1. Introduction

Depression is characterized by recurrent episodes of sadness and despondency (depressed mood) frequently accompanied by anhedonia, loss of appetite, reduced concentration and energy, excessive guilt, and recurrent suicidal ideation [1]. Despite treatment, more than 50% of patients experience recurrent episodes and approximately 80% of those with a history of two episodes experience another relapse [2]. Both the incidence and prevalence of depression are increasing, and depression is now a major global healthcare burden and cause of lost economic productivity [3]. Current treatment guidelines recommend modulators of monoaminergic transmission such as monoamine oxidase (MAO) inhibitors and specific serotonin reuptake inhibitors (SSRIs) as first-line therapy based on the theory that depression arises from abnormal monoaminergic transmission. However, despite the availability of many monoamine modulators, approximately 50% of patients are unresponsive to these treatments [4].

Indeed, the clinical diagnosis and treatment of depression based on the Diagnostic and Statistical Manual of Mental Disorders (DSM) or the wide-ranging International Statistical Classification of Diseases and Related Health Problems (ICD) have focused on observable behaviors (signs) and self-reported feelings and thoughts (symptoms). Classifying mental disorders according to clinical signs and symptoms has led to a limitation in reflecting the underlying pathophysiology, and to heterogeneity within groups diagnosed with the same psychiatric disease [5]. Thus, attempts have emerged to suggest the novel classification of mental disorders that reflects biological mechanisms, such as Research Domain Criteria (RDoC) and biological classification of mental disorders (BeCOME) study ^[6][7][6,7]. Furthermore, many studies have aimed to identify the pathomechanism of depression to overcome the limitations of other existing tools for its diagnosis and treatment.

In addition to the well-known monoaminergic neurotransmitter dysfunction, altered hypothalamic-pituitary-adrenal (HPA) axis activity, dysfunctional brain network activity, impaired neurotrophic factor signaling, and neuroinflammation have been implicated in depression and studied for potential diagnostic biomarkers and therapeutic targets ^[8][9][10][8,9,10]. Additionally, changes in brain structure ^[11][12][11,12], gastrointestinal factors ^[13][14][13,14], oxidative stress [15], and endocannabinoid system components [16] have also been implicated in depression [17]. In addition, correlation studies for the aforementioned biomarkers such as inflammatory factors and brain structural changes also have been conducted in depression ^[18][19][18,19]. Family, twin, and adoption studies suggest that genetic factors account for 30–40% of the variance in depression risk [20], but early genome-wide association studies (GWASs) failed to identify genetic variants strongly associated with depression, suggesting that genetic susceptibility is mediated by heterogeneous combinations of risk alleles ^[21][22][23][21,22,23]. However, recent GWASs have identified several genetic loci reproducibly associated with depression ^{[24][25][26][27][28]}[24,25,26,27,28].

The remaining 60–70% of the variation in depression risk appears to be determined by environmental factors [29]. Environmental stressors such as physical, emotional, and sexual abuse, social rejection, and other early adverse experiences and stressful life events such as the death of a loved one, illness, injury, disability, and functional decline are demonstrated risk factors for depression ^[30][31][32][30,31,32]. Individual variations in susceptibility to such stimuli may be explained in part by genetic factors. Indeed, a gene-environment interaction model positing that penetrant and complex genetic predispositions interact with environmental factors to determine depression susceptibility is now widely accepted [33].

In this gene-environmental interaction model, epigenetic mechanisms act as a bridge between genes and environmental factors [34]. Epigenetics refers to “heritable, but reversible, regulation of various genomic functions mediated principally through changes in DNA methylation and chromatin structure” [35]. Thus, epigenetic mechanisms are the processes by which various types of cells within the same organism acquire unique transcriptional properties and functions during development [36]. This dynamic and reversible process also contributes to the transcriptional plasticity manifested by the neurons and glia in the brain. Therefore, it is associated with learning and memory, age-related neurodegeneration, cognitive and behavioral effects of early experiences, repeated drug exposure, chronic stress, prolonged changes in nutritional status, and exposure to environmental toxins [37]. The functional analyses of DNA methylation quantitative trait locus (meQTL) and non-coding RNA (ncRNA) in depression-associated single nucleotide polymorphisms (SNPs) revealed that alterations in DNA methylation and ncRNAs interact with genetic factors in depression, which underscores the importance of epigenetic regulation for depression [38].