disorders or schizophrenia were as high as 70% to 80%. On the other hand, the heritability rates of depressive disorders were only 30% to 40%. Thirdly, monozygotic twins affected with MDD exhibited high discordance rates. The discordance rates were as high as 50%. On the other hand, the authors acknowledged there is epidemiological evidence that links environmental factors (exposure to stressful life events) and the risk of depressive disorders.
Dudley et al. (2011) indicated that there is a significant variation in response towards environmental stressors amongst individuals. The authors implicated that some individual is more vulnerable to environmental stressors and are at increased risk of developing MDD. Hence, the authors speculated that environmental factors could interact with genetic factors (genes) in modulating the severity of depressive disorders and in predisposing individuals toward MDD. The speculation of Dudley et al. (2011) was supported by Vialou et al. (2012). Vialou et al. (2012) acknowledged the involvement of gene-environment interactions in predisposing the risk of MDD. The authors implicated that susceptibility and resistance to a certain disease are determined by complex genetic variations. These variations are moderated by different environmental triggers and by different random or stochastic events that occur during brain development. The assumptions of Dudley et al. (2011) and Vialou et al. (2012) were supported by animal and human models of MDD.
Childhood maltreatment and exposure to stressful life events (during later years/or adulthood) increases the risk of MDD in concerned individuals. The individuals who were predisposed to the symptoms of MDD had a short allele (s) of the Serotonin Transporter Promoter Polymorphism (5-HT TLPR). On the other hand, individuals bearing a long allele (S) of the Serotonin Transporter Promoter Polymorphism (5-HT TLPR) were resistant to depressive disorders. The authors also indicated that childhood maltreatment was a predictive risk factor for adult depressive disorders in individuals bearing the small “s” allele only (Akbarian et al., 2011).
Sterrenburg et al. (2011) reported the presence of epigenetic mechanisms in murine models. The authors showed that differences in maternal caring elicited different fearful behavior in their offspring. Fearful responses were less prevalent in individuals raised by well-caring mothers, compared to their counterparts who were raised by docile mothers. This distinction was correlated with epigenetic changes in the glucocorticoid receptor gene in the hippocampus. The authors indicated that the epigenetic changes include histone acetylation and DNA methylation. However, these changes were reversed by infusion of histone deacetylase inhibitor (HDACi). The study reflected that behavioral programming of epigenetic changes (due to stressful events) are reversible.
Akbarian et al. (2011) implicated that transcriptional dysregulation of different genes could explain the behavioral manifestation of different psychological and neuropsychiatric disorders. The authors hypothesized that environmental factors modulate the epigenetic machinery of the brain that is associated normal development and differentiation. On the other, a combination of such events along with the risk of genetic predispositions leads to behavioral manifestations of depressive disorders. Different studies on animal models have endorsed that exposure to early life stress leads to epigenetic changes. Such changes are strongly correlated with the development of depressive disorders. Based on these facts McGowan et al. (2011) proposed that exposure to stressful events, during early life, could leave persistent and permanent epigenetic imprints in the genome of an individual. Such epigenetic marks could alter gene expressions, which might lead to neural and behavior dysfunctions during adulthood. Sun et al. (2013) reported that monoamine oxidase inhibitors (MAOI) are commonly used as anti-depressants. On the other hand, sodium valproate is used as a mood stabilizer. MAOI are potent inhibitors of histone demethylase (LSD1), while potent valproate inhibitors of histone deacetylases (HDACs). This evidence suggests that anti-depressants could prevent or modulate the epigenetic changes, which are associated with the presence of MDD (Abe et al., 2011, Yamawaki et al., 2011).
McGowan et al. (2011) also elucidated the methylation features of the promoter for the Neuron-specific glucocorticoid receptor (NR3C1). The NR3C1 receptor is located in the hippocampus. The methylation features of the promoter were evaluated in suicide victims with or without a history of child abuse. These features were compared with control subjects who committed suicide but were not exposed to child abuse. The authors indicated that the level of DNA methylation at the NR3C1 promoter was significantly higher in the hippocampus of abused individuals compared to their control counterparts. The expression of the NR3C1 receptor was also lower in the hippocampus of abused individuals compared to their control counterparts. Hence, the authors concluded that altered expression of the NR3C1 receptor in the hippocampus is strongly associated with the genesis of depressive disorders.
Christoffel et al. (2011) implicated functional changes in the cortico-striatal-limbic circuitry are strongly associated with the genesis of MDD. Changes in the prefrontal cortex have been associated with cognitive dysfunctions, while changes in the hippocampus, amygdala, and nucleus accumbens have been associated with emotional dysfunctions. These changes are speculated to interact with each other in determining the presence and severity of symptoms, which are associated with depression or depressive disorders. Moreover, changes in the hypothalamic-pituitary-adrenal axis have been associated with stress and homeostatic responses (copying) that are associated with depressive disorders. The authors indicated that decreased the volume of gray-matter in the prefrontal cortex and hippocampus is strongly correlated with the presence of MDD (p<0.001). The authors also reported that MDD was strongly associated with increased metabolism in the amygdala and prefrontal cortex. Christoffel et al. (2011) further reported that alterations in dendritic spines, decreased activation of nucleus accumbens to rewarding stimuli (enjoyable events as perceived by others), and hyperactivity of HPA axis increased the risk of MDD. The authors concluded that epigenetic changes might alter the functional status of these anatomical structures.
Postmortem studies on humans revealed, that patients who suffered from depression had reduced levels of BDNF (Brain-Derived Growth factor) in their hippocampus (Sun et al.2013). Moreover, there was also a significant reduction in hippocampal mass and hippocampal volume in individuals affected with MDD (Sun et al.2013). Gambrill & Barria (2011) reported that patients suffering from depressive disorders displayed decreased levels of NMDA glutamate receptor subunits (NR2A and NR2B). These receptors are essential for maintaining the structural and functional integrity of the dendritic spines. Sun et al. (2013) reported that chronic stress reduced the levels of levels of BDNF (Brain-Derived Growth factor) in the prefrontal cortex of individuals affected with depression. On the other hand, such changes were reversed with the application of anti-depressants like valproate or MAOI. Such observations complement the findings that histone deacetylation and DNA-methylation underpin the epigenetic changes, which are associated with Major Depressive Disorders.
Sun et al. (2013) reported a study that evaluated the impact of early life stress on methylation features of the enhancer region of the Arginine vasopressin (AVP) gene. The authors further explored the consequences of methylation on MeCP2 occupancy in the PVN (paraventricular nucleus) of the hypothalamus. The study was conducted in murine models. Separation of newborn pups from their mothers during the first ten postnatal days resulted in significant up-regulation of AVP receptors. Increased up-regulation of AVP receptors was associated with hypomethylation of the enhancer region. AVP-stimulated the HPA axis (Hypothalamic-Pituitary- Adrenal axis) and induced a state of stress in concerned pups. The stressed pups exhibited deficits in forced swim test and avoidance learning tasks. However, these changes were altered by administration of antagonists to the AVP receptor. On the other hand, hypomethylation of the enhancer region of AVP gene remained unchanged despite after short-term administration of AVP receptor antagonists. Hypomethylation of the AVP gene enhancer region was altered by MeCP2 (Murgatroyd et al., 2010) Hence; the authors concluded that MeCP2 might be effective in protecting DNA methylation patterns over a period.
Sun et al. (2013) reported the findings of a study that revealed increased plasma corticosterone levels and reduced levels of NGF (nerve growth factor) in the hippocampus of rat pups. The rat pups were exposed to maternal separation during the early postnatal period. However, the authors did not notice any changes in the DNA-methylation pattern in the promoter region of the hippocampal glucocorticoid receptor. Hence, the authors concluded that epigenetic mechanisms are not solely responsible for the behavioral manifestations of MDD.
A study was conducted to investigate the expression of an RNA-binding protein in the oligodendrocytes (QKI) of suicide patients. Once again, the authors did not note any epigenetic changes in the promoter region of the gene (expressing the RNA-binding protein). However, the authors noted a significant decrease in the levels of RNA-binding protein in the orbitofrontal cortex of individuals who committed suicide as a consequence of MDD. However, the levels of RNA-binding protein were not reduced in control subjects who died of heart attack or other accidental causes (Sun et al., 2013).
Wilkinson et al. (2011) suggested that resilience and susceptibility to depressive disorders are modulated by signaling cascades in Nucleus Accumbens. The authors demonstrated such assumptions through the evaluation of the “Wingless Signaling Cascade” (WNT) in the Nucleus Accumbens of MDD patients. The authors implicated that MDD is associated with a down-regulation of the WNT signaling pathway and an up-regulation of the “Glycogen Synthase Kinase -3B” pathway. Such alterations in the signaling cascades could stem from epigenetic changes. The authors concluded that epigenetic changes influenced the expression of structural genes associated with the signaling cascades.
Swartz, Hariri & Williamson (2016) evaluated the role of epigenetic mechanisms in linking socioeconomic status with the symptoms of depression. The authors speculated that methylation of regulatory regions of a gene changes their expression. DNA-methylation of the regulatory regions has been associated with neurological dysfunctions. The authors conducted a prospective, randomized, longitudinal study on 132 adolescents to evaluate the epigenetic mechanisms that linked socioeconomic status with symptoms of depression. The authors demonstrated that changes in DNA-methylation were strongly related with lower socioeconomic status. The authors reported that lower socioeconomic status during adolescence was strongly correlated, with increased methylation of the promoter region of the Serotonin Transporter Gene (STG). Such changes increased the threat related reactivity of the amygdala. On the other hand, increased amygdala reactivity is associated with the genesis of depressive disorder. Moreover, such modifications are inherited. This study demonstrated the role of genetics and epigenetic mechanisms in predisposing the risk of MDD. Moreover, the study also implicated the possible gene-environment interactions that are involved in the genesis of MDD.
Discussion and Conclusion
The present article clearly portrayed the involvement of epigenetic mechanisms in the genesis of Major Depressive Disorder. However, the article also reflected that epigenetic mechanisms could not solely explain the etiology of MDD. Rather, the genesis of MDD could be viewed as the interplay of different regulatory factors. The different regulatory factors that lead to the genesis of MDD include neurological, endocrine, environmental and genetic alterations. Hence, epigenetic changes might modulate the severity or symptoms of MDD. Future research should try to explore the role of altered gene expressions in determining the severity and symptoms of MDD. Such research may elucidate tailor-made approaches for implementing psychological and pharmacological interventions in individuals affected with MDD. Hence, future research should try to explore the epigenetic changes that underpin the development of various comorbid disorders associated with MDD. Such studies might improve the prognosis of MDD and reduce the prevalence of depressive disorders in at-risk individuals.
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