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Epigenetics factors in schizophrenia: future directions for etiologic and therapeutic study approaches

Annals of General Psychiatry volume 24, Article number: 21 (2025) Cite this article

Abstract

Schizophrenia is a complex, heterogeneous, and highly disabling severe mental disorder whose pathogenesis has not yet been fully elucidated. Epigenetics, as a bridge between genetic and environmental factors, plays an important role in the pathophysiology of schizophrenia. Over the past decade, epigenetic-wide association studies have rapidly become an important branch of psychiatric research, especially in deciphering the molecular mechanisms of schizophrenia. This review systematically analyzes recent advances in epigenome-wide association studies (EWAS) of schizophrenia, focusing on technological developments. We synthesize findings from large-scale EWAS alongside emerging evidence on DNA methylation patterns, histone modifications, and regulatory networks, emphasizing their roles in disease mechanisms and treatment responses. In addition, this review provides a prospective outlook, evaluating the impact that technological developments may have on future studies of schizophrenia. With the continuous advancement of high-throughput sequencing technology and the increasing maturity of big data analysis methods, epigenetics is expected to have a significant impact on the early diagnosis, prognosis assessment and even personalized treatment of schizophrenia.

Introduction

Schizophrenia is a serious mental disorder with an insidious, heterogeneous and complicated onset and poor prognosis, characterized by a series of symptoms such as hallucinations, delusions, disorganized thinking, emotional flatness, cognitive deficits, or behavioral abnormalities, which affects about 1% of the global population, resulting in a huge burden of disease [1,2,3]. Even though research in the past decades has yielded remarkable genetic findings that schizophrenia is a polygenic disorder, the etiology of schizophrenia remains poorly understood.

Genome-wide association studies (GWAS) have provided genetic evidence for the pathogenesis of schizophrenia, with 287 genetic loci associated with schizophrenia reported in 2022 [4]. On the other hand, the “second hit” hypothesis of schizophrenia has enormous implications in etiology, indicating that a variety of environmental factors, such as adverse events before and after pregnancy, as well as childhood and adolescent traumas including abuse or neglect, stressful events and social ostracism, may interact with genetic risk factors to trigger the onset of schizophrenia [5, 6]. Epigenetics, for its part, explores the interrelationships between environmental risk factors and genetics, providing a novel perspective on the pathophysiological mechanisms and genetic variation of schizophrenia, and potentially revealing new therapeutic targets [7]. Recent technological advances in epigenome-wide association studies (EWAS) have revolutionized our understanding of the epigenetic landscape of schizophrenia.

In recent years, the emergence of high-throughput sequencing and comprehensive methylation arrays has facilitated the identification of novel epigenetic signatures associated with disease onset, progression, and treatment response, with recent EWAS employing these technologies to assess epigenetic marks across the genome [8, 9]. These EWASs have been instrumental in identifying differentially methylated regions and histone modification patterns that are associated with schizophrenia [10, 11]. Indeed, by comparing the epigenetic profiles of schizophrenia patients with those of healthy controls, researchers have begun to unravel the complex epigenetic architecture that may underlie the disorder’s phenotypic variability [6]. Recent EWAS have revealed several key findings: the identification of differential methylation patterns in specific genomic regions, the discovery of novel epigenetic markers associated with treatment response, and the integration of methylation data with genetic risk factors [11,12,13]. Furthermore, EWAS have identified numerous epigenetic modifications in schizophrenia that are involved in critical biological pathways, including neurodevelopment, synaptic plasticity and immune function [5, 14, 15]. For instance, aberrant methylation patterns have been found in genes related to dopaminergic and glutamatergic neurotransmission, suggesting a link between epigenetic regulation and the neurotransmitter imbalances observed in schizophrenia [16, 17].

The etiology of schizophrenia is intricate and this brief review highlights the potential pathophysiologic role of epigenetics in schizophrenia and the relationship with clinical symptoms and therapies. Integrating epigenetic data with schizophrenia information will provide a more holistic view of the disease mechanisms.

Literature selection approach

While this is not a systematic review, we applied specific criteria to ensure the quality and relevance of included studies. We focused on peer-reviewed publications from 2000 to 2024, with emphasis on recent developments since 2020. For inclusion, studies needed to: (1) directly investigate epigenetic mechanisms in schizophrenia; (2) employ validated measurement methods; (3) include appropriate controls; and (4) provide clear statistical analysis. We prioritized studies with larger sample sizes (≥ 50 participants for human studies) and those that provided replication or validation of findings. Both clinical and basic research studies using various sample types (post-mortem brain tissue, peripheral blood, and animal models) were considered.

Regulatory processes in epigenetics

Epigenetic studies have revealed that many exogenous and endogenous factors, such as environmental exposures, developmental processes and gene-environment interactions influence gene expression without altering gene sequences via a variety of primary processes that include DNA methylation, histone modification and non-coding RNA (ncRNA) expression [18, 19]. DNA methylation is a complex and dynamic epigenetic modification process, wherein a methyl group (-CH3) is added to the fifth carbon atom of cytosine in DNA molecules by specific enzymes—DNA methyltransferases—predominantly occurring at the cytosine and guanine (CG) dinucleotide sequences, known as CpG sites [20, 21]. This chemical modification not only regulates gene expression and affects gene activity but also plays a crucial role in cell differentiation, development, and various physiological and pathological processes. Histone modification refers to the post-translational chemical modifications of histone proteins within chromatin, including but not limited to acetylation, methylation, and phosphorylation [22]. These modifications predominantly occur on the tails or globular domains of histones in nucleosomes, the fundamental units of chromatin [23]. By altering the interaction between histones and DNA, these modifications can influence chromatin structure and dynamics, thereby regulating gene expression and other DNA-dependent processes [24]. The ncRNA molecules do not encode proteins but can be involved in regulating gene expression, such as preventing the production of proteins by interfering with the translation or stability of mRNAs [25]. The etiology of schizophrenia is still uncertain, and existing research has indicated that it may be the result of a combination of genetic and environmental risk factors that are directly related to relevant regulatory mechanisms of epigenetics.

Relationship between environmental risk factors and schizophrenia

The pathogenesis of schizophrenia is multifaceted, with genetic, biochemical and neuroanatomical factors having a significant impact on the onset of schizophrenia; however, environmental risk factors as “second-hit” predisposing factors such as maternal pregnancy, stress, trauma and other undesirable factors play an important role in the occurrence of this disorder. As shown in Fig. 1.

Fig. 1
figure 1

Overview of the epigenetics of schizophrenia. Genetic and environmental risk factors interact and play an important role in the pathogenesis of schizophrenia. Negative factors during maternal pregnancy and adverse life events during childhood and adolescence may possibly trigger altered epigenetics

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Pregnancy is a crucial period for fetal brain development. Although previous study suggested that adverse events during this period may activate microglia in the fetal brain, potentially leading to significant impacts on future psychological health, the evidence in this area was still variable and influenced by factors such as sex and the timing of gestation [26]. Existing research provides the first empirical evidence that early-life environmental conditions during pregnancy can lead to epigenetic alterations in humans, which persist throughout an individual's lifetime [27]. It has been shown that experiencing extreme stress and adverse life events such as famine, emotional stress and substance abuse may stimulate alterations in the epinephrine system, increasing the risk of development of schizophrenia in offspring [28, 29]. Trauma suffered by individuals during childhood or adolescence, such as abuse or neglect, affects the stress system and may contribute to long-term neurodevelopmental and emotional regulation difficulties, and has been recognized as an important predictor of the onset of schizophrenia [30,31,32]. Chronic stress or sudden major stressful life events, including unemployment and loss of a loved one, among other factors, has also been implicated in the onset of schizophrenia [33,34,35]. Stressful events may trigger or exacerbate schizophrenia, especially in adolescents and those who are genetically predisposed to the disease [36, 37]. Alterations in hormone and cytokine levels and neuronal plasticity resulting from the stress response may also be an important factor in the pathogenesis of schizophrenia [38,39,40]. Furthermore, prolonged social exclusion has been shown to increase the likelihood of schizophrenic episodes by increasing an individual's psychological stress and disrupting social support systems [41, 42]. Likewise, social exclusion has been found to be associated with cognitive deficits, decreased self-efficacy and increased negative emotions [43, 44].

Environmental factors may play a crucial role in the development of schizophrenia, especially when they interact with genes. Early interventions targeting environmental factors and ongoing psychosocial support may help to reduce the onset of schizophrenia and improve patient prognosis. Future research needs to focus on how to fine-tune interactions between environmental factors interact genes to develop more effective prevention and treatment strategies.

Epigenetics and schizophrenia

DNA methylation and schizophrenia

DNA methylation levels are altered in patients with schizophrenia and correlated with clinical symptoms

Development and functional maintenance of the nervous system depend on precise, spatiotemporal-specific regulation of gene expression, which is affected by DNA methylation-mediated gene modifications that in turn regulate neuronal differentiation and maturation as well as regulate neural network formation [45]. For example, the regulation of brain-derived neurotrophic factor (BDNF), which plays a key role in brain developmental processes and neuroplasticity [46, 47], is strongly associated with DNA methylation. Furthermore, the BDNF gene and its methylation are known to be significantly associated with the etiology of schizophrenia [48, 49]. Several studies have demonstrated that abnormal DNA methylation of genes such as GAD67, MARLIN-1, KCNJ6, HELT, DRDs and NR3B, which encode for γ-aminobutyric acid (GABA), glutamate, 5-hydroxytryptophan, N-methyl-D-aspartate receptors (NMDAR) and dopamine, among others—neurotransmitters associated with the pathological mechanisms of schizophrenia—occurs in schizophrenic patients [10, 16, 50]. Mill et al. conducted a comprehensive DNA methylation analysis of the major psychosis, revealing distinct epigenetic profiles in schizophrenia [51]. Their seminal work demonstrated significant disease-associated methylation differences at numerous loci, particularly in genes involved in neurotransmitter metabolism and neurodevelopment. The affected genes are also involved in a variety of key processes in neurodevelopment and neurotransmission, such as the methylation the MB-COMT promoter and DRD2 and NR3C1 genes, all of which are closely related to the dopamine D2 receptor. Interestingly, expression of these genes is significantly altered in schizophrenia patients compared with healthy controls, and has been shown to affect neurotransmitter signaling [52] and the DNA methylation status of the TCF4 promoter region [53]. Changes in the methylation of CCL17, MMP10 and PRG2 have also been shown to be significantly associated with the core symptom of cognitive dysfunction in schizophrenia [13]. In addition, hypermethylation of the SHANK3 promoter has been found to be negatively correlated with the left inferotemporal cortex surface volume and positively correlated with negative symptoms in patients with schizophrenia [54]. A study of postmortem brain examinations in patients with schizophrenia found altered methylation of RELN, GAD67, COMT, NR3B, GRIA2 and FOXP2 genes [10]. DNA methylation is associated with the pathophysiology of schizophrenia, providing new perspectives on explaining the etiology of this complex disorder.

DNA methylation correlates with treatment response in schizophrenia

DNA methylation positions (DMPs) or regions (DMRs) influence patient response to treatment, as found in patients treated with the antipsychotic drug risperidone. Interestingly, CYP46A1, SPATS2 and ATP6V1E1 have a significant number of DMPs, whereas the two most significant DMRs were located on Chr7 and Chr9, corresponding to the PTPRN2 and EHMT1 gene, respectively, suggesting that alterations in the methylation of specific genes associated with the response to antipsychotics are related to synaptic function and neurotransmission [55]. Recently, the latest epigenome-wide study identified 82 major methylation loci related to antipsychotic drug treatment [56]. In particular, MTHFR, which is significantly associated with schizophrenia, was shown to affect histamine metabolism, catecholamine metabolism, serotonin metabolism, oxidative stress, DNA methylation and nicotinamide synthesis, and has become a hot research area in the targeted treatment of severe mental disorders [57]. Furthermore, the interaction of the risk genes LINC01795, DDHD2, SBNO1, KCNG2, SEMA7A and RUFY1 and epigenetics, by methylation quantitative trait loci analysis, relevant to schizophrenia has been linked to treatment response [58]. In patients with tardive dyskinesia (TD), a severe adverse reaction to medications in schizophrenia, the methylation level of the CYP2E1 gene promoter at the CpG sites was lower than that of healthy controls and non-TD patients, suggesting that aberrant DNA methylation may be a potential etiology of TD [59]. The DNA methyltransferase 1 inhibitor RG108 was found to reduce the hypermethylation status of Gad67, Reln and Bdnf in a mouse model, providing a new research approach for the treatment of schizophrenia [60]. Recent review has highlighted the potential role of epigenetic regulation in TRS, particularly focusing on the relationship between DNA methylation patterns of genes such as Gad1, Reln, and Bdnf, and the therapeutic effects of antipsychotics including clozapine and mGlu2/3 receptor agonists [61]. As shown in Table 1. However, the results of studies on the association of DNA methylation with treatment-resistant schizophrenia (TRS) have been inconsistent. The inconsistent results regarding DNA methylation in TRS may be attributed to several factors: (1) the intrinsic pathophysiological characteristics of TRS, (2) interspecies differences between human and murine models, and crucially, (3) tissue-specific variations in epigenetic modifications. For instance, while Chen et al. demonstrated that specific blood DNA methylation patterns correlate with functional alterations in the dorsolateral prefrontal cortex and hippocampus [62], the direct extrapolation of peripheral findings to brain tissue necessitates careful consideration.

Table 1 Key DNA methylation findings in schizophrenia studies
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Perspectives on DNA methylation in schizophrenia studies

DNA methylation has become a promising biomarker for the diagnosis and treatment of schizophrenia due to its dynamic and reversible nature, which is the focus of ongoing research as to whether it can be used for early identification of schizophrenia patients, monitoring of disease progression and prediction of treatment effects. Meanwhile, specific blood DNA methylation characteristics of schizophrenia are associated with functional alterations in the dorsolateral prefrontal cortex and hippocampus, as well as with methylation differences in postmortem brain samples [62], and epigenetic clocks may bridge the gap between risk factors and aging in schizophrenia and potentially predict aging outcomes [63]. Further studies integrating large-scale cohort analyses and molecular mechanism investigations are essential to elucidate the complex role of epigenetics in schizophrenia and translate this knowledge into clinical applications to enhance patient quality of life.

Histone modifications and schizophrenia

Histone modifications constitute an important epigenetic mechanism that affects chromatin structure and gene expression, and mainly comprise four forms: histone methylation, deacetylation, histone acetylation and phosphorylation. Histone acetylation is commonly associated with the activation of gene expression, whereas histone methylation can induce the activation or inhibition of gene expression depending on the amino acid residue and the extent to which it occurs [64,65,66]. It is important to note that histone modification patterns exhibit substantial tissue specificity. While postmortem brain studies provide direct evidence of epigenetic alterations in relevant neural tissues (e.g., HDAC2 changes in the dorsolateral prefrontal cortex) [67, 68], findings from peripheral tissues should be interpreted with caution.

Histone modifications are altered in schizophrenia and correlate with clinical symptoms

Histone modifications alter the compactness of chromatin, which in turn affects the accessibility of regulatory proteins, such as transcription factors, to DNA [69, 70]. It has been shown that variants in the histone deacetylase of NAD + , commonly known as acetylase (SIRT)− 1, increase the risk of developing schizophrenia [71]. Furthermore, schizophrenia risk gene variants are enriched in the histone H3K4me methylation region of the prefrontal cortex, and multiple loci related to the upper- and lower-regulation of schizophrenia risk gene expression were identified in the H3K4me chromatin region [72]. Variations in histone modifications have been considered as one of the possible molecular bases of clinical symptoms in schizophrenia. Interestingly, histone acetylation and methylation have been found to determine oligodendrocyte and myelin susceptibility in schizophrenia, and histone acetylase and methylase activities are severely dysregulated in schizophrenia [14]. Meanwhile, the histone modification-related genes H3F3B and NSD2 have been found to be associated with clinical symptoms schizophrenia [73], and the relationship between histone acetylation and cognitive deficits in schizophrenia has also been reported [74]. Furthermore, significantly reduced levels of the histone deacetylase HDAC2 in the dorsolateral prefrontal cortex were found in a study of the postmortem brain of patients with schizophrenia [67]. Taken together these findings suggest that histone modifications may be important epigenetic regulators affecting schizophrenia.

Histone modifications associated with schizophrenia treatment

Abnormalities in histone modifications may be related with schizophrenia pathogenesis, treatment response and genetic predisposition [75]. Histone modifications have become the centerpiece of the therapeutic outcomes of several antipsychotics such as quetiapine, clozapine, risperidone, olanzapine and aripiprazole, and may be possible predictors of therapeutic effects [76, 77]. In addition, histone modifying enzymes may have potential therapeutic roles in schizophrenia. For example, as reported by Kurita et al. [78] the mGlu2 receptor gene was found to be downregulated by histone deacetylation in the frontal cortex of schizophrenia patients and mice administered long-term doses clozapine and risperidone. The authors also found increased expression of HDAC2 and decreased expression of mGlu2 in the prefrontal cortex of mouse models induced to have schizophrenia-like behavior. Furthermore, the expression of three H3K9me-specific scavenging histone demethylases, KDM4B, KDM1A and PHF2, were found to be increased in olanzapine-treated rats [79]. These findings provide new ideas for therapeutic research to understand histone modification abnormalities in schizophrenia. Targeting specific histone modification by using pharmacological interventions that modify enzymes may help to correct modification abnormalities. For example, HDAC inhibitors of histone deacetylase have been demonstrated to modulate gene expression and improve cognitive dysfunction and other related schizophrenia symptoms [61]. Although the application of such agents is still in the exploratory phase, the findings suggest the possibility of histone-modifying enzymes as potential therapeutic targets for schizophrenia. Histone modifications in schizophrenia and treatment response as shown in Table 2.

Table 2 Histone modifications in schizophrenia and treatment response
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The ncRNA and schizophrenia

The microRNA and schizophrenia

The microRNAs (miRNAs) are a class of small molecule RNAs of about 22 nucleotides, which regulate gene expression by complementary pairing with the 3' non-coding region of target messenger RNA (mRNA). In the nervous system, miRNAs regulate a variety of life activities such as neuronal differentiation, synapse formation, and plasticity, which are essential for the normal development and function of the nervous system [80]. For example, miRNAs are able to respond to environmental stimuli and participate in cognitive processes such as learning and memory by precisely regulating the stability of target mRNAs or their protein synthesis [81, 82]. In individuals with schizophrenia, several studies have identified altered expression levels of a range of miRNAs, several of which may be involved in in pathophysiological processes such as altered dopamine, glutamate, GABA serotonin synthesis; BDNF expression, oxidative stress, inflammation and immunity [83]. A series of miRNAs target genes are generally implicated in neurotransmitter release, related signaling pathways, and neurodevelopmental processes [84]. Clinical studies suggest that abnormal miRNA expression may be associated with clinical symptoms, course of illness and medication response in schizophrenia [85, 86]. A longitudinal study by Antimonic et al. in a population of at extreme high risk for psychosis patients showed that plasma miR-150-5p and miR-3191-5p variants were significantly correlated with psychotic episodes, and that the correlations were independent of age, sex, cannabis and substance use [87].

In patients with TRS, the proteins p53, SIRT1, MDM2 and TRIM28 may play a mediating role between TRS and the stress response, and that miRNA-regulated molecular pathways may be correlated with symptoms of TRS [88]. A Mendelian randomization study suggested a causal relationship between six miRNAs: hsa-miR-570-3p, hsa-miR-550a-3p, hsa-miR-130a-3p, hsa-miR-210, hsa-miR-337-3p, and hsa-miR-130b-3p and schizophrenia [89]. In a mouse model, miRNA-124-3p expression was found to be upregulated in the medial prefrontal cortex, which in turn increased GRIA2-deficient calcium channel-type AMPA receptor permeability and disrupted AMPA receptor-mediated excitatory synaptic transmission. Taken together the results suggest that the miRNA-124-3pAMPAR pathway is involved in the generation of schizophrenia-like behavior [90].

Long non-coding RNAs and schizophrenia

Long non-coding RNAs (lncRNAs) are large RNA molecules more than 200 nucleotides in length, capable of forming complex three-dimensional structures through various mechanisms such as pairing and folding, thus participating in the regulation of gene expression [91]. Recent studies have revealed that specific lncRNAs are dysregulated in schizophrenia; for instance, Eghtedarian et al. found that Lnc-FOXF1 expression was significantly elevated in the blood of schizophrenic patients compared with healthy controls [92]. In addition, lower expression levels of LINC0046-lncRNA predicted a lower transcriptional level of LINC00461 in the hippocampus [93]. Furthermore, increased PNKY-lncRNA expression in TRS patients has strong diagnostic validity compared to BDNF and other lncRNAs such as BDNF-AS, MIR137HG, MIAT [94]. Mukhopadhyay et al. found that rs2072806 in the lncRNA hsaLB_IO39983 had a regulatory role in BTN3A2, which was associated with schizophrenia, and that rs2710323 in hsaLB_IO_2331 played a role in the dysregulation of ITIH1, which was associated with tardive dyskinesia. The authors also found that four lncRNA single nucleotide polymorphisms were associated with cognitive impairment [95]. The above mentioned lncRNAs may be involved in the progression of schizophrenia by regulating gene expression through influencing chromatin structure, miRNA stability and interactions with proteins [96, 97]. Establishing the exact role and clinical potential of these ncRNAs in schizophrenia will be an important aspect of schizophrenia research as future studies are conducted. Table 3 showed non-coding RNA studies in schizophrenia.

Table 3 Non-coding RNA studies in schizophrenia
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Epigenetic regulatory networks

A complex interplay between epigenetic factors exists, and factors such as DNA methylation, specific histone modifications and ncRNAs may act synergistically to regulate gene expression and affect neurotransmitters in the brain through different pathways [10, 56, 98, 99]. In schizophrenia, such interactions may contribute to persistent alterations in gene expression that could affect brain function and behavior. Recent studies have shown that the piggyBac transposable element-derived gene 1 (PGBD1) has DNA-binding activity, and DNA-binding assays have demonstrated specific binding of PGBD1 in the lncRNA NEAT1 promoter and the region within the gene itself [100]. Aberrant expression of specific miRNAs may alter DNA methylation patterns, which in turn affects the expression of related genes. In turn, changes in histone modifications may also affect miRNA expression, generating complex epigenetic feedback regulatory mechanisms [101, 102]. Epigenetic regulatory networks maintain normal nervous system function by regulating the expression of a large number of genes [103]. In the pathogenesis of schizophrenia, these networks may be disturbed due to genetic factors, environmental exposures and their interactions, and these disturbances may affect neuronal differentiation, migration, synaptic plasticity and neurotransmission, ultimately resulting in cognitive impairments, affective symptoms and social dysfunction in patients with schizophrenia [72, 104, 105].

Given the role of epigenetic regulatory networks in the pathogenesis of schizophrenia, therapeutic strategies that target specific epigenetic factors and their interactions hold great potential. Studies have focused on the development of drugs to modulate DNA methylation, histone modifications, and ncRNA expression with the aim of recovering or optimizing gene expression in patients with schizophrenia [106, 107]. Such therapeutic predictions may not only improve existing symptoms, but may also be valuable in preventing disease progression. Epigenetic regulatory networks are key bridges between genetic background, environmental factors and schizophrenia symptoms. With a deeper understanding of the function of these networks in association with schizophrenia, future strategies for the treatment of schizophrenia may focus more on the fine regulation of gene expression rather than just the traditional pharmacological modulation of the neurotransmission system.

Tissue specificity, methodological and medication considerations

A key consideration in interpreting epigenetic findings in schizophrenia research is the tissue-specificity of epigenetic modifications. Given the limited accessibility of brain tissue, researchers typically utilize blood or saliva as surrogate specimens [108]. While blood-based studies present practical advantages for biomarker development, the relationship between peripheral and central nervous system epigenetic patterns requires careful evaluation. Several studies have demonstrated correlations between blood-based epigenetic markers and brain-specific changes [62], whereas others highlight significant tissue-specific differences [109]. This tissue specificity must be taken into account when interpreting results and designing future studies. Furthermore, the use of different tissue types across studies (blood, postmortem brain tissue, or animal model tissues) may contribute to seemingly contradictory findings in the literature.

In addition to tissue-specific variations, the interpretation of epigenetic findings in schizophrenia research must account for the effects of medication as critical modifying factors [108]. Recent systematic reviews have revealed distinct epigenetic signatures associated with different antipsychotic medications—haloperidol tends to increase global DNA methylation, whereas clozapine promotes genome-wide hypomethylation. Moreover, antipsychotics exhibit selective effects on histone modifications in specific neural circuits, such as clozapine’s impact on H3K4me3 at the Gad1 gene in the prefrontal cortex [110]. This drug-specific epigenetic modulation introduces additional layer of complexity to understanding disease-related epigenetic alterations and emphasizes the importance of medication status in evaluating research findings.

Measurement tools in genetics and epigenetics research

With the rapid development of bioinformatics and statistics, new measurement tools have enabled researchers to analyze large datasets with greater precision, revealing the association between genetic variations and complex diseases, as well as how environmental factors influence gene expression through epigenetic mechanisms. This plays a crucial role in understanding genetic mechanisms and the onset of diseases. Measurement techniques and statistical methods in genetics are summarized in Table 4.

Table 4 Genetic and epigenetic measurement tools
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In the field of genetics, the analysis methods for GWAS are continually being optimized, enhancing the detection capability for genetic markers. For example, multivariate analysis methods can consider multiple phenotypes simultaneously, as opposed to traditional univariate GWAS analyses. The latest single-cell research technologies offer potential solutions to the heterogeneity that traditional population-level analysis cannot address [124]. By conducting detailed analyses of gene expression and epigenetic markers in individual cells, single-cell studies have revealed disease-related changes in different cell types within schizophrenia, as well as variations among patients [125, 126]. The advancement of EWAS technologies and analytical methods presents new opportunities for understanding schizophrenia. The integration of multi-omics data with clinical information may lead to more precise diagnostics.

Limitations

Our review has several limitations. First, the heterogeneity of methodologies and populations across studies makes direct comparisons difficult. Second, publication bias may be present, as negative findings are less likely to be published. Third, some of the included studies had relatively small sample sizes, particularly in biomarker identification studies, although we endeavored to focus on those with adequate statistical power and proper validation cohorts. Fourth, when citing review articles, we have made a concerted efforts to clearly differentiate between original research findings and conclusions derived from reviews, in order to prevent potential misinterpretation. Finally, while peripheral tissues offer more accessible samples for study, the degree to which these findings reflect brain-specific epigenetic changes remains uncertain. Future studies combining multiple tissue types and using advanced single-cell technologies may help overcome these limitations.

Conclusion

In summary, EWAS have revolutionized our understanding of the epigenetic landscape of schizophrenia. The integration of genome-wide methylation data with clinical information has provided novel insights into disease mechanisms and treatment responses. Future research should focus on leveraging these findings to develop personalized therapeutic approaches.

Data availability

No datasets were generated or analysed during the current study.

References

  1. Fišar Z. Biological hypotheses, risk factors, and biomarkers of schizophrenia. Prog Neuro-Psychopharmacol Biol Psychiatry. 2023;120:110626.

    Article  Google Scholar 

  2. Faden J, Citrome L. Schizophrenia: one name, many different manifestations. Med Clin North Am. 2023;107(1):61–72.

    Article  PubMed  Google Scholar 

  3. Saha S, Chant D, Welham J, McGrath J. A systematic review of the prevalence of schizophrenia. PLoS Med. 2005;2(5): e141.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Trubetskoy V, Pardinas AF, Qi T, Panagiotaropoulou G, Awasthi S, Bigdeli TB, et al. Mapping genomic loci implicates genes and synaptic biology in schizophrenia. Nature. 2022;604(7906):502–8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  5. Schmitt A, Falkai P, Papiol S. Neurodevelopmental disturbances in schizophrenia: evidence from genetic and environmental factors. J Neural Transm. 2023;130(3):195–205.

    Article  PubMed  Google Scholar 

  6. Richetto J, Meyer U. Epigenetic modifications in schizophrenia and related disorders: molecular scars of environmental exposures and source of phenotypic variability. Biol Psychiatry. 2021;89(3):215–26.

    Article  PubMed  CAS  Google Scholar 

  7. de Sousa TR, Dt C, Novais F. Exploring the hypothesis of a schizophrenia and bipolar disorder continuum: biological, genetic and pharmacologic data. CNS Neurol Disord Drug Targets. 2023;22(2):161–71.

    Article  PubMed  Google Scholar 

  8. Wahl S, Drong A, Lehne B, Loh M, Scott WR, Kunze S, et al. Epigenome-wide association study of body mass index, and the adverse outcomes of adiposity. Nature. 2016;541(7635):81–6.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Modi A, Vai S, Caramelli D, Lari M. The illumina sequencing protocol and the NovaSeq 6000 system. In: Mengoni A, Bacci G, Fondi M, editors. Bacterial pangenomics methods in molecular biology. New York: Humana; 2021. p. 15–42.

    Chapter  Google Scholar 

  10. Khavari B, Cairns MJ. Epigenomic dysregulation in schizophrenia: in search of disease etiology and biomarkers. Cells. 2020;9(8):1837.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  11. Hannon E, Dempster EL, Mansell G, Burrage J, Bass N, Bohlken MM, et al. DNA methylation meta-analysis reveals cellular alterations in psychosis and markers of treatment-resistant schizophrenia. Elife. 2021;10: e58430.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  12. Campos-Martin R, Bey K, Elsner B, Reuter B, Klawohn J, Philipsen A, et al. Epigenome-wide analysis identifies methylome profiles linked to obsessive-compulsive disorder, disease severity, and treatment response. Mol Psychiatry. 2023;28(10):4321–30.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  13. Kiltschewskij DJ, Reay WR, Geaghan MP, Atkins JR, Xavier A, Zhang X, et al. Alteration of DNA methylation and epigenetic scores associated with features of schizophrenia and common variant genetic risk. Biol Psychiatry. 2024;95(7):647–61.

    Article  PubMed  CAS  Google Scholar 

  14. Li M, Xiao L, Chen X. Histone acetylation and methylation underlie oligodendroglial and myelin susceptibility in schizophrenia. Front Cell Neurosci. 2022;16:823708.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  15. Alameda L, Liu Z, Sham PC, Aas M, Trotta G, Rodriguez V, et al. Exploring the mediation of DNA methylation across the epigenome between childhood adversity and First Episode of Psychosis-findings from the EU-GEI study. Mol Psychiatry. 2023;28(5):2095–106.

    Article  PubMed  CAS  Google Scholar 

  16. Pries LK, Guloksuz S, Kenis G. DNA methylation in schizophrenia. Adv Exp Med Biol. 2017;978:211–36.

    Article  PubMed  CAS  Google Scholar 

  17. Forero DA, González-Giraldo Y. Integrative in silico analysis of genome-wide DNA methylation profiles in schizophrenia. J Mol Neurosci. 2020;70(11):1887–93.

    Article  PubMed  CAS  Google Scholar 

  18. Spadafora C. The epigenetic basis of evolution. Prog Biophys Mol Biol. 2023;178:57–69.

    Article  PubMed  CAS  Google Scholar 

  19. Chen X, Xu H, Shu X, Song CX. Mapping epigenetic modifications by sequencing technologies. Cell Death Differ. 2023. https://doiorg.publicaciones.saludcastillayleon.es/10.1038/s41418-023-01213-1.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Haig D. The (dual) origin of epigenetics. Cold Spring Harb Symp Quant Biol. 2004;69:67–70.

    Article  PubMed  CAS  Google Scholar 

  21. Mattei AL, Bailly N, Meissner A. DNA methylation: a historical perspective. Trends Genet. 2022;38(7):676–707.

    Article  PubMed  CAS  Google Scholar 

  22. Lawrence M, Daujat S, Schneider R. Lateral thinking: how histone modifications regulate gene expression. Trends Genet. 2016;32(1):42–56.

    Article  PubMed  CAS  Google Scholar 

  23. Bannister AJ, Kouzarides T. Regulation of chromatin by histone modifications. Cell Res. 2011;21(3):381–95.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  24. Song H, Shen R, Liu X, Yang X, Xie K, Guo Z, et al. Histone post-translational modification and the DNA damage response. Genes Dis. 2023;10(4):1429–44.

    Article  PubMed  CAS  Google Scholar 

  25. Olufunmilayo EO, Holsinger RMD. Roles of non-coding RNA in Alzheimer’s disease pathophysiology. Int J Mol Sci. 2023;24(15):12498.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  26. Mawson ER, Morris BJ. A consideration of the increased risk of schizophrenia due to prenatal maternal stress, and the possible role of microglia. Prog Neuro-Psychopharmacol Biol Psychiatry. 2023;125:110773.

    Article  CAS  Google Scholar 

  27. Heijmans BT, Tobi EW, Stein AD, Putter H, Blauw GJ, Susser ES, et al. Persistent epigenetic differences associated with prenatal exposure to famine in humans. Proc Natl Acad Sci USA. 2008;105(44):17046–9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  28. Fineberg AM, Ellman LM, Schaefer CA, Maxwell SD, Shen L, Chaudhury NH, et al. Fetal exposure to maternal stress and risk for schizophrenia spectrum disorders among offspring: differential influences of fetal sex. Psychiatry Res. 2016;236:91–7.

    Article  PubMed  Google Scholar 

  29. Peedicayil J. Genome-environment interactions and psychiatric disorders. Biomedicines. 2023;11(4):1209.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  30. Lee SH, Jung E-M. Adverse effects of early-life stress: focus on the rodent neuroendocrine system. Neural Regen Res. 2024;19(2):336–41.

    Article  PubMed  CAS  Google Scholar 

  31. Oginga FO, Mpofana T. The impact of early life stress and schizophrenia on motor and cognitive functioning: an experimental study. Front Integr Neurosci. 2023;17:1251387.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Köhler-Forsberg O, Ge F, Hauksdóttir A, Thordardottir EB, Ásbjörnsdóttir K, Rúnarsdóttir H, et al. Adverse childhood experiences and psychological functioning among women with schizophrenia or bipolar disorder: population-based study. Br J Psychiatry. 2023;224(1):6–12.

    Article  Google Scholar 

  33. Matsunaga M, Li Y, He Y, Kishi T, Tanihara S, Iwata N, et al. Physical, psychiatric, and social comorbidities of individuals with schizophrenia living in the community in Japan. Int J Environ Res Public Health. 2023;20(5):4336.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Tay DL, Thygesen LC, Kozlov E, Ornstein KA. Serious mental illness exacerbation post-bereavement: a population-based study of partners and adult children. Clin Epidemiol. 2022;14:1065–77.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Misra S, Gelaye B, Koenen KC, Williams DR, Borba CPC, Quattrone D, et al. Early parental death and risk of psychosis in offspring: a six-country case-control study. J Clin Med. 2019;8(7):1081.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Warrier V, Kwong ASF, Luo M, Dalvie S, Croft J, Sallis HM, et al. Gene-environment correlations and causal effects of childhood maltreatment on physical and mental health: a genetically informed approach. Lancet Psychiatry. 2021;8(5):373–86.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Perez SM, Lodge DJ. Adolescent stress contributes to aberrant dopamine signaling in a heritable rodent model of susceptibility. Prog Neuropsychopharmacol Biol Psychiatry. 2019;95:109701.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  38. King S, Mothersill D, Holleran L, Patlola SR, Burke T, McManus R, et al. Early life stress, low-grade systemic inflammation and weaker suppression of the default mode network (DMN) during face processing in Schizophrenia. Transl Psychiatry. 2023;13(1):213.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Howes OD, Onwordi EC. The synaptic hypothesis of schizophrenia version III: a master mechanism. Mol Psychiatry. 2023;28(5):1843–56.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Brandt JM, Hemager N, Ellersgaard D, Gregersen M, Søndergaard A, Ohland J, et al. Hair cortisol concentrations and daily life stress in 7-year-old children at familial high-risk of schizophrenia or bipolar disorder: The Danish High Risk and Resilience Study—VIA 7. Prog Neuro-Psychopharmacol Biol Psychiatry. 2023;125:110750.

    Article  CAS  Google Scholar 

  41. Reinhard MA, Dewald-Kaufmann J, Wustenberg T, Musil R, Barton BB, Jobst A, et al. The vicious circle of social exclusion and psychopathology: a systematic review of experimental ostracism research in psychiatric disorders. Eur Arch Psychiatry Clin Neurosci. 2020;270(5):521–32.

    Article  PubMed  Google Scholar 

  42. Dodell-Feder D, Shovestul B, Woodyatt J, Popov V, Germine L. Social anhedonia, social networks, and psychotic-like experiences: a test of social deafferentation. Psychiatry Res. 2020;284:112682.

    Article  PubMed  Google Scholar 

  43. Reddy LF, Irwin MR, Breen EC, Reavis EA, Green MF. Social exclusion in schizophrenia: psychological and cognitive consequences. J Psychiatr Res. 2019;114:120–5.

    Article  PubMed  Google Scholar 

  44. Jaya ES, Pillny M, Lincoln TM, Riehle M. Does social defeat cause negative symptoms? A prospective study in a multi-national community sample. Compr Psychiatry. 2022;113:152289.

    Article  PubMed  Google Scholar 

  45. Fodder K, de Silva R, Warner TT, Bettencourt C. The contribution of DNA methylation to the (dys)function of oligodendroglia in neurodegeneration. Acta Neuropathol Commun. 2023;11(1):106.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  46. Zhu JH, Bo HH, Liu BP, Jia CX. The associations between DNA methylation and depression: a systematic review and meta-analysis. J Affect Disord. 2023;327:439–50.

    Article  PubMed  CAS  Google Scholar 

  47. Treble-Barna A, Heinsberg LW, Stec Z, Breazeale S, Davis TS, Kesbhat AA, et al. Brain-derived neurotrophic factor (BDNF) epigenomic modifications and brain-related phenotypes in humans: a systematic review. Neurosci Biobehav Rev. 2023;147:105078.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  48. Farcas A, Hindmarch C, Iftene F. BDNF gene Val66Met polymorphisms as a predictor for clinical presentation in schizophrenia—recent findings. Front Psychiatry. 2023;14:1234220.

    Article  PubMed  PubMed Central  Google Scholar 

  49. van den Oord E, Xie LY, Zhao M, Campbell TL, Turecki G, Kahler AK, et al. Genes implicated by a methylome-wide schizophrenia study in neonatal blood show differential expression in adult brain samples. Mol Psychiatry. 2023;28(5):2088–94.

    Article  PubMed  Google Scholar 

  50. Flynn LT, Gao WJ. DNA methylation and the opposing NMDAR dysfunction in schizophrenia and major depression disorders: a converging model for the therapeutic effects of psychedelic compounds in the treatment of psychiatric illness. Mol Psychiatry. 2023. https://doiorg.publicaciones.saludcastillayleon.es/10.1038/s41380-023-02235-4.

    Article  PubMed  PubMed Central  Google Scholar 

  51. Mill J, Tang T, Kaminsky Z, Khare T, Yazdanpanah S, Bouchard L, et al. Epigenomic profiling reveals DNA-methylation changes associated with major psychosis. Am J Hum Genet. 2008;82(3):696–711.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  52. Aytac HM, Oyaci Y, Pehlivan M, Pehlivan S. DNA methylation pattern of gene promoters of MB-COMT, DRD2, and NR3C1 in Turkish patients diagnosed with schizophrenia. Clin Psychopharmacol Neurosci. 2022;20(4):685–93.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  53. Yazarlou F, Tabibian M, Azarnezhad A, Sadeghi Rad H, Lipovich L, Sanati G, et al. Evaluating gene expression and methylation profiles of TCF4, MBP, and EGR1 in peripheral blood of drug-free patients with schizophrenia: correlations with psychopathology, intelligence, and cognitive impairment. J Mol Neurosci. 2023;73(9–10):738–50.

    Article  PubMed  CAS  Google Scholar 

  54. Ni P, Zhou C, Liang S, Jiang Y, Liu D, Shao Z, et al. YBX1-Mediated DNA methylation-dependent SHANK3 expression in PBMCs and developing cortical interneurons in schizophrenia. Adv Sci. 2023;10(20): e2300455.

    Article  Google Scholar 

  55. Du H, Ma J, Zhou W, Li M, Huai C, Shen L, et al. Methylome-wide association study of different responses to risperidone in schizophrenia. Front Pharmacol. 2022;13:1078464.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  56. Rowbal T, Kajy M, Burghardt KJ. Epigenome-wide studies of antipsychotics: a systematic review and pathway meta-analysis. Epigenomics. 2023;15(20):1085–94.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  57. Fryar-Williams S, Strobel J, Clements P. Molecular mechanisms provide a landscape for biomarker selection for schizophrenia and schizoaffective psychosis. Int J Mol Sci. 2023;24(20):15296.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  58. Guo LK, Su Y, Zhang YY, Yu H, Lu Z, Li WQ, et al. Prediction of treatment response to antipsychotic drugs for precision medicine approach to schizophrenia: randomized trials and multiomics analysis. Mil Med Res. 2023;10(1):24.

    PubMed  PubMed Central  CAS  Google Scholar 

  59. Zhang P, Li Y, Wang K, Huang J, Su BB, Xu C, et al. Altered DNA methylation of CYP2E1 gene in schizophrenia patients with tardive dyskinesia. BMC Med Genom. 2022;15(1):253.

    Article  CAS  Google Scholar 

  60. Wawrzczak-Bargiela A, Bilecki W, Mackowiak M. Epigenetic targets in schizophrenia development and therapy. Brain Sci. 2023;13(3):426.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  61. Matrisciano F. Epigenetic regulation of metabotropic glutamate 2/3 receptors: potential role for ultra-resistant schizophrenia? Pharmacol Biochem Behav. 2023;229:173589.

    Article  PubMed  CAS  Google Scholar 

  62. Chen J, Zang Z, Braun U, Schwarz K, Harneit A, Kremer T, et al. Association of a reproducible epigenetic risk profile for schizophrenia with brain methylation and function. JAMA Psychiat. 2020;77(6):628–36.

    Article  Google Scholar 

  63. Higgins-Chen AT, Boks MP, Vinkers CH, Kahn RS, Levine ME. Schizophrenia and epigenetic aging biomarkers: increased mortality, reduced cancer risk, and unique clozapine effects. Biol Psychiat. 2020;88(3):224–35.

    Article  PubMed  CAS  Google Scholar 

  64. Kitazawa R, Haraguchi R, Kitazawa S. Histone modification in histochemistry and cytochemistry. Acta Histochem Cytochem. 2023;56(3):41–7.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  65. Meng Y, Du J, Liu N, Qiang Y, Xiao L, Lan X, et al. Epigenetic modulation: research progress on histone acetylation levels in major depressive disorders. J Drug Target. 2023;31(2):142–51.

    Article  PubMed  CAS  Google Scholar 

  66. Zhang L, Zhou T, Su Y, He L, Wang Z. Involvement of histone methylation in the regulation of neuronal death. J Physiol Biochem. 2023;79(4):685–93.

    Article  PubMed  Google Scholar 

  67. Schroeder FA, Gilbert TM, Feng N, Taillon BD, Volkow ND, Innis RB, et al. Expression of HDAC2 but not HDAC1 transcript is reduced in dorsolateral prefrontal cortex of patients with schizophrenia. ACS Chem Neurosci. 2017;8(3):662–8.

    Article  PubMed  CAS  Google Scholar 

  68. Martínez-Peula O, Morentin B, Callado LF, Meana JJ, Rivero G, Ramos-Miguel A. Permissive epigenetic regulatory mechanisms at the histone level are enhanced in postmortem dorsolateral prefrontal cortex of individuals with schizophrenia. J Psychiatry Neurosci. 2024;49(1):E35-e44.

    Article  PubMed  PubMed Central  Google Scholar 

  69. Abdallah DI, de Araujo ED, Patel NH, Hasan LS, Moriggl R, Kramer OH, et al. Medicinal chemistry advances in targeting class I histone deacetylases. Explor Target Antitumor Ther. 2023;4(4):757–79.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  70. Joseph FM, Young NL. Histone variant-specific post-translational modifications. Semin Cell Dev Biol. 2023;135:73–84.

    Article  PubMed  CAS  Google Scholar 

  71. Leite JA, Ghirotto B, Targhetta VP, de Lima J, Camara NOS. Sirtuins as pharmacological targets in neurodegenerative and neuropsychiatric disorders. Br J Pharmacol. 2022;179(8):1496–511.

    Article  PubMed  CAS  Google Scholar 

  72. Bilecki W, Mackowiak M. Gene expression and epigenetic regulation in the prefrontal cortex of schizophrenia. Genes. 2023;14(2):243.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  73. Liu W, Fang Y, Shi Y, Cheng Y, Sun C, Cui D. The interaction of histone modification related H3F3B and NSD2 genes increases the susceptibility to schizophrenia in a Chinese population. Prog Neuropsychopharmacol Biol Psychiatry. 2020;101:109918.

    Article  PubMed  CAS  Google Scholar 

  74. Ganguly S, Seth S. A translational perspective on histone acetylation modulators in psychiatric disorders. Psychopharmacology. 2018;235(7):1867–73.

    Article  PubMed  CAS  Google Scholar 

  75. Gürel Ç, Kuşçu GC, Yavaşoğlu A, Biray AÇ. The clues in solving the mystery of major psychosis: the epigenetic basis of schizophrenia and bipolar disorder. Neurosci Biobehav Rev. 2020;113:51–61.

    Article  PubMed  Google Scholar 

  76. Micale V, Di Bartolomeo M, Di Martino S, Stark T, Dell’Osso B, Drago F, et al. Are the epigenetic changes predictive of therapeutic efficacy for psychiatric disorders? A translational approach towards novel drug targets. Pharmacol Ther. 2023;241:108279.

    Article  PubMed  CAS  Google Scholar 

  77. Swathy B, Banerjee M. Understanding epigenetics of schizophrenia in the backdrop of its antipsychotic drug therapy. Epigenomics. 2017;9(5):721–36.

    Article  PubMed  CAS  Google Scholar 

  78. Kurita M, Holloway T, Garcia-Bea A, Kozlenkov A, Friedman AK, Moreno JL, et al. HDAC2 regulates atypical antipsychotic responses through the modulation of mGlu2 promoter activity. Nat Neurosci. 2012;15(9):1245–54.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  79. Su Y, Liu X, Lian J, Deng C. Epigenetic histone modulations of PPARgamma and related pathways contribute to olanzapine-induced metabolic disorders. Pharmacol Res. 2020;155:104703.

    Article  PubMed  CAS  Google Scholar 

  80. Hwang H, Chang HR, Baek D. Determinants of functional MicroRNA targeting. Mol Cells. 2023;46(1):21–32.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  81. Zhang L, Li D, Yi P, Shi J, Guo M, Yin Q, et al. Peripheral origin exosomal microRNAs aggravate glymphatic system dysfunction in diabetic cognitive impairment. Acta Pharm Sin B. 2023;13(7):2817–25.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  82. Pinto-Hernandez P, Castilla-Silgado J, Coto-Vilcapoma A, Fernández-Sanjurjo M, Fernández-García B, Tomás-Zapico C, et al. Modulation of microRNAs through lifestyle changes in Alzheimer’s disease. Nutrients. 2023;15(17):3688.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  83. Zhang HC, Du Y, Chen L, Yuan ZQ, Cheng Y. MicroRNA schizophrenia: etiology, biomarkers and therapeutic targets. Neurosci Biobehav Rev. 2023;146:105064.

    Article  PubMed  CAS  Google Scholar 

  84. Kolosowska KA, Schratt G, Winterer J. microRNA-dependent regulation of gene expression in GABAergic interneurons. Front Cell Neurosci. 2023;17:1188574.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  85. Peng Q, Dai Z, Yin J, Lv D, Luo X, Xiong S, et al. Schizophrenia plausible protective effect of microRNA-137 is potentially related to estrogen and prolactin in female patients. Front Psychiatry. 2023;14:1187111.

    Article  PubMed  PubMed Central  Google Scholar 

  86. Martinez B, Peplow PV. MicroRNAs as potential biomarkers for diagnosis of schizophrenia and influence of antipsychotic treatment. Neural Regen Res. 2024;19(7):1523–31.

    Article  PubMed  CAS  Google Scholar 

  87. Iftimovici A, He Q, Jiao C, Duchesnay E, Krebs MO, Kebir O, et al. Longitudinal mMicroRNA signature of conversion to psychosis. Schizophr Bull. 2023. https://doiorg.publicaciones.saludcastillayleon.es/10.1093/schbul/sbad080.

    Article  PubMed Central  Google Scholar 

  88. Perez-Rodriguez D, Penedo MA, Rivera-Baltanas T, Pena-Centeno T, Burkhardt S, Fischer A, et al. MiRNA differences related to treatment-resistant schizophrenia. Int J Mol Sci. 2023;24(3):1891.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  89. Mu C, Dang X, Luo XJ. Mendelian randomization reveals the causal links between microRNA and schizophrenia. J Psychiatr Res. 2023;163:372–7.

    Article  PubMed  Google Scholar 

  90. Namkung H, Yukitake H, Fukudome D, Lee BJ, Tian M, Ursini G, et al. The miR-124-AMPAR pathway connects polygenic risks with behavioral changes shared between schizophrenia and bipolar disorder. Neuron. 2023;111(2):220-35.e9.

    Article  PubMed  CAS  Google Scholar 

  91. Mattick JS, Amaral PP, Carninci P, Carpenter S, Chang HY, Chen LL, et al. Long non-coding RNAs: definitions, functions, challenges and recommendations. Nat Rev Mol Cell Biol. 2023;24(6):430–47.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  92. Eghtedarian R, Akbari M, Badrlou E, Mahmud Hussen B, Eslami S, Akhavan-Bahabadi M, et al. Assessment of expression of oxytocin-related lncRNAs in schizophrenia. Eur J Pharmacol. 2022;932:175205.

    Article  PubMed  CAS  Google Scholar 

  93. Rao S, Tian L, Cao H, Baranova A, Zhang F. Involvement of the long intergenic non-coding RNA LINC00461 in schizophrenia. BMC Psychiatry. 2022;22(1):59.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  94. Badrlou E, Ghafouri-Fard S, Omrani MD, Neishabouri SM, Arsang-Jang S, Taheri M, et al. Expression of BDNF-associated lncRNAs in treatment-resistant schizophrenia patients. J Mol Neurosci. 2021;71(11):2249–59.

    Article  PubMed  CAS  Google Scholar 

  95. Mukhopadhyay A, Deshpande SN, Bhatia T, Thelma BK. Significance of an altered lncRNA landscape in schizophrenia and cognition: clues from a case-control association study. Eur Arch Psychiatry Clin Neurosci. 2023. https://doiorg.publicaciones.saludcastillayleon.es/10.1007/s00406-023-01596-9.

    Article  PubMed  Google Scholar 

  96. Baruah C, Nath P, Barah P. LncRNAs in neuropsychiatric disorders and computational insights for their prediction. Mol Biol Rep. 2022;49(12):11515–34.

    Article  PubMed  CAS  Google Scholar 

  97. Hosseini E, Bagheri-Hosseinabadi Z, De Toma I, Jafarisani M, Sadeghi I. The importance of long non-coding RNAs in neuropsychiatric disorders. Mol Aspects Med. 2019;70:127–40.

    Article  PubMed  CAS  Google Scholar 

  98. Ma Z-L, Wang R-L, Meng L, Gong CX. Construction of a diagnostic model and a lncRNA-associated ceRNA network based on apoptosis-related genes for schizophrenia. Behav Neurol. 2023;2023:1–17.

    Google Scholar 

  99. Du X, Lv J, Feng J, Li X, Gao Y, Wang X, et al. Plasma exosomes lncRNA-miRNA-mRNA network construction and its diagnostic efficacy identification in first-episode schizophrenia. BMC Psychiatry. 2023;23(1):611.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  100. Raskó T, Pande A, Radscheit K, Zink A, Singh M, Sommer C, et al. A novel gene controls a new structure: PiggyBac transposable element-derived 1, unique to mammals, controls mammal-specific neuronal paraspeckles. Mol Biol Evol. 2022;39(10): msac175.

    Article  PubMed  PubMed Central  Google Scholar 

  101. Kan RL, Chen J, Sallam T. Crosstalk between epitranscriptomic and epigenetic mechanisms in gene regulation. Trends Genet. 2022;38(2):182–93.

    Article  PubMed  CAS  Google Scholar 

  102. Zhang Y, Wang X, Zhang C, Yi H. The dysregulation of lncRNAs by epigenetic factors in human pathologies. Drug Discov Today. 2023;28(9):103664.

    Article  PubMed  CAS  Google Scholar 

  103. Zhu J, Cheng X, Naumovski N, Hu L, Wang K. Epigenetic regulation by quercetin: a comprehensive review focused on its biological mechanisms. Crit Rev Food Sci Nutr. 2023. https://doiorg.publicaciones.saludcastillayleon.es/10.1080/10408398.2023.2278760.

    Article  PubMed  Google Scholar 

  104. Karpova NN, Sales AJ, Joca SR. Epigenetic basis of neuronal and synaptic plasticity. Curr Top Med Chem. 2017;17(7):771–93.

    Article  PubMed  CAS  Google Scholar 

  105. Rajarajan P, Akbarian S. Use of the epigenetic toolbox to contextualize common variants associated with schizophrenia risk. Dialog Clin Neurosci. 2022;21(4):407–16.

    Article  Google Scholar 

  106. Mitchell AC, Jiang Y, Peter C, Akbarian S. Transcriptional regulation of GAD1 GABA synthesis gene in the prefrontal cortex of subjects with schizophrenia. Schizophr Res. 2015;167(1–3):28–34.

    Article  PubMed  Google Scholar 

  107. Morishita H, Kundakovic M, Bicks L, Mitchell A, Akbarian S. Interneuron epigenomes during the critical period of cortical plasticity: Implications for schizophrenia. Neurobiol Learn Mem. 2015;124:104–10.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  108. Ovenden ES, McGregor NW, Emsley RA, Warnich L. DNA methylation and antipsychotic treatment mechanisms in schizophrenia: progress and future directions. Prog Neuropsychopharmacol Biol Psychiatry. 2018;81:38–49.

    Article  PubMed  CAS  Google Scholar 

  109. Al-Chalabi N, Nader G, Fischer C, Graff A, Gerretsen P, De Luca V. Effect of DNA methylation and AUDIT-C polygenic scores on alcohol use disorder comorbidity in psychoses: no evidence of epigenetic basis of polygenic risk. Schizophr Res. 2024;271:138–41.

    Article  PubMed  CAS  Google Scholar 

  110. Marques D, Vaziri N, Greenway SC, Bousman C. DNA methylation and histone modifications associated with antipsychotic treatment: a systematic review. Mol Psychiatry. 2025;30(1):296–309.

    Article  PubMed  CAS  Google Scholar 

  111. Lu H, Giordano F, Ning Z. Oxford nanopore MinION sequencing and genome assembly. Genom Proteom Bioinform. 2016;14(5):265–79.

    Article  Google Scholar 

  112. Vaisvila R, Ponnaluri VKC, Sun Z, Langhorst BW, Saleh L, Guan S, et al. Enzymatic methyl sequencing detects DNA methylation at single-base resolution from picograms of DNA. Genome Res. 2021;31(7):1280–9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  113. Wang T, Fowler JM, Liu L, Loo CE, Luo M, Schutsky EK, et al. Direct enzymatic sequencing of 5-methylcytosine at single-base resolution. Nat Chem Biol. 2023;19(8):1004–12.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  114. Zhang T, Li H, Ma S, Cao J, Liao H, Huang Q, et al. The newest Oxford Nanopore R10.4.1 full-length 16S rRNA sequencing enables the accurate resolution of species-level microbial community profiling. Appl Environ Microbiol. 2023;89(10): e0060523.

    Article  PubMed  Google Scholar 

  115. Gao C, Zhang M, Chen L. The comparison of two single-cell sequencing platforms: BD rhapsody and 10 × genomics chromium. Curr Genomics. 2020;21(8):602–9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  116. Nakabayashi K, Yamamura M, Haseagawa K, Hata K. Reduced representation bisulfite sequencing (RRBS). In: Hatada I, Horii T, editors. Methods in molecular biology, vol. 2577. New York: Springer; 2023. p. 39–51.

    Google Scholar 

  117. Luo L, Gribskov M, Wang S. Bibliometric review of ATAC-Seq and its application in gene expression. Brief Bioinform. 2022;23(3): bbac061.

    Article  PubMed  PubMed Central  Google Scholar 

  118. Nakato R, Sakata T. Methods for ChIP-seq analysis: a practical workflow and advanced applications. Methods. 2021;187:44–53.

    Article  PubMed  CAS  Google Scholar 

  119. Lafontaine DL, Yang L, Dekker J, Gibcus JH. Hi-C 3.0: improved protocol for genome-wide chromosome conformation capture. Curr Protoc. 2021;1(7): e198.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  120. Smallwood SA, Lee HJ, Angermueller C, Krueger F, Saadeh H, Peat J, et al. Single-cell genome-wide bisulfite sequencing for assessing epigenetic heterogeneity. Nat Methods. 2014;11(8):817–20.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  121. Gu H, Raman AT, Wang X, Gaiti F, Chaligne R, Mohammad AW, et al. Smart-RRBS for single-cell methylome and transcriptome analysis. Nat Protoc. 2021;16(8):4004–30.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  122. Mulqueen RM, Pokholok D, Norberg SJ, Torkenczy KA, Fields AJ, Sun D, et al. Highly scalable generation of DNA methylation profiles in single cells. Nat Biotechnol. 2018;36(5):428–31.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  123. Ziegenhain C, Vieth B, Parekh S, Reinius B, Guillaumet-Adkins A, Smets M, et al. Comparative analysis of single-cell RNA sequencing methods. Mol Cell. 2017;65(4):631-43.e4.

    Article  PubMed  CAS  Google Scholar 

  124. Li YE, Preissl S, Miller M, Johnson ND, Wang Z, Jiao H, et al. A comparative atlas of single-cell chromatin accessibility in the human brain. Science. 2023;382(6667): eadf7044.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  125. Wu Y, Zhang C-Y, Wang L, Li Y, Xiao X. Genetic insights of schizophrenia via single cell RNA-sequencing analyses. Schizophr Bull. 2023;49(4):914–22.

    Article  PubMed  PubMed Central  Google Scholar 

  126. Shi Y, Wang M, Mi D, Lu T, Wang B, Dong H, et al. Mouse and human share conserved transcriptional programs for interneuron development. Science. 2021;374(6573): eabj6641.

    Article  PubMed  CAS  Google Scholar 

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Funding

The study was supported by the Suzhou clinical Medical Center for mood disorders (No. Szlcyxzx202109), Suzhou Key Laboratory (SZS2024016), Multicenter Clinical Research on Major Diseases in Suzhou (DZXYJ202413); Guidance Project of Jiangsu Provincial Health Commission (Z2023074), Science foundation of Kangda college of Nanjing medical university (KD2023KYJJ130) and General Program of Lianyungang Health Committee (NO.202130). The funding sources of this study had no role in study design, data collection and analysis, decision to publish, or preparation of the article.

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  1. Department of Psychiatry, The Fourth People’s Hospital of Lianyungang, The Affiliated KangDa College of Nanjing Medical University, Lianyungang, 222003, People’s Republic of China

    Haidong Yang

  2. Institute of Mental Health, Suzhou Psychiatric Hospital, The Affiliated Guangji Hospital of Soochow University, Suzhou, 215137, People’s Republic of China

    Haidong Yang, Wenxi Sun, Jin Li & Xiaobin Zhang

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All authors have made substantial and contributions to researching data for this article, to discussions of content, and to writing the manuscript. Haidong Yang and Xiaobin Zhang were involved in the conception, drafting, reviewing, and revising of the manuscript. Haidong Yang, Wenxi Sun, and Jin Li performed the literature search. All authors contributed to and have approved the final paper.

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Yang, H., Sun, W., Li, J. et al. Epigenetics factors in schizophrenia: future directions for etiologic and therapeutic study approaches. Ann Gen Psychiatry 24, 21 (2025). https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s12991-025-00557-x

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Annals of General Psychiatry

ISSN: 1744-859X