The Neuroscience of Depression: Genetics, Cell Biology, Neurology, Behavior, and Diet

By Colin R Martin, Victor R Preedy and Rajkumar Rajendram

The Neuroscience of Depression: Genetics, Cell Biology, Neurology, Behaviour and Diet is a comprehensive reference to the aspects, features and effects of depression. This book provides readers with the behavior and psychopathological effects of depression, linking anxiety, anger and PSTD to depression. Readers are provided with a detailed outline of the genetic aspects of depression including synaptic genes and the genome-wide association studies (GWAS) of depression, followed by a thorough analysis of the neurological and imaging techniques used to study depression. This book also includes three full sections on the various effects of depression, including diet, nutrition and molecular and cellular effects. The Neuroscience of Depression: Genetics, Cell Biology, Neurology, Behaviour and Diet is the only resource for researchers and practitioners studying depression.

• Features a section on neurological and imaging, including SPECT Neuroimaging
• Analyzes how diet and nutrition effect depression
• Examines the molecular and cellular effects of depression
• Covers genetics of depression
• Includes more than 250 illustrations and tables

• Language: English
• Publisher: Academic Press
• Release date: Mar 5, 2021
• ISBN: 9780128179369

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libraries.

Part I

Genetic aspects of depression

Chapter 1: Epigenetics in depression

Piotr Czarnya; Katarzyna Bialekb; Sylwia Ziolkowskaa; Monika Talarowskac; Tomasz Śliwińskib    a Department of Medical Biochemistry, Medical University of Lodz, Lodz, Poland

b Laboratory of Medical Genetics, Department of Molecular Genetics, Faculty of Biology and Environmental Protection, University of Lodz, Lodz, Poland

c Department of Personality and Individual Differences, Institute of Psychology, University of Lodz, Lodz, Poland

Abstract

Recent studies have found the hypothesis that depression arises through the interaction between environmental and genetic factors alone to be insufficient, and research is now turning to a third factor, epigenetics. Epigenetic modifications, such as DNA methylation, histone posttranslational modifications, and microRNA interference, are thought to be able to modulate vulnerability to the disease after stressful events. Interestingly, several studies have indicated the potential for the microRNAs circulating in blood, plasma, or serum to be used as peripheral markers of depression. Moreover, recent studies have raised the possibility of therapeutic use; more precisely, histone deacetylase inhibitors may serve as new therapeutic agents due to their antidepressant properties. Although, a number of studies have examined the role of epigenetics in depression, we are only beginning to understand the exact mechanisms of its pathogenesis. Therefore, longitudinal studies are needed to further explore the promising value of epigenetic mechanisms.

Keywords

Depression; Neuroplasticity; Epigenetics; DNA methylation; Histone posttranslational modifications; Histone code; microRNA

List of abbreviations

5hmC 

5-hydroxymethylcytosine

5HT 

serotonin

5mC 

5-methylcytosine

BDNF 

brain-derived neurotrophic factor

BNST 

stria terminalis

CpG 

cytosine-guanine dyad

CREB 

cAMP response element-binding protein

DNMT 

DNA methyltransferases

ds-miRNAs 

miRNA duplexes

G9a/GLP 

G9a-like protein

G × E 

gene–environment

HATs 

histone acetyltransferases

HDACi 

HDAC inhibitor

HDACs 

histone deacetylases

HDMs 

histone demethylases

HMTs 

histone methyltransferases

HPA 

hypothalamic–pituitary–adrenal

KMTs 

lysine methyltransferases

MBD1 

methyl-CpG binding domain protein 1

MeCP2 

methyl-CpG binding protein 2

miRNAs 

microRNAs

NAc 

nucleus accumbens

NR3C1 

nuclear receptor subfamily 3, group C, member 1

pri-miRNAs 

long primary miRNAs

PTMs 

posttranslational modifications

RISC 

RNA inducing silencing complex

SAHA 

suberoylanilide hydroxamic acid

SERT 

serotonin transporter

SIRT1 

Sirtuin 1

SLC6A4 

solute carrier family 6 member 4

Tet 

ten-eleven enzyme

ZBTB 33 Zinc finger and BTB domain containing protein 33

Introduction

A recent genome-wide association meta-analysis of 135,458 patients suffering from depression and 344,901 controls has identified 44 independent and significant loci (Wray et al., 2018); however, a further meta-analysis of studies on twins has found the heritability of the disease to be only 37% (Sullivan, Neale, & Kendler, 2000). Hence, the susceptibility to depression cannot be fully explained by changes in the DNA sequence. In addition, vulnerability to environmental stress is surprisingly varied, and only a fraction of individuals will be affected by depression after exposure to stress. Therefore, current perspectives are turning more to explaining the occurrence of depression through interactions between genetic and environmental factors (G × E—gene–environment), where the effect of the environment, such as the occurrence of stressful and traumatic life events, is modulated by the genotype and vice versa (Sun, Kennedy, & Nestler, 2013) (Fig. 1).

Fig. 1

Fig. 1 The interplays between environmental, genetic, and epigenetic factors, and their impact on phenotype.

In recent years, epigenetics has emerged as a possible third modulating factor. This phenomenon refers to the regulation of gene activity and expression which is not encoded by the DNA nucleotide sequence, but is nevertheless potentially heritable and affected by environmental changes. Such epigenetic mechanisms facilitate cross talk between environment and genetic factors, and modulate their impact on the eventual phenotype. A growing number of reports indicate that epigenetic factors may play a crucial role not only in the formation and course of depression, but also in response to its pharmacotherapy; the latter is of particular interest since one-third of cases is drug resistant (Li et al., 2019; Uchida, Yamagata, Seki, & Watanabe, 2018). Three major epigenetic mechanisms controlling the expression of genetic information can be distinguished: (i) two modifications of cytosine, i.e., methylation of fifth carbon atom in its heterocyclic aromatic ring, resulting in the formation of 5-methylcytosine (5mC) (Chen, Meng, Pei, Zheng, & Leng, 2017) and further oxidation of 5mC giving 5-hydroxymethylcytosine (5hmC) (Kriaucionis & Heintz, 2009); (ii) chromatin remodeling via the introduction of covalent modifications such as methylation, phosphorylation, ubiquitination, acetylation, SUMOylation, serotonylation, citrullination, and ADP-ribosylation to core histones, mainly in the N-terminus flexible tail (Sun et al., 2013); and (iii) the action of small noncoding RNAs, among which microRNAs (miRNAs) are the most extensively studied class and able to posttranscriptionally modulate gene expression by mRNA degradation and/or translation repression (Catalanotto, Cogoni, & Zardo, 2016). Interestingly, these three mechanisms demonstrate cross talk between each other and coordinate their impact on phenotype, e.g., DNA methylation and chromatin remodeling can modulate the expression of miRNAs, whereas the presence of 5-methylcytosines recruits modification-introducing enzymes to histones.

The mechanisms of the pathogenesis of depression, including those related to epigenetic regulation, remain poorly understood, and studies conducted so far have not yielded definite conclusions. Nevertheless, this chapter attempts to summarize the current state of knowledge about this topic, and formulate key points that need to be addressed in future research.

DNA methylation

One of the most extensively studied epigenetics mechanisms in humans is DNA methylation. This modification, leading to the formation of 5-methylocytosine, is catalyzed by a family of DNA methyltransferases (DNMTs) (Fig. 2). In mammals, DNA methylation predominantly occurs at a palindromic sequence of cytosine-guanine dyads (CpG sites) within the promoter region, but has also been observed in the transcribed region of the gene. In the promoter region, hypermethylation has been found to lead to gene silencing while hypomethylation is associated with increased gene transcription; conversely, in the coding region, DNA methylation is associated with higher gene expression. However, it is still unclear how this process occurs. There are two hypothesized mechanisms explaining how the presence of 5mC could affect gene expression: (i) a direct mechanism, in which 5mC prevents transcription by reducing access of transcription factors to regulatory elements; (ii) an indirect mechanism, where 5mC could establish gene silencing by cooperating with histone modifications. It has been proposed that this interrelation may be mediated by proteins such as zinc finger and BTB domain containing protein 33 (ZBTB 33), methyl-CpG binding protein 2 (MeCP2), and methyl-CpG binding domain protein 1 (MBD1), which display methyl DNA-binding activity and the ability to recruit a protein complex containing histone deacetylases (HDACs) and methyltransferases (Chen et al., 2017; Kondo, 2009).

Fig. 2

Fig. 2 Methylation and demethylation occurring in cytosine residues.

In the human genome, 5mC plays a pivotal role in many biological processes such as gene imprinting, chromosomal inactivation, cell differentiation, and the silencing of repetitive elements, and approximately 3% of cytosines are methylated (Nafee, Farrell, Carroll, Fryer, & Ismail, 2008). Although DNA methylation markers are stable, the process is reversible and methyl groups can be removed by enzymatic catalysis. One of the proposed mechanisms by which demethylation can occur is mediated by ten-eleven (Tet) enzymes. Specifically, Tet enzymes are able to add a hydroxyl group to methyl group of 5mC and form 5hmC, which was first discovered in mammals in 2009 (Kriaucionis & Heintz, 2009) (Fig. 2). Furthermore, 5hmC was found to be abundant in neuronal cells of the central nervous system, which could indicate the importance of this mechanism in the brain.

DNA methylation is among several epigenetics modifications that may play an important role in mediating the effects of stress and could be considered as proposed mechanism in the development of experience-driven changes to the brain; this is an especially interesting possibility in the context of neuropsychiatric diseases. Recent evidence indicates that alterations in DNA methylation, i.e., both hyper- and hypomethylation at the same loci, as well as methylation variance, are frequently present in depressed individuals (Lin & Tsai, 2019).

Early-life events, DNA methylation, and depression

Epigenetic modifications occurring in early life and even in utero may have long-term effects in later age. The first information about DNA methylation in depression was based on studies on animal models. Animals exposed to stress at an early age showed changes in methylation patterns which may last for a lifetime and increased vulnerability to stress. These results were later confirmed in human studies. An interesting model in this regard is that based on monozygotic twins, whose DNA sequence may be virtually identical but epigenetic profiles can differ due to environmental or stochastic factors (Saavedra, Molina-Márquez, Saavedra, Zambrano, & Salazar, 2016). DNA methylation studies using differentially methylated probes and variably methylated probes in monozygotic twins confirmed a relationship between changes in methylation and the presence of altered psychological characteristics (Córdova-Palomera et al., 2015).

Different gene methylation profiles in depression models

The first genome-wide DNA methylation scan in patients with depression identified altered DNA methylation in 224 gene regions connected with neuronal growth and development (Sabunciyan et al., 2012). It has been demonstrated that increased DNA methylation of the brain-derived neurotrophic factor (BDNF) gene, encoding the protein responsible for regulating neuron growth, differentiation and maintenance, as well as plasticity and cognitive function, is associated with depression in the human population (Fuchikami et al., 2011). Increased methylation of CpG in its promoter correlates with significantly lower synthesis in neurons, and such increases have been observed in patients with depressive symptoms, as well as in subjects with suicidal ideation (Fuchikami et al., 2011; Januar, Ancelin, Ritchie, Saffery, & Ryan, 2015; Kang et al., 2013). However, there are also studies indicating lowered DNA methylation level in depressed individuals (Chen et al., 2017). Interestingly, decrease in BDNF methylation has been observed in depressed patients undergoing antidepressant treatment (D’Addario et al., 2013). Furthermore, maternal depressive symptoms during the prenatal period are frequently associated with hypomethylation of the BDNF promoter in infants (Braithwaite, Kundakovic, Ramchandani, Murphy, & Champagne, 2015). This has also been confirmed by animal studies, where changes in methylation were found in rats subjected to an animal model of childhood maltreatment, suggesting it may be associated with stressful early-life experience (Lin & Tsai, 2019; Roth, Lubin, Funk, & Sweatt, 2009). The same trend is observed in case of solute carrier family 6 member 4 (SLC6A4, encoding serotonin transporter—SERT) gene, which has been especially well studied in the context of serotonergic signaling in depression; however, most recent evidence demonstrates that SLC6A4 displays increased DNA methylation in depressive disorders (Chen et al., 2017; Kang et al., 2013). In addition, similar to BDNF, maternal depressed mood in pregnancy is connected with decreased methylation status in newborns (Chen et al., 2017). Methylation of the nuclear receptor subfamily 3, group C, member 1 (NR3C1) gene may account for the dysregulation of the HPA (hypothalamic–pituitary–adrenal) axis, which is frequently observed in depression (Chen et al., 2017). However, despite wide research, results are inconsistent; while evidence exists for the hypermethylation of NR3C1 gene in depressed women and their offspring, recent research reports no such association between its methylation and depression (Chen et al., 2017). To conclude, DNA methylation could be one of the epigenetic mechanisms by which the environment and stressors may exert long-term effects on the phenotype via gene expression, influencing individuals in the course of depression.

Histone modifications

Histone modifications are covalent, posttranslational modifications (PTMs) associated with the regulation of gene expression. Here, the working hypothesis assumes that the sum of these modifications, the so-called histone code, affects the structure of chromatin and thus the expression of target genes. Among the range of possible PTMs, acetylation and methylation seem to have the greatest impact on chromatin structure and are the most intensively studied in the context of depression (Saavedra et al., 2016). In acetylation, histone acetyltransferases (HATs) unfold the chromatin molecule, thus revealing attachment sites for transcription factors, while histone deacetylases (HDACs) condense the chromatin by removing the acetyl group from the histone tail, thus limiting access of transcription factors to DNA and reducing gene expression (Fig. 3). Methylation is mediated by histone methyltransferases (HMTs) and demethylases (HDMs), which accordingly add or remove methyl groups to arginine, histidine, or lysine residues. In contrast to acetylation, the impact on gene expression depends on the location of the methylated residue and degree of its methylation, i.e., mono-, di-, or tri-methylation (me1 et al., 2, or 3, respectively) (Table 1). For example, H3K4me2/3 can activate transcription, while H3K27me3 inhibits it (Bagot, Labonte, Pena, & Nestler, 2014).

Fig. 3

Fig. 3 The function of acetyltransferases and deacetylases in the regulation of gene expression. Binding of acetyl group causes chromatin to unfold, whereas removal of acetyl group results in tightly folded chromatin. Inhibition of HDACs relaxes chromatin and facilitates binding of transcription factors to genes such as BDNF and CREB.

Table 1

aS. cerevisiae.

b Mammals.

Histone acetylation and depression

The importance of acetylation in the course of depression was first noticed in animal models. Studies conducted on a stressed C57BL/6 J mouse model confirmed that after chronic social stress, acetylation of lysin-14 of histone H3 in the nucleus accumbens (NAc) first decreased for a transient period and then gradually increased (Covington et al., 2009). This region of the hypothalamus plays a role in the cognitive processing of learning, motivation, reward, and aversion. Moreover, higher acetylation levels result in reduced HDAC2 levels. Interestingly, animal models expressing dominant-negative HDAC2 in the NAc exhibited more antidepressant behavior than models that overexpressed S-nitrosylation sites, which lacked the HDAC2 variant that strongly binds to chromatin (Uchida et al., 2011) Therefore, it was hypothesized that systemic or intracerebral administration of HDAC inhibitors (HDACi) could be used in pharmacotherapy. Accordingly, the administration of entinostat (MS275), belonging to HDACi, has improved the antidepressant response in social defeat model based on the study conducted on C57/Bl6J male mice (Covington et al., 2009).

However, the opposite situation is observed for HDAC5. It has been found to be downregulated in mouse models subjected to chronic social defeat stress, while treatment with an antidepressant (imipramine) causes its upregulation. In addition, HDAC5 knockout animals that were subjected to chronic stress showed increased depressive-like behavior. These findings may suggest that genes targeted by HDAC2 may mediate antidepressant responses, whereas those associated with HDAC5 might have the opposite, depression-related role (Renthal et al., 2007).

Many studies have shown that histone acetylation in the hippocampus varies in response to stress and antidepressants; both mouse and rat models displayed increased histone acetylation after being exposed to various stressors. For instance, mice with lower levels of anxiety had downregulated HDAC3, higher levels of acetylated H3 and H2B histones, and greater levels of HATs in their hippocampus (Hollis, Duclot, Gunjan, & Kabbaj, 2011). Interestingly, the administration of HDACi directly to this part of the brain caused a reversal of the anhedonia, without affecting other symptoms, such as social exclusion (Covington, Vialou, LaPlant, Ohnishi, & Nestler, 2011). There is also some evidence suggesting peripheral dysregulation of histone acetylation; studies conducted on peripheral blood cells indicated the elevated levels of HDAC2 and HDAC5 in depressive patients but not in those in remission (Hobara et al., 2010). These findings indicate that changes in histone acetylation in the brain might play an adaptive and pro-depressive role in the course of this disease.

Histone methylation and depression

Of all amino acid residues known to be methylated in histones, the effect of lysine methylation on gene expression, catalyzed by lysine methyltransferases (KMTs), is best understood. Studies have found that after social defeat, NAc KMT expression was reduced in stress-susceptible mice but upregulated in the resilient animals. In addition, Covington et al. (2011) indicated that H3K9me2 associated with transcriptional repression was reduced only in susceptible mice, and overexpression of G9a (a KMT) in the NAc of mice caused antidepressant-like behavior; interestingly, its knockdown resulted in the opposite effect, suggesting that histone methylation may have a pro-adaptive action in response to stress. Wilkinson et al. (2009) reported the presence of widespread changes in H3K9/K27 methylation in the chromatin in mice after social defeat or social isolation, the majority of which are reversible after chronic administration of antidepressant drugs. Interestingly, while acute and subchronic stress increased H3K9me3 level in the hippocampus (Hunter, McCarthy, Milne, Pfaff, & McEwen, 2009), it was reduced by chronic stress, and this change was reversible by antidepressant treatment. Hence, it appears that H3K9me3 may play an adaptive role in depression, especially since the enzymes catalyzing its creation have antidepressant properties.

The BDNF gene is not only targeted by DNA methylation but also by the PTMs of histones. For instance, electroconvulsive shock has been shown to induce the acetylation of H3 and H4 histones located near the BNDF promoter in the hippocampus, while chronic social defeat stress reduces BDNF expression and increases the level of H3K27me2 in BDNF promoters. It can be therefore assumed that histone modifications are related to depression-related behavior (Tsankova, Kumar, & Nestler, 2004).

HDAC inhibitors as antidepressants

Based on the studies provided in the previous section it is possible that HDACi could be used as antidepressants or as adjuvant drugs. Accordingly, treatment with sodium butyrate, an HDACi, was able to prevent and normalize the effects of a chronic restraint stress model in mice (Han, Sung, Chung, & Kwon, 2014). However, no such effect was observed after the administration of fluoxetine, a selective serotonin reuptake inhibitor widely used as an antidepressant and an anxiety treatment (Misztak, Panczyszyn-Trzewik, & Sowa-Kucma, 2018). Injections of other HDACis, such as suberoylanilide hydroxamic acid (SAHA; vorinostat) or MS275, into the NAc of mice subjected to chronic social defeat stress reversed the stress-induced social avoidance and increased the time spent on social interactions. Moreover, antidepressant-like activity was observed in sucrose intake test following MS275 administration (Misztak et al., 2018).

Unfortunately, the initial promising results regarding HDACi usage in antidepressant therapy have been quenched due to their lack of specificity, resulting in the activation of untargeted genes, including oncogenes, during long-term administration. This phenomenon causes side effects such as diarrhea, nausea, and fatigue (Misztak et al., 2018). A single administration of HDACis was not enough to obtain an antidepressant-like effect, and often drugs had to be administered chronically; in addition, due to their low specificity and the limited penetration of the blood–brain barrier, the drugs also needed to be administered at higher doses (Fuchikami et al., 2016; Misztak et al., 2018).

Histone modification associated with gestational stress and gender differences

Studies on pregnant mice showed that exposure to stress during pregnancy negatively affects offspring. They exhibited depressive and anxiety behaviors, upregulated HDAC1 and HDAC2 expression, as well as reduced BDNF expression and lowered H3K14ac levels in the hippocampus (Zheng, Fan, Zhang, & Dong, 2016). It was also found that G9a/GLP (G9a-like protein) inhibition yields different effects when applied to adult mice and fetuses; adult mice demonstrated reduced anxiety-like behaviors and decreased H3K9 methylation in the brain, while adults demonstrated increased anxiety-like behaviors and decreased social interaction, with a normal H3K9me level when the inhibitors were administered in the embryonic stage. Results suggest that the effect of G9a/GLP depends on the stage of brain development (Wang et al., 2018).

Histone modifications have also been found to regulate brain development and sexual behavior. Males and females demonstrate differences in the acetylation of H3 and H4 histones in the estrogen receptor alpha promoter regions within the brain during prenatal development (Hodes, Walker, Labonté, Nestler, & Russo, 2017). Interestingly, epigenetic changes in histones can affect brain areas that differ between the sexes, and these dimorphic areas may be associated with anxiety. One such area is the bed nucleus of the stria terminalis (BNST), whose activity correlates with monitoring of risk, and which is masculinized by a combination of histone H3 lysine-9 and 14 acetylation and testosterone exposure during the early postnatal period (Bangasser & Shors, 2008). Men have a larger BNST volume than women, and treatment with HDACi during the critical period in men leads to feminized BNST (Murray, Hien, de Vries, & Forger, 2009). Despite the fact that depression occurs more frequently in women than in men, more studies have been performed on the latter. Unfortunately, studies that also included women did not analyze gender differences in histone modifications.

miRNA mechanisms of action

Currently, miRNAs are the most extensively studied group of ncRNAs. These single-stranded, RNAs typically measuring about 21-nucleotides in length utilize various mechanisms to trigger downregulation of their target mRNAs. They are initially transcribed as long primary miRNAs (pri-miRNAs) which are then shortened to precursor miRNAs (pre-miRNAs) and finally to miRNA duplexes (ds-miRNAs). These duplexes, together with Argonaute, Dicer, and trans-activation response RNA-binding protein, formulate the RNA-inducing silencing complex (RISC) in the cytoplasm. Following this, one of the ds-miRNA strands is removed, creating a so-called miRISC, and repression mechanisms are initiated by Watson-Crick pairing between the seed region of mature miRNA, located between positions 2 and 8 in the 5′ end, and the responsive element, which is present mainly in the 3 untranslated region (UTR), but also in the 5′-UTR and gene coding sequence (Bartel, 2009).

Repression is enacted by hindering translation or performing mRNA degradation; however, the newest model assumes that these two mechanisms are linked to each other and the former is preceded by the latter. Yet increasing amount of data suggests that miRISCs are not only involved in posttranscriptional gene regulation in cytoplasm, but are also present in nuclei, where they are able to inhibit or even activate transcription. Interestingly, each miRNA is able to regulate hundreds of genes through these nuclear and cytoplasmic mechanisms (Catalanotto et al., 2016). By doing so, they exert a huge influence on both the transcriptome and the proteome, and are thought to play a pivotal role in etiopathogenesis of many diseases, including depression. Indeed, in recent years, disturbances in the expression of several dozen miRNAs have been associated with a response to acute and chronic stress, as well as the occurrence and therapy of depression, by clinical and preclinical studies and those based on animal models (Dwivedi, 2016; Issler et al., 2014; Lopez et al., 2014).

miRNAs and neuroplasticity in depression

A growing body of evidence based on research using various types of chronic stress models in rodents, postmortem samples from depressed patients, or neuroimaging methods supports the theory that depression is associated with impairment in neuronal and structural plasticity (Uchida et al., 2018). Interestingly, neuroplasticity seems to be heavily regulated by epigenetic mechanisms, including miRNAs (Fig. 4). Indeed, several candidates are thought to control these process, including miR-134, miR-132, miR-124, miR-138, miR-125b, and miR-9 (Dwivedi, 2016), of which the first three are closely linked with BDNF, CREB (cAMP response element-binding protein), and SIRT1 (Sirtuin 1) insofar that either their expression is regulated by these proteins or vice versa (Smalheiser, 2014). Since the proteins have been found to be involved in the pathogenesis of depression, this clearly indicate that miRNAs could mediate the interaction between disturbances of neuroplasticity and the occurrence of the disease.

Fig. 4

Fig. 4 Dysregulation of microRNA and their impact on the brain. Two microRNAs, miR-16 and miR-132, have been found to be upregulated peripherally, while miR-135a was found to be downregulated both peripherally and in the brain, rising question whether level of circulating microRNAs is somehow associated with their counterparts in brain.

miRNAs and animal models of depression

The involvement of miRNAs in depression has not only been confirmed indirectly, but also directly through the use of validated animal models of the disease based on stress-inducing methods. Although it could be argued that the results obtained from such models are hard to interpret and cannot be easily extrapolated into humans, they nevertheless provide valuable insights into the relationship between brain tissue, which can be obtained only post mortem, and peripheral tissue, where useful diagnosis markers can be found. These studies identified several miRNAs whose expression was altered in the various brain parts of rats exposed to stress; among them, the expression of miR-125a and miR-182 was restored after the administration of drugs (Cao, Chen, Zhang, & Wu, 2013; Rinaldi et al., 2010). In addition, resilient rats showed significantly larger downregulation of 12 miRNAs encoded by shared polycistronic loci in their frontal cortex than those which developed depressive symptoms after repeated inescapable shock, indicating that miRNAs may modulate susceptibility to the disease (Smalheiser et al., 2011). The presence of miRNAs also seems to determine, to a certain degree, the symptoms that may surface, since anhedonia after chronic unpredictable stress was present only in rats with high hippocampal expression of Let-7a (Bai et al., 2014). Finally, it was demonstrated that miRNAs may also be responsible for parental imprinting; their expression was found to be altered in the sperm of mice exposed to stress, and these differences were found to cause changes in HPA axis of their offspring (Rodgers, Morgan, Bronson, Revello, & Bale, 2013).

miRNAs and postmortem brain

The number of postmortem studies on human brains is limited and involves mainly subjects who committed suicide. One such study found that the miRNAs that were dysregulated in the dorsolateral prefrontal cortex of depressed patients are able to regulate genes involved in cellular growth and differentiation (Smalheiser et al., 2011). Another study on miRNA expression in brain and blood found miR-135a to be downregulated in both tissues (Issler et al., 2014). Interestingly, this miRNA is involved not only in neuroplasticity, but also in controlling serotonergic (5HT) neuron activity, and the authors suggest that it might be crucial for positive response to the pharmacotherapy (Fig. 4).

miRNAs as a peripheral markers of depression

Several studies have explored the possibility of using miRNAs circulating in blood, plasma, or serum as peripheral markers of depression. A recent review identified 23 such studies on humans and 6 performed on animals (Yuan, Mischoulon, Fava, & Otto, 2018). Although 178 miRNAs were found to be dysregulated in depressed patients, i.e., 97 were upregulated, 75 were downregulated, and 6 were up- or downregulated depending on the study, the authors emphasize that little replication could be found across the studies; among all of the molecules, only the results for miR-132 were replicated four times, while miR-16 was present in two animal studies, which utilized different stress-inducing models (Fig. 4). miR-132 was also found to influence neuroplasticity by affecting the expression of BDNF (Smalheiser, 2014). miR-16 targets SERT, and in a study of stressed mice, its level was found to be either up- or downregulated, depending on the brain region, following chronic administration of fluoxetine; this treatment also prevented the surfacing of depression-like symptoms (Baudry, Mouillet-Richard, Schneider, Launay, & Kellermann, 2010). These results could indicate the mechanism which links the peripheral and brain levels of miRNAs; however, very little is known about how this link manifests itself and how circulating miRNAs can affect expression in the brain (Yuan et al., 2018).

Conclusion

To date, much work has been carried out to elucidate the role of epigenetic mechanisms in depression. It seems that epigenetic changes are involved in neuroplasticity and the mechanisms of antidepressant action, and could be used as disease markers. Moreover, the compounds that affect these changes were found to have therapeutic properties. However, as many discrepancies exist between the studies, it was recently suggested that particular issues concerning methodology should be addressed in future research (Yuan et al., 2018). Although it appears that the previous studies have only scratched the surface of this topic, the implications they have hinted at regarding the epigenetic mechanisms involved in the pathogenesis of depression and the promising results achieved so far give hope that further studies will yield much needed major breakthroughs.

Key facts of epigenetics

•There are three major epigenetic mechanisms controlling expression of genetic information: DNA methylation, histone posttranslational modifications, and microRNA interference.

•DNA methylation leads to the formation of 5-methylcytosine via covalent addition of a methyl group to the C-5 position of cytosine in the DNA molecule by DNA methyltransferases.

•In mammals, DNA methylation predominantly occurs at palindromic sequences of cytosine-guanine dyads (CpG sites) within the promoter region, but also in transcribed region of the gene.

•It is established that the hypermethylation leads to gene silencing, while hypomethylation is associated with increased gene transcription.

•Histone modifications are covalent, posttranslational modifications that have been associated with the regulation of gene expression.

•Among the histone modifications, acetylation and methylation appear to have the greatest influence on chromatin structure.

•microRNAs are the most extensively studied group among noncoding RNAs, which play important roles in the silencing and posttranscriptional regulation of gene expression.

Summary points

•Etiopathogenesis of depression can be explained through interactions between the genetic and environment factors mediated by epigenetic mechanisms.

•DNA methylation alterations are frequently observed in depressed individuals.

•Exposure to stress at an early age causes changes in methylation patterns that may last for a lifetime and increase vulnerability to depression.

•Histone acetylation and methylation are the most significant epigenetic changes associated with the development of depression.

•HDAC inhibitors are promising candidates for new lines of antidepressants.

•Dysregulation of miRNA expression may be implicated in depression occurrence and therapy.

•The circulatory miRNAs levels are somehow linked to those of their counterparts in the brain and could be used as markers of depression.

Mini-dictionary of terms

GxE 

Gene–environment interactions; interactions between genetic and environmental factors, where the effect of the environment depends on the genotype and vice versa.

Epigenetics 

The study of changes in gene function that are mitotically and/or meiotically heritable and that do not involve alterations in the DNA sequence; specifically, the interaction of genetic factors, environment, and the developmental processes through which the genotype is expressed in the phenotype.

miRNA—microRNA 

A single-stranded, noncoding RNA molecule containing about 21–23 nucleotides that functions in the silencing and posttranscriptional regulation of gene expression.

DNA methylation Enzymatic modification of DNA involving covalent addition of a methyl group to the C-5 position of cytosine residues in the DNA molecule by DNA methyltransferases, which may result in changes in gene expression.

CpG 

CpG dinucleotides are regions of DNA where a cytosine nucleotide is followed by a guanine nucleotide; and regions of DNA where the frequency of CpG is 10 times greater than average are called CpG islands.

Histone modification Covalent, posttranslational modifications that are associated with the regulation of gene expression and DNA repair, for example, methylation, phosphorylation, ubiquitination, acetylation, SUMOylation, serotonylation, citrullination, and ADP-ribosylation.

Histone code The hypothesis that the products of gene expression, i.e., proteins, could be regulated through changes appearing in histone structure.

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Chapter 2: Genes, depression, and nuclear DNA

Xenia Gondaa,b,c; Peter Petschnerb,c,d    a Department of Psychiatry and Psychotherapy, Semmelweis University, Budapest, Hungary

b MTA-SE Neuropsychopharmacology and Neurochemistry Research Group, Hungarian Academy of Sciences, Semmelweis University, Budapest, Hungary

c NAP-2-SE New Antidepressant Target Research Group, Hungarian Brain Research Program, Semmelweis University, Budapest, Hungary

d Department of Pharmacodynamics, Semmelweis University, Budapest, Hungary

Abstract

Although depression is a prevalent condition with a high illness burden, its neurobiological basis is not fully understood and we know even less about its genetic architecture. Depression is a multigenic and multifactorial disorder with a moderate heritability of approximately 37%–42%, and a very large number of variants with a minor individual contribution play a role in its development. The initial candidate gene approaches yielded most likely false positive results with low replicability, while novel whole-genome analytical approaches in large databases describe an increasing number of significantly associated variants, distributed randomly across the genome in genes and genomic regions with mostly unknown function. However, several shortcomings of this method, including minimal phenotyping, lack of consideration of genetic interactions, and the significant heterogeneity of depression, still present an obstacle in understanding the genetic underpinnings of depression.

Keywords

Depression; Genetic; GWAS; Candidate gene; Polymorphism; GxE interaction

List of abbreviations

5-HTTLPR 

serotonin transporter-linked polymorphic region

ABCB1 

ATP binding cassette subfamily B member 1

ACE 

angiotensin converting enzyme

APOE 

apolipoprotein E

BDNF 

brain-derived neurotrophic factor

CDCV 

common disease-common variant

CDRV 

common disease-rare variant

CLOCK 

circadian locomotor output cycles kaput

COMT 

catechol-O-methyltransferase

DBH 

dopamine beta-hydroxylase

DRD2 

dopamine 2 receptor

DRD3 

dopamine 3 receptor

DRD4 

dopamine 4 receptor

DSM 

diagnostic and statistical manual of mental disorders

DTNBP1 

dystrobrevin-binding protein 1

G x E gene–environment interaction

GNB3 

G-protein beta-3 subunit

GWAS 

genome-wide association study

HTR2A 

serotonin 2A receptor

ICD-10 

10th revision of the international statistical classification of diseases and related health problems

LHPP 

phospholysine phosphohistidine inorganic pyrophosphate phosphatase

MAOA 

monoamine oxidase A

MEF2C 

myocyte enhancer factor 2C

MTHFR 

methylenetetrahydrofolate reductase

NEGR1 

neuronal growth regulator 1

OLFM4 

olfactomedin-4 gene

PGC 

psychiatric genetic consortium

SIRT1 

sirtuin 1

SLC6A3 

dopamine transporter

SLC6A4 

serotonin transporter

SNP 

single nucleotide polymorphism

SORCS3 

sortilin-related VPS10-domain-containing receptor 3

TCF4 

transcription factor 4

TMEM161B 

transmembrane protein 16B

TPH1 

tryptophan hydroxylase 1

TPH2 

tryptophan hydroxylase 2

Introduction

Major depressive disorder is a fairly common psychiatric disorder, and in many cases it is recurrent or even chronic. It leads to severe suffering as well as increased morbidity, disability, and risk of premature mortality not only via suicide but also through its increased comorbidity with somatic illnesses and significant costs (Wray, Ripke, et al., 2018). Recently, depression worldwide rose to becoming one of the leading causes of disease-associated disability affecting approximately 1 in every 6 people (Friedrich, 2017; Kessler et al., 2003; WHO, 2017), cumulating to a 2%–4% point prevalence, 5% 1-year prevalence, and 15% lifetime prevalence and altogether accounting for at least 4% of all years lived with disability (GBD, 2017; Kessler et al., 2003).

In spite of this, currently available treatments for depression are far from effective, and there is both a lack of paradigm shift in antidepressant pharmacotherapy, and a lack of emerging new target pathways or molecules. One of the manifold reasons behind this frustrating lack of successful treatment options is the fact that our understanding concerning the molecular and genetic ethiopathology of depression is still limited. The incompletely explored molecular background, consequently, prohibits not only the development of new molecules and the identification of new treatment targets, but also our understanding of how to prevent and screen for increased depression risk effectively (Fang, Scott, Song, Burmeister, & Sen, 2020).

Similarly our knowledge concerning the genetic background of depressive disorders (Gonda, Petschner, et al., 2018) is limited in spite of (1) more than three decades of vigorous research, (2) a paradigm shift from candidate gene studies to genome-wide approaches, and (3) an identification of replicable variants in very large samples in the most recently published meta-analyses (Howard et al., 2019), which held the promise of suggesting drug targets or checkpoints in the development of the disorder. However, our strengthening view of the genetic architecture of depression holds promise for delivering a network of risk variants where the gaps can be filled by future results.

Heritability of depression

A long history of several twin and family studies clearly points to a substantial heritability in the emergence of depression. Based on twin studies it is estimated that heritability and genetic contribution explains about 37%–42% variance in the risk for major depression in general (Polderman et al., 2015; Sullivan, Neale, & Kendler, 2000) and an even higher heritability is attributed to more severe phenotypes such as early onset or recurrent variants or postpartum subtypes (Viktorin et al., 2016; Wray, Ripke, et al., 2018). Severe phenotypes contribute to a heritability of 75% in case of recurrent, hospitalized samples (Uher, 2014) clearly indicating severity dependence. It is estimated that about 25% of the phenotype heritability of major depressive disorder is attributable to common genetic variants (Bulik-Sullivan et al., 2015).

Heterogeneity of depression

One feature of depression that greatly hinders unraveling its neurobiology and genetic background is the high heterogeneity of what we label as depression, not only observable on the phenotypical level in its manifestation, but also involved in its neurobiological background (Gonda, Petschner, et al., 2018).

While there are core symptoms of depression including persistent low mood or persistently diminished capacity for feeling of joy, pleasure, motivation, and interest, even these two core symptoms of depression grab different phenomena. On one hand, low mood represents the occurrence of negative emotions, while loss of motivation or interest is a manifestation of the disappearance of positive ones, thus these core symptoms are likely to develop on divergent neurobiological and genetic backgrounds. That none of the core or additional symptoms has to be present in all cases (APA, 2013) consequently leads to the fact that two syndromes without a single overlapping symptom can equally be diagnosed as depression. In fact there are 1497 possible symptom combinations for depression based on DSM-IV criteria (Ostergaard, Jensen, & Bech, 2011), while the STAR*D study identified 1030 unique symptom profiles according to DSM-5, with even the most common profile described in only 1.8% of the cases (Fried & Nesse, 2015). Beyond the divergent symptomatic picture, it appears that distinct severity of manifestation and diverging temporal course may also further distinguish the differing neurobiological entities. Thus, depression is an illness group with high heterogeneity not only in its manifestation but also in its biological background. This heterogeneity renders depression difficult to understand and to treat, and also difficult to research, as it is generally not considered in basic or clinical studies. Variability of depression on both the phenotypical and the genotypic level means that in the absence of more homogeneous samples focusing on different subtypes, the variance for specific genetic variants is most probably significantly diluted (Ormel, Hartman, & Snieder, 2019). In addition to these subtypes, recent results from genetic studies suggest that liability toward depression or its endophenotypes may follow a normal distribution in the population, and marked or dominant appearance of phenotypes or clinical diagnosis is associated with different thresholds along this normal distribution of liability (McIntosh, Sullivan, & Lewis, 2019).

The multifactorial background of depression

The heterogeneity of the disorder affects not only the neurobiological pathways and the involved genetic variations but also the relative contribution of genetic variants vs environmental determinants, which may be different in case of different subtypes. On a general population level, depression can be explained by around 40% by genetic factors, which implicates that a 40%–50% contribution of environmental stressors to variation must also be considered (Kessler, 1997). This heritability is severity dependent and has been reported to be much higher, above 70% in severely and recurrently depressed, frequently hospitalized populations (Uher, 2014). What in previous nomenclatures has been termed as endogenous depression (Gillespie, 1929) may carry a higher genetic determination, while environmental stress is likely to play a role in stress-induced forms, previously termed as reactive depressions (Gillespie, 1929). Studies show that a relevant environmental exposure can be identified as preceding a major depressive episode in 80% of the cases (Maciejewski & Mazure, 2000). This clearly renders the dichotomous distinction obsolete and rather suggests that both environmental and genetic factors are decisive factors in most cases, yet with variable contributions. A logical way for such effects is through interactions between the genetic background and environmental exposures of individuals. In support, a plethora of evidence shows that environmental interactions with genetic variations (GxE interactions) play a role in the emergence and manifestation of depression, with environmental effects often obscuring detection of genetic influences. More recently, there is increasing appreciation of this environmental influence, which, however, questions the validity of results from previous oversimplified approaches, where environmental interaction was not considered potentially leading to false negative results (Gonda, Petschner, et al., 2018).

The candidate gene approach in depression

There has been a long chase, however, with little success to identify the underlying genetic variants in depression.

For approximately 25–30 years from the mid-1990s in the early era of molecular genetic studies of depression following family and twin approaches, candidate gene studies was the major approach in studying the genetic background of psychiatric disorders. Candidate gene and/or variant selection was based on previous theoretical assumptions that stemmed from already described knowledge concerning the neuronal elements in depression. In candidate gene studies, either a comparison of allele frequencies in a case–control design or observation of the associations with measures of depression or its endophenotypes was performed. There was also a presumed public health impact coming from the identification of variants as potential biomarkers (Fig. 1).

Fig. 1

Fig. 1 Timeline of genetic research in depression.

One of the most widely investigated variants in depression, the 5-HTTLPR variant of the serotonin transporter gene, was first suggested to be involved in the development of depression following stress exposure in a longitudinal follow-up study published in 2003 (Caspi et al., 2003) (Fig. 1). Subsequently, a large number of studies and several meta-analyses attempted to replicate the results, with no support in the latest and largest meta-analysis with more than 38,000 participants (Culverhouse et al., 2018).

Besides the most popular 5-HTTLPR, other investigated genes and genetic variants included BDNF (brain-derived neurotrophic factor), COMT (catechol-O-methyltransferase), HTR2A (serotonin 2A receptor), TPH1 (tryptophan hydroxylase 1), TPH2 (tryptophan hydroxylase 2), DRD2 (dopamine 2 receptor), MAOA (monoamino-oxidase-A), DRD4 (dopamine 4 receptor), MTHFR (methylenetetrahydrofolate reductase) APOE (apolipoprotein E), CLOCK (circadian locomotor output cycles kaput), SLC6A3 (dopamine transporter), DTNBP1 (dystrobrevin binding protein 1), DRD3 (dopamine 3 receptor), ACE (angiotensin converting enzyme), DBH (dopamine-beta-hydroxylase), and ABCB1 (ATP binding cassette subfamily B member 1) in decreasing order of popularity as reflected in a number of published studies (Border et al., 2019) (Fig. 1).

A large meta-analysis published 10 years ago found that among 393 genetic variants investigated in association with depression in 183 papers, only 22 have been studied in at least 3 different studies and could be investigated in a meta-analysis. The study reported significantly elevated odds ratios for APOE (apolipoprotein E), GNB3 (G-protein beta-3 subunit, C825T variant), MTHFR (methylenetetrahydrofolate reductase, C677T variant), SLC6A4 [serotonin transporter, 40 bp VNTR, serotonin-transporter-linked polymorphic region (5-HTTLPR)], and SLC6A3 (dopamine transporter 44 bp Ins/Del) polymorphism carriers (Lopez-Leon et al., 2008). However, in case of the majority of candidate genes, replication and meta-analysis attempts mostly ended in failures suggesting that the significant results of the initial individual studies were artifacts. A recently published study testing 18 of the above most widely investigated candidate genes in depression in altogether 621,214 subjects, including main and interaction effects, with the use of multiple depression phenotypes and measures as well as multiple forms of environmental exposure, found no support for the involvement of any of these variants either as main or interaction effects (Border et al., 2019). These negative results also let the authors conclude that the majority of such findings are false positive results (Fig.