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Epigenetic Modifications in Schizophrenia and Related Disorders: Molecular Scars of Environmental Exposures and Source of Phenotypic Variability

  • Juliet Richetto
    Correspondence
    Address correspondence to Juliet Richetto, Ph.D.
    Affiliations
    Institute of Pharmacology and Toxicology, University of Zurich–Vetsuisse, and Neuroscience Center Zurich, University of Zurich and ETH Zurich, Zurich, Switzerland
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  • Urs Meyer
    Affiliations
    Institute of Pharmacology and Toxicology, University of Zurich–Vetsuisse, and Neuroscience Center Zurich, University of Zurich and ETH Zurich, Zurich, Switzerland
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Open AccessPublished:March 28, 2020DOI:https://doi.org/10.1016/j.biopsych.2020.03.008

      Abstract

      Epigenetic modifications are increasingly recognized to play a role in the etiology and pathophysiology of schizophrenia and other psychiatric disorders with developmental origins. Here, we summarize clinical and preclinical findings of epigenetic alterations in schizophrenia and relevant disease models and discuss their putative origin. Recent findings suggest that certain schizophrenia risk loci can influence stochastic variation in gene expression through epigenetic processes, highlighting the intricate interaction between genetic and epigenetic control of neurodevelopmental trajectories. In addition, a substantial portion of epigenetic alterations in schizophrenia and related disorders may be acquired through environmental factors and may be manifested as molecular “scars.” Some of these scars can influence brain functions throughout the entire lifespan and may even be transmitted across generations via epigenetic germline inheritance. Epigenetic modifications, whether caused by genetic or environmental factors, are plausible molecular sources of phenotypic heterogeneity and offer a target for therapeutic interventions. The further elucidation of epigenetic modifications thus may increase our knowledge regarding schizophrenia’s heterogeneous etiology and pathophysiology and, in the long term, may advance personalized treatments through the use of biomarker-guided epigenetic interventions.

      Keywords

      Schizophrenia is a chronic and severe mental disorder that affects approximately 1 in 100 individuals worldwide (
      • Charlson F.J.
      • Ferrari A.J.
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      • Stockings E.
      • Scott J.G.
      • et al.
      Global epidemiology and burden of schizophrenia: Findings from the Global Burden of Disease Study 2016.
      ). It is characterized by varying degrees of cognitive impairments, emotional aberrations, and behavioral anomalies, which together undermine basic processes of perception, reasoning, and judgment. Typically, the onset of full-blown schizophrenia is in early adulthood and includes a myriad of symptoms, which are referred to as positive symptoms (e.g., visual and/or auditory hallucinations, delusions, paranoia, psychomotor agitation), negative symptoms (e.g., social withdrawal, apathy, deficits in motivation and reward-related functions), and cognitive symptoms (e.g., deficits in executive functioning, working memory, and attention) (
      • Owen M.J.
      • Sawa A.
      • Mortensen P.B.
      Schizophrenia.
      ).
      The etiology of schizophrenia is likely to be multifactorial, with multiple small-effect and fewer large-effect susceptibility genes interacting with several environmental factors (
      • Owen M.J.
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      • Mortensen P.B.
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      ,
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      Unravelling the genetic basis of schizophrenia and bipolar disorder with GWAS: A systematic review.
      ,
      Schizophrenia Working Group of the Psychiatric Genomics Consortium
      Biological insights from 108 schizophrenia-associated genetic loci.
      ). The combination of genetic and environmental risk factors is believed to affect the normal course of brain development and maturation, manifesting in a cascade of neurotransmitter and circuit dysfunctions and impaired connectivity in early adulthood (
      • Landek-Salgado M.A.
      • Faust T.E.
      • Sawa A.
      Molecular substrates of schizophrenia: Homeostatic signaling to connectivity.
      ,
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      ). While common and rare genetic abnormalities provide the basis for the substantial heritability of schizophrenia, environmental factors may contribute to the disorder’s etiology partly through epigenetic processes (
      • Peedicayil J.
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      An epigenetic basis for an omnigenic model of psychiatric disorders.
      ,
      • Tsankova N.
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      Epigenetic regulation in psychiatric disorders.
      ). The latter are commonly referred to as the combination of mechanisms that confer short- and long-term changes in gene expression without altering the DNA code itself (
      • Peedicayil J.
      • Grayson D.R.
      An epigenetic basis for an omnigenic model of psychiatric disorders.
      ,
      • Tsankova N.
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      ). Epigenetic processes include several interrelated mechanisms such as chromatin remodeling, histone modifications, DNA methylation (DNAm), and expression of noncoding RNAs (ncRNAs) (Figure 1 and Supplement). The orchestrated action of these epigenetic processes has a considerable influence on gene expression and may further provide a basis for transgenerational nongenetic inheritance of environmentally acquired traits (
      • Bohacek J.
      • Mansuy I.M.
      Molecular insights into transgenerational non-genetic inheritance of acquired behaviours.
      ).
      Figure thumbnail gr1
      Figure 1Schematic representation of chromatin structure and major epigenetic processes. The DNA–protein complex within chromosomes is referred to as chromatin. The functional unit of the chromatin is the nucleosome (not shown), which is composed of DNA wrapped around a core octamer of histone proteins. The DNA–histone interaction occurs at the N-terminal tails of these histones, which provide sites for epigenetic marks known as histone modifications. A number of histone modifications exist, including methylation (me), acetylation (ac), phosphorylation (pho), ubiquitination (ub), and SUMOylation (sum). Histone modifications determine the extent to which chromatin is wrapped around histone proteins. Loosely coiled chromatin contains transcriptionally accessible DNA regions, whereas tightly coiled chromatin comprises transcriptionally inactive DNA regions. DNA methylation refers to the covalent modification of the DNA at position 5′ in the cytosine ring (5mC), which is found primarily at CpG dinucleotides. 5mC (and other methylation-related epigenetic marks) can also exist at non-CpG sites (not shown). Whereas 5mC is established and maintained by methyltransferases (DNMTs), it is oxidized by the TET family of dioxygenase proteins to 5-hydroxymethylcytosine (5hmC). In successive steps, TET enzymes further hydroxylate 5hmC to generate 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC). Whereas 5fC and 5caC are recognized and removed by TDG, the created abasic site is repaired by the BER pathway, generating an unmodified cytosine. Besides epigenetic modifications at histone proteins and DNA, noncoding RNAs provide an additional level of epigenetic regulation involved in chromatin and nuclear remodeling, gene transcription, translational repression, and degradation of messenger RNAs. Based on their size, noncoding RNAs can be broadly subdivided into lncRNAs (>200 nucleotides) and sncRNAs (<200 nucleotides), the latter of which contain small inhibiting RNAs, microRNAs, PIWI-interacting RNAs, and small nuclear RNAs (not shown). BER, base excision repair; DNMT, DNA methyltransferase; lncRNAs, long noncoding RNAs; sncRNAs, short noncoding RNAs; TDG, thymine-DNA glycosylase; TET, ten-eleven translocation.
      While epigenetic processes have long been speculated to contribute to monozygotic twin discordance (
      • Petronis A.
      • Gottesman II,
      • Kan P.
      • Kennedy J.L.
      • Basile V.S.
      • Paterson A.D.
      • et al.
      Monozygotic twins exhibit numerous epigenetic differences: Clues to twin discordance?.
      ), their importance is increasingly recognized for virtually every aspect of normal and pathological brain development and functioning (
      • Li M.
      • Santpere G.
      • Imamura Kawasawa Y.
      • Evgrafov O.V.
      • Gulden F.O.
      • Pochareddy S.
      • et al.
      Integrative functional genomic analysis of human brain development and neuropsychiatric risks.
      ). Not only may epigenetic processes mediate the effects of environmental risk in schizophrenia and other multifactorial neuropsychiatric disorders, but also they can interact with the genomic risk associated with these disorders (
      • Hannon E.
      • Dempster E.
      • Viana J.
      • Burrage J.
      • Smith A.R.
      • Macdonald R.
      • et al.
      An integrated genetic-epigenetic analysis of schizophrenia: Evidence for co-localization of genetic associations and differential DNA methylation.
      ,
      • Montano C.
      • Taub M.A.
      • Jaffe A.
      • Briem E.
      • Feinberg J.I.
      • Trygvadottir R.
      • et al.
      Association of DNA methylation differences with schizophrenia in an epigenome-wide association study.
      ). Hence, the exploration of epigenetic modifications holds the promise of new discoveries at the crossroads of genes and environment. In this review article, we summarize clinical and preclinical findings of epigenetic alterations in schizophrenia and relevant disease models and discuss their putative origin. We also speculate how such modifications may contribute to pathological trait variability and offer avenues for novel treatments.

      Epigenetic Modifications in Schizophrenia

      DNA Methylation

      Alterations in DNAm were among the first epigenetic modifications to be associated with schizophrenia. Pioneering work conducted by Costa, Guidotti, Grayson, and colleagues indicated that reduced transcription of the extracellular matrix protein reelin (RELN) in the brains of people with schizophrenia might be caused by hypermethylation of its promoter region (
      • Guidotti A.
      • Grayson D.R.
      • Caruncho H.J.
      Epigenetic RELN dysfunction in schizophrenia and related neuropsychiatric disorders.
      ,
      • Grayson D.R.
      • Jia X.
      • Chen Y.
      • Sharma R.P.
      • Mitchell C.P.
      • Guidotti A.
      • et al.
      Reelin promoter hypermethylation in schizophrenia.
      ,
      • Tamura Y.
      • Kunugi H.
      • Ohashi J.
      • Hohjoh H.
      Epigenetic aberration of the human REELIN gene in psychiatric disorders.
      ). This notion was further supported by findings showing that patients with schizophrenia display increased cortical and subcortical expression of DNMT1 (
      • Kundakovic M.
      • Chen Y.
      • Costa E.
      • Grayson D.R.
      DNA methyltransferase inhibitors coordinately induce expression of the human reelin and glutamic acid decarboxylase 67 genes.
      ,
      • Veldic M.
      • Guidotti A.
      • Maloku E.
      • Davis J.M.
      • Costa E.
      In psychosis, cortical interneurons overexpress DNA-methyltransferase 1.
      ), which primarily functions to maintain DNAm at CpG sites (
      • Feng J.
      • Zhou Y.
      • Campbell S.L.
      • Le T.
      • Li E.
      • Sweatt J.D.
      • et al.
      Dnmt1 and Dnmt3a maintain DNA methylation and regulate synaptic function in adult forebrain neurons.
      ). In addition to RELN, numerous other (historical) candidate risk genes for schizophrenia were found to be differentially methylated, including genes involved in gamma-aminobutyric acidergic (GABAergic) (GAD1) functions (
      • Huang H.S.
      • Akbarian S.
      GAD1 mRNA expression and DNA methylation in prefrontal cortex of subjects with schizophrenia.
      ), dopaminergic (DRD2, DRD3, COMT, IGF2) functions (
      • Petronis A.
      • Gottesman II,
      • Kan P.
      • Kennedy J.L.
      • Basile V.S.
      • Paterson A.D.
      • et al.
      Monozygotic twins exhibit numerous epigenetic differences: Clues to twin discordance?.
      ,
      • Kordi-Tamandani D.M.
      • Sahranavard R.
      • Torkamanzehi A.
      Analysis of association between dopamine receptor genes’ methylation and their expression profile with the risk of schizophrenia.
      ,
      • Zhang A.P.
      • Yu J.
      • Liu J.X.
      • Zhang H.Y.
      • Du Y.Y.
      • Zhu J.D.
      • et al.
      The DNA methylation profile within the 5'-regulatory region of DRD2 in discordant sib pairs with schizophrenia.
      ,
      • Dempster E.L.
      • Mill J.
      • Craig I.W.
      • Collier D.A.
      The quantification of COMT mRNA in post mortem cerebellum tissue: Diagnosis, genotype, methylation and expression.
      ,
      • Pai S.
      • Li P.
      • Killinger B.
      • Marshall L.
      • Jia P.
      • Liao J.
      • et al.
      Differential methylation of enhancer at IGF2 is associated with abnormal dopamine synthesis in major psychosis.
      ,
      • Abdolmaleky H.M.
      • Cheng K.H.
      • Faraone S.V.
      • Wilcox M.
      • Glatt S.J.
      • Gao F.
      • et al.
      Hypomethylation of MB-COMT promoter is a major risk factor for schizophrenia and bipolar disorder.
      ,
      • Abdolmaleky H.M.
      • Smith C.L.
      • Zhou J.R.
      • Thiagalingam S.
      Epigenetic alterations of the dopaminergic system in major psychiatric disorders.
      ,
      • Dai D.
      • Cheng J.
      • Zhou K.
      • Lv Y.
      • Zhuang Q.
      • Zheng R.
      • et al.
      Significant association between DRD3 gene body methylation and schizophrenia.
      ), serotonergic (HTR2A) functions (
      • Abdolmaleky H.M.
      • Yaqubi S.
      • Papageorgis P.
      • Lambert A.W.
      • Ozturk S.
      • Sivaraman V.
      • et al.
      Epigenetic dysregulation of HTR2A in the brain of patients with schizophrenia and bipolar disorder.
      ,
      • Ghadirivasfi M.
      • Nohesara S.
      • Ahmadkhaniha H.R.
      • Eskandari M.R.
      • Mostafavi S.
      • Thiagalingam S.
      • et al.
      Hypomethylation of the serotonin receptor type-2A gene (HTR2A) at T102C polymorphic site in DNA derived from the saliva of patients with schizophrenia and bipolar disorder.
      ), and oligodendrocyte (SOX10) functions (
      • Iwamoto K.
      • Bundo M.
      • Yamada K.
      • Takao H.
      • Iwayama Y.
      • Yoshikawa T.
      • et al.
      A family-based and case-control association study of SOX10 in schizophrenia.
      ,
      • Iwamoto K.
      • Bundo M.
      • Yamada K.
      • Takao H.
      • Iwayama-Shigeno Y.
      • Yoshikawa T.
      • et al.
      DNA methylation status of SOX10 correlates with its downregulation and oligodendrocyte dysfunction in schizophrenia.
      ). However, some of these initial findings could not be replicated (
      • Mill J.
      • Tang T.
      • Kaminsky Z.
      • Khare T.
      • Yazdanpanah S.
      • Bouchard L.
      • et al.
      Epigenomic profiling reveals DNA-methylation changes associated with major psychosis.
      ,
      • Tochigi M.
      • Iwamoto K.
      • Bundo M.
      • Komori A.
      • Sasaki T.
      • Kato N.
      • et al.
      Methylation status of the reelin promoter region in the brain of schizophrenic patients.
      ), which is likely explained by the use of small sample sizes and/or differences in the methods used to quantify DNAm in postmortem samples, with initial studies lacking technological sensitivity as compared with contemporary methods.
      As a counterpart to targeted approaches, technical and theoretical advances have recently facilitated DNAm profiling across the entire genome (Table 1). These studies are based on sample sizes that range among 10 (
      • Zhao H.
      • Xu J.
      • Pang L.
      • Zhang Y.
      • Fan H.
      • Liu L.
      • et al.
      Genome-wide DNA methylome reveals the dysfunction of intronic microRNAs in major psychosis.
      ,
      • Ruzicka W.B.
      • Subburaju S.
      • Benes F.M.
      Circuit- and diagnosis-specific DNA methylation changes at gamma-aminobutyric acid-related genes in postmortem human hippocampus in schizophrenia and bipolar disorder.
      ,
      • Ruzicka W.B.
      • Subburaju S.
      • Benes F.M.
      Variability of DNA methylation within schizophrenia risk loci across subregions of human hippocampus.
      ,
      • Alelu-Paz R.
      • Carmona F.J.
      • Sanchez-Mut J.V.
      • Cariaga-Martinez A.
      • Gonzalez-Corpas A.
      • Ashour N.
      • et al.
      Epigenetics in schizophrenia: A pilot study of global DNA methylation in different brain regions associated with higher cognitive functions.
      ), 20 to 40 (
      • Mill J.
      • Tang T.
      • Kaminsky Z.
      • Khare T.
      • Yazdanpanah S.
      • Bouchard L.
      • et al.
      Epigenomic profiling reveals DNA-methylation changes associated with major psychosis.
      ,
      • Pidsley R.
      • Viana J.
      • Hannon E.
      • Spiers H.
      • Troakes C.
      • Al-Saraj S.
      • et al.
      Methylomic profiling of human brain tissue supports a neurodevelopmental origin for schizophrenia.
      ,
      • Wockner L.F.
      • Noble E.P.
      • Lawford B.R.
      • Young R.M.
      • Morris C.P.
      • Whitehall V.L.
      • et al.
      Genome-wide DNA methylation analysis of human brain tissue from schizophrenia patients.
      ,
      • Chen C.
      • Zhang C.
      • Cheng L.
      • Reilly J.L.
      • Bishop J.R.
      • Sweeney J.A.
      • et al.
      Correlation between DNA methylation and gene expression in the brains of patients with bipolar disorder and schizophrenia.
      ,
      • van den Oord E.J.
      • Clark S.L.
      • Xie L.Y.
      • Shabalin A.A.
      • Dozmorov M.G.
      • Kumar G.
      • et al.
      A whole methylome CpG-SNP association study of psychosis in blood and brain tissue.
      ,
      • Viana J.
      • Hannon E.
      • Dempster E.
      • Pidsley R.
      • Macdonald R.
      • Knox O.
      • et al.
      Schizophrenia-associated methylomic variation: Molecular signatures of disease and polygenic risk burden across multiple brain regions.
      ,
      • McKinney B.
      • Ding Y.
      • Lewis D.A.
      • Sweet R.A.
      DNA methylation as a putative mechanism for reduced dendritic spine density in the superior temporal gyrus of subjects with schizophrenia.
      ,
      • Mendizabal I.
      • Berto S.
      • Usui N.
      • Toriumi K.
      • Chatterjee P.
      • Douglas C.
      • et al.
      Cell type-specific epigenetic links to schizophrenia risk in the brain.
      ), and more than 60 (
      • Numata S.
      • Ye T.
      • Herman M.
      • Lipska B.K.
      DNA methylation changes in the postmortem dorsolateral prefrontal cortex of patients with schizophrenia.
      ,
      • Wockner L.F.
      • Morris C.P.
      • Noble E.P.
      • Lawford B.R.
      • Whitehall V.L.
      • Young R.M.
      • et al.
      Brain-specific epigenetic markers of schizophrenia.
      ,
      • Jaffe A.E.
      • Gao Y.
      • Deep-Soboslay A.
      • Tao R.
      • Hyde T.M.
      • Weinberger D.R.
      • et al.
      Mapping DNA methylation across development, genotype and schizophrenia in the human frontal cortex.
      ) patients and control subjects. They are mostly based on the Infinium Human Methylation 450K BeadChip, which allows the user to assess more than 450,000 CpGs located throughout the genome, and they mainly focus on the prefrontal cortex (PFC) (
      • Mill J.
      • Tang T.
      • Kaminsky Z.
      • Khare T.
      • Yazdanpanah S.
      • Bouchard L.
      • et al.
      Epigenomic profiling reveals DNA-methylation changes associated with major psychosis.
      ,
      • Zhao H.
      • Xu J.
      • Pang L.
      • Zhang Y.
      • Fan H.
      • Liu L.
      • et al.
      Genome-wide DNA methylome reveals the dysfunction of intronic microRNAs in major psychosis.
      ,
      • Alelu-Paz R.
      • Carmona F.J.
      • Sanchez-Mut J.V.
      • Cariaga-Martinez A.
      • Gonzalez-Corpas A.
      • Ashour N.
      • et al.
      Epigenetics in schizophrenia: A pilot study of global DNA methylation in different brain regions associated with higher cognitive functions.
      ,
      • Pidsley R.
      • Viana J.
      • Hannon E.
      • Spiers H.
      • Troakes C.
      • Al-Saraj S.
      • et al.
      Methylomic profiling of human brain tissue supports a neurodevelopmental origin for schizophrenia.
      ,
      • Wockner L.F.
      • Noble E.P.
      • Lawford B.R.
      • Young R.M.
      • Morris C.P.
      • Whitehall V.L.
      • et al.
      Genome-wide DNA methylation analysis of human brain tissue from schizophrenia patients.
      ,
      • van den Oord E.J.
      • Clark S.L.
      • Xie L.Y.
      • Shabalin A.A.
      • Dozmorov M.G.
      • Kumar G.
      • et al.
      A whole methylome CpG-SNP association study of psychosis in blood and brain tissue.
      ,
      • Viana J.
      • Hannon E.
      • Dempster E.
      • Pidsley R.
      • Macdonald R.
      • Knox O.
      • et al.
      Schizophrenia-associated methylomic variation: Molecular signatures of disease and polygenic risk burden across multiple brain regions.
      ,
      • Mendizabal I.
      • Berto S.
      • Usui N.
      • Toriumi K.
      • Chatterjee P.
      • Douglas C.
      • et al.
      Cell type-specific epigenetic links to schizophrenia risk in the brain.
      ,
      • Numata S.
      • Ye T.
      • Herman M.
      • Lipska B.K.
      DNA methylation changes in the postmortem dorsolateral prefrontal cortex of patients with schizophrenia.
      ,
      • Wockner L.F.
      • Morris C.P.
      • Noble E.P.
      • Lawford B.R.
      • Whitehall V.L.
      • Young R.M.
      • et al.
      Brain-specific epigenetic markers of schizophrenia.
      ,
      • Jaffe A.E.
      • Gao Y.
      • Deep-Soboslay A.
      • Tao R.
      • Hyde T.M.
      • Weinberger D.R.
      • et al.
      Mapping DNA methylation across development, genotype and schizophrenia in the human frontal cortex.
      ), the hippocampus (
      • Ruzicka W.B.
      • Subburaju S.
      • Benes F.M.
      Circuit- and diagnosis-specific DNA methylation changes at gamma-aminobutyric acid-related genes in postmortem human hippocampus in schizophrenia and bipolar disorder.
      ,
      • Ruzicka W.B.
      • Subburaju S.
      • Benes F.M.
      Variability of DNA methylation within schizophrenia risk loci across subregions of human hippocampus.
      ,
      • Alelu-Paz R.
      • Carmona F.J.
      • Sanchez-Mut J.V.
      • Cariaga-Martinez A.
      • Gonzalez-Corpas A.
      • Ashour N.
      • et al.
      Epigenetics in schizophrenia: A pilot study of global DNA methylation in different brain regions associated with higher cognitive functions.
      ,
      • Viana J.
      • Hannon E.
      • Dempster E.
      • Pidsley R.
      • Macdonald R.
      • Knox O.
      • et al.
      Schizophrenia-associated methylomic variation: Molecular signatures of disease and polygenic risk burden across multiple brain regions.
      ), and, to a lesser extent, the striatum (
      • Viana J.
      • Hannon E.
      • Dempster E.
      • Pidsley R.
      • Macdonald R.
      • Knox O.
      • et al.
      Schizophrenia-associated methylomic variation: Molecular signatures of disease and polygenic risk burden across multiple brain regions.
      ,
      • McKinney B.
      • Ding Y.
      • Lewis D.A.
      • Sweet R.A.
      DNA methylation as a putative mechanism for reduced dendritic spine density in the superior temporal gyrus of subjects with schizophrenia.
      ), cerebellum (
      • Pidsley R.
      • Viana J.
      • Hannon E.
      • Spiers H.
      • Troakes C.
      • Al-Saraj S.
      • et al.
      Methylomic profiling of human brain tissue supports a neurodevelopmental origin for schizophrenia.
      ,
      • Chen C.
      • Zhang C.
      • Cheng L.
      • Reilly J.L.
      • Bishop J.R.
      • Sweeney J.A.
      • et al.
      Correlation between DNA methylation and gene expression in the brains of patients with bipolar disorder and schizophrenia.
      ,
      • Viana J.
      • Hannon E.
      • Dempster E.
      • Pidsley R.
      • Macdonald R.
      • Knox O.
      • et al.
      Schizophrenia-associated methylomic variation: Molecular signatures of disease and polygenic risk burden across multiple brain regions.
      ), and anterior cingulate cortex (
      • Alelu-Paz R.
      • Carmona F.J.
      • Sanchez-Mut J.V.
      • Cariaga-Martinez A.
      • Gonzalez-Corpas A.
      • Ashour N.
      • et al.
      Epigenetics in schizophrenia: A pilot study of global DNA methylation in different brain regions associated with higher cognitive functions.
      ). The largest study to date, performed by Jaffe et al. (
      • Jaffe A.E.
      • Gao Y.
      • Deep-Soboslay A.
      • Tao R.
      • Hyde T.M.
      • Weinberger D.R.
      • et al.
      Mapping DNA methylation across development, genotype and schizophrenia in the human frontal cortex.
      ), identified 2104 differentially methylated CpGs in the PFC of subjects with schizophrenia relative to control subjects. The differentially methylated CpGs were found to be enriched in genes relevant for embryonic development, cell fate commitment, and nervous system differentiation. The authors also observed that the epigenetic landscape, as represented by DNAm, varied markedly across development, possibly mirroring shifts in neuronal composition across the lifespan and age-dependent changes in gene expression profiles. Interestingly, schizophrenia risk loci were primarily enriched for loci expressing these shifting epigenetic states, particularly those that change during the transition from prenatal to postnatal life. Together, these data implicate an epigenetic component to the developmental origins of schizophrenia and suggest that there is an early epigenetic intermediate between genetically and biologically determined risks for the disorder (
      • Jaffe A.E.
      • Gao Y.
      • Deep-Soboslay A.
      • Tao R.
      • Hyde T.M.
      • Weinberger D.R.
      • et al.
      Mapping DNA methylation across development, genotype and schizophrenia in the human frontal cortex.
      ).
      Table 1Genome-wide DNA Methylation Changes in Schizophrenia: Brain Tissue
      SampleBrain RegionMethodMost SignificantReference
      35 SZ and 35 CTRFCCpG island microarrayMale subjects: EXOSC7, GRIA2, ELMOD1, KCNJ6, WDR18

      Female subjects: C6orf84, HCG9, SLC17A7, NR4A2, AB051500
      (
      • Mill J.
      • Tang T.
      • Kaminsky Z.
      • Khare T.
      • Yazdanpanah S.
      • Bouchard L.
      • et al.
      Epigenomic profiling reveals DNA-methylation changes associated with major psychosis.
      )
      20 SZ and 23 CTRPFC (London)450K arrayGSDMD, RASA3, HTR5A, PPFIA1, CACNA1G (from DMPs associated with SZ)(
      • Pidsley R.
      • Viana J.
      • Hannon E.
      • Spiers H.
      • Troakes C.
      • Al-Saraj S.
      • et al.
      Methylomic profiling of human brain tissue supports a neurodevelopmental origin for schizophrenia.
      )
      21 SZ and 23 CTRCBL (London)ANO4, NRN1, PPAPDC1B, NAIF1, SNX26 (from DMRs associated with SZ)
      18 SZ and 15 CTRPFC (Montreal)NAV1, ZNF200, PRH2, NFIA, COL16A1 (from DMPs associated with SZ)
      24 SZ and 24 CTRPFC450K arrayTNR6C6, C21orf33, HOXA11, CCNI, HOXA13, NOS1, AKT1, DNMT1, SOX10, DTNBP1, PPP3CC(
      • Wockner L.F.
      • Noble E.P.
      • Lawford B.R.
      • Young R.M.
      • Morris C.P.
      • Whitehall V.L.
      • et al.
      Genome-wide DNA methylation analysis of human brain tissue from schizophrenia patients.
      )
      106 SZ and 110 CTRDLPFC27K arrayASTN2, IL1RL1, GRIA4, LRRIQ2, SH2BP1, ABCB1, CEACAM19(
      • Numata S.
      • Ye T.
      • Herman M.
      • Lipska B.K.
      DNA methylation changes in the postmortem dorsolateral prefrontal cortex of patients with schizophrenia.
      )
      39 SZ and 43 CTRCBL27K arrayPIK3R1, BTN3A3, NHLH1, SLC16A7(
      • Chen C.
      • Zhang C.
      • Cheng L.
      • Reilly J.L.
      • Bishop J.R.
      • Sweeney J.A.
      • et al.
      Correlation between DNA methylation and gene expression in the brains of patients with bipolar disorder and schizophrenia.
      )
      62 SZ and 62 CTRPFC450K arrayCERS3, DPPA5, PRDM9, DDX43, REC8, LY6G5C (DMRs)(
      • Wockner L.F.
      • Morris C.P.
      • Noble E.P.
      • Lawford B.R.
      • Whitehall V.L.
      • Young R.M.
      • et al.
      Brain-specific epigenetic markers of schizophrenia.
      )
      5 SZ and 6 CTRPFCMeDIP-seq

      RNA-seq
      PLP1, NR4A1, IL1B, GFAP, APC, TAAR1, MYT1L, GRIP1, ASTN2, EGFR, CD28, SLC6A2(
      • Zhao H.
      • Xu J.
      • Pang L.
      • Zhang Y.
      • Fan H.
      • Liu L.
      • et al.
      Genome-wide DNA methylome reveals the dysfunction of intronic microRNAs in major psychosis.
      )
      8 SZ and 8 CTRH (CA1 vs. CA2/3)450K arrayMSX1, DAXX, CCND2, FOXG1, GAD1(
      • Ruzicka W.B.
      • Subburaju S.
      • Benes F.M.
      Circuit- and diagnosis-specific DNA methylation changes at gamma-aminobutyric acid-related genes in postmortem human hippocampus in schizophrenia and bipolar disorder.
      )
      19 SZ and 3 CTRH450K arrayNUBP1, STK32B, AIG1, PRKCE, RASA3(
      • Alelu-Paz R.
      • Carmona F.J.
      • Sanchez-Mut J.V.
      • Cariaga-Martinez A.
      • Gonzalez-Corpas A.
      • Ashour N.
      • et al.
      Epigenetics in schizophrenia: A pilot study of global DNA methylation in different brain regions associated with higher cognitive functions.
      )
      DLPFCHLA-DQA1, HCN2, AJAP1, HLA-B, HLA-DRB5
      ACCC4orf50, GALNT1, VSX2, SAPS2, KCNK7
      108 SZ and 136 CTRDLPFC450K arrayCD164, COPZ2, SUGT1, HAT1, TYW1B(
      • Jaffe A.E.
      • Gao Y.
      • Deep-Soboslay A.
      • Tao R.
      • Hyde T.M.
      • Weinberger D.R.
      • et al.
      Mapping DNA methylation across development, genotype and schizophrenia in the human frontal cortex.
      )
      26 SZ and 27 CTRPFCMBD-seqFOXP1, IL1RAP, AKAP13, SLC39A11, RPTOR(
      • van den Oord E.J.
      • Clark S.L.
      • Xie L.Y.
      • Shabalin A.A.
      • Dozmorov M.G.
      • Kumar G.
      • et al.
      A whole methylome CpG-SNP association study of psychosis in blood and brain tissue.
      )
      38 SZ and 38 CTRPFC450K arrayNCAM1, SND1, LILRB1, GSDMD, ABTB(
      • Viana J.
      • Hannon E.
      • Dempster E.
      • Pidsley R.
      • Macdonald R.
      • Knox O.
      • et al.
      Schizophrenia-associated methylomic variation: Molecular signatures of disease and polygenic risk burden across multiple brain regions.
      )
      37 SZ and 45 CTRSTRSYNPO, HECW1, GRINL1A, DEFB115, GBP4
      14 SZ and 13 CTRHATP6V0D, CACNA1G, RBM24, ZCCHC10, RASIP1
      37 SZ and 40 CTRCBLGART, ELK3, PDX1, ZNF586, ZNF217
      8 SZ and 8 CTRH (GABAergic interneurons)450K arraySLC7A6(
      • Ruzicka W.B.
      • Subburaju S.
      • Benes F.M.
      Variability of DNA methylation within schizophrenia risk loci across subregions of human hippocampus.
      )
      22 SZ and 22 CTRSTG450K arrayDLG1 (or BDH1), SERGET, TPGS2, CLEC16A, AHRR; BAIAP2, and DLG1 strongly associated with dendritic spine density(
      • McKinney B.
      • Ding Y.
      • Lewis D.A.
      • Sweet R.A.
      DNA methylation as a putative mechanism for reduced dendritic spine density in the superior temporal gyrus of subjects with schizophrenia.
      )
      23 SZ and 27 CTRBrodmann area 46WGBSCell type–specific whole-genome methylomes from neurons and oligodendrocytes obtained from SZ and CTR; DNA methylation differences tended to occur in cell type differentially methylated sites. 97 DM CpGs (14 NeuN+ and 83 OLIG2+ specific). Top NeuN+: FSTL5, GNA14, ERC2, LHFPL2, OSBPL6. Top OLIG2+: PPP1R9A, CHN2, CBLN4, TRIM49B, MGC32805(
      • Mendizabal I.
      • Berto S.
      • Usui N.
      • Toriumi K.
      • Chatterjee P.
      • Douglas C.
      • et al.
      Cell type-specific epigenetic links to schizophrenia risk in the brain.
      )
      The table summarizes the main findings from studies assessing genome-wide DNA methylation profiles in brain tissue of patients with schizophrenia (SZ) relative to matched control subjects (CTR) and/or in subjects at high risk for psychosis relative to control subjects. The table specifies the study sample, brain region, method used to assess DNA methylation profiles, and genes and loci with the most significant DNA methylation changes.
      ACC, anterior cingulate cortex; CA, cornu ammonis subfield of hippocampus; CBL, cerebellum; DMP, differentially methylated position; DMR, differentially methylated region; DLPFC, dorsolateral prefrontal cortex; FC, frontal cortex; GABAergic, gamma-aminobutyric acidergic; H, hippocampus; MBD-seq, methyl-CpG binding domain protein-enriched genome sequencing; MeDIP-seq, methylated DNA immunoprecipitation sequencing; PFC, prefrontal cortex; RNA-seq, RNA sequencing; STG, superior temporal gyrus; STR, striatum; WGBS, whole genome bisulfate sequencing.
      There is also an increasing number of genome-wide DNAm profiling studies of non–central nervous system (CNS) tissues such as blood (
      • Hannon E.
      • Dempster E.
      • Viana J.
      • Burrage J.
      • Smith A.R.
      • Macdonald R.
      • et al.
      An integrated genetic-epigenetic analysis of schizophrenia: Evidence for co-localization of genetic associations and differential DNA methylation.
      ,
      • Montano C.
      • Taub M.A.
      • Jaffe A.
      • Briem E.
      • Feinberg J.I.
      • Trygvadottir R.
      • et al.
      Association of DNA methylation differences with schizophrenia in an epigenome-wide association study.
      ,
      • Dempster E.L.
      • Pidsley R.
      • Schalkwyk L.C.
      • Owens S.
      • Georgiades A.
      • Kane F.
      • et al.
      Disease-associated epigenetic changes in monozygotic twins discordant for schizophrenia and bipolar disorder.
      ,
      • Castellani C.A.
      • Laufer B.I.
      • Melka M.G.
      • Diehl E.J.
      • O’Reilly R.L.
      • Singh S.M.
      DNA methylation differences in monozygotic twin pairs discordant for schizophrenia identifies psychosis related genes and networks.
      ,
      • Kebir O.
      • Chaumette B.
      • Rivollier F.
      • Miozzo F.
      • Lemieux Perreault L.P.
      • Barhdadi A.
      • et al.
      Methylomic changes during conversion to psychosis.
      ,
      • Roberts S.
      • Suderman M.
      • Zammit S.
      • Watkins S.H.
      • Hannon E.
      • Mill J.
      • et al.
      Longitudinal investigation of DNA methylation changes preceding adolescent psychotic experiences.
      ,
      • Aberg K.A.
      • McClay J.L.
      • Nerella S.
      • Clark S.
      • Kumar G.
      • Chen W.
      • et al.
      Methylome-wide association study of schizophrenia: Identifying blood biomarker signatures of environmental insults.
      ,
      • Ciuculete D.M.
      • Bostrom A.E.
      • Voisin S.
      • Philipps H.
      • Titova O.E.
      • Bandstein M.
      • et al.
      A methylome-wide mQTL analysis reveals associations of methylation sites with GAD1 and HDAC3 SNPs and a general psychiatric risk score.
      ) and saliva (
      • Fisher H.L.
      • Murphy T.M.
      • Arseneault L.
      • Caspi A.
      • Moffitt T.E.
      • Viana J.
      • et al.
      Methylomic analysis of monozygotic twins discordant for childhood psychotic symptoms.
      ) (Table 2). These can be further subdivided into longitudinal studies (
      • Dempster E.L.
      • Pidsley R.
      • Schalkwyk L.C.
      • Owens S.
      • Georgiades A.
      • Kane F.
      • et al.
      Disease-associated epigenetic changes in monozygotic twins discordant for schizophrenia and bipolar disorder.
      ,
      • Castellani C.A.
      • Laufer B.I.
      • Melka M.G.
      • Diehl E.J.
      • O’Reilly R.L.
      • Singh S.M.
      DNA methylation differences in monozygotic twin pairs discordant for schizophrenia identifies psychosis related genes and networks.
      ,
      • Kebir O.
      • Chaumette B.
      • Rivollier F.
      • Miozzo F.
      • Lemieux Perreault L.P.
      • Barhdadi A.
      • et al.
      Methylomic changes during conversion to psychosis.
      ,
      • Roberts S.
      • Suderman M.
      • Zammit S.
      • Watkins S.H.
      • Hannon E.
      • Mill J.
      • et al.
      Longitudinal investigation of DNA methylation changes preceding adolescent psychotic experiences.
      ,
      • Fisher H.L.
      • Murphy T.M.
      • Arseneault L.
      • Caspi A.
      • Moffitt T.E.
      • Viana J.
      • et al.
      Methylomic analysis of monozygotic twins discordant for childhood psychotic symptoms.
      ), which assessed markers of conversion to psychosis in twins discordant for schizophrenia or high-risk individuals, and biomarker studies (
      • Hannon E.
      • Dempster E.
      • Viana J.
      • Burrage J.
      • Smith A.R.
      • Macdonald R.
      • et al.
      An integrated genetic-epigenetic analysis of schizophrenia: Evidence for co-localization of genetic associations and differential DNA methylation.
      ,
      • Montano C.
      • Taub M.A.
      • Jaffe A.
      • Briem E.
      • Feinberg J.I.
      • Trygvadottir R.
      • et al.
      Association of DNA methylation differences with schizophrenia in an epigenome-wide association study.
      ,
      • Aberg K.A.
      • McClay J.L.
      • Nerella S.
      • Clark S.
      • Kumar G.
      • Chen W.
      • et al.
      Methylome-wide association study of schizophrenia: Identifying blood biomarker signatures of environmental insults.
      ,
      • Ciuculete D.M.
      • Bostrom A.E.
      • Voisin S.
      • Philipps H.
      • Titova O.E.
      • Bandstein M.
      • et al.
      A methylome-wide mQTL analysis reveals associations of methylation sites with GAD1 and HDAC3 SNPs and a general psychiatric risk score.
      ), which aim at uncovering biomarkers for schizophrenia in large cohorts. One advantage of such studies is that they provide a means to perform noninvasive and longitudinal epigenetic examinations, which would not be possible using brain tissue. Peripheral epigenetic profiling, however, does not necessarily capture disease-associated epigenetic changes occurring in the CNS. In support of the latter notion, there is only minimal overlap between the findings obtained by genome-wide DNAm profiling in CNS and non-CNS tissues of schizophrenia (Tables 1 and 2). Hence, while peripheral epigenetic profiling may still be valid for the identification of molecular biomarkers, it appears that peripheral epigenetic signatures do not grossly mirror those in the CNS and vice versa.
      Table 2Genome-wide DNA Methylation Changes in Schizophrenia: Peripheral Tissue
      SampleTissue TypeMethodMost SignificantReference
      Longitudinal Studies
       11 MZ twin pairs discordant for SZWhole blood27K arrayPUS3, SYNGR2, KDELR1, PDK3, PPARGC1A(
      • Dempster E.L.
      • Pidsley R.
      • Schalkwyk L.C.
      • Owens S.
      • Georgiades A.
      • Kane F.
      • et al.
      Disease-associated epigenetic changes in monozygotic twins discordant for schizophrenia and bipolar disorder.
      )
       2 MZ twin pairs discordant for SZWhole bloodNimbleGen 720K arrayHIST2H2AA3, HIST2H2AA4, HIST2H3A, HIST2H3Ac AK2 (pair 1)

      DVL1, KIAA1751, CEP104, DFFB, CAMTA1 (pair 2)
      (
      • Castellani C.A.
      • Laufer B.I.
      • Melka M.G.
      • Diehl E.J.
      • O’Reilly R.L.
      • Singh S.M.
      DNA methylation differences in monozygotic twin pairs discordant for schizophrenia identifies psychosis related genes and networks.
      )
       24 MZ twin pairs discordant for psychotic symptoms at 12 years of ageBuccal cells450K arrayC5orf42, MORF4L1, GALNTL4, LOC340094, DIP2C(
      • Fisher H.L.
      • Murphy T.M.
      • Arseneault L.
      • Caspi A.
      • Moffitt T.E.
      • Viana J.
      • et al.
      Methylomic analysis of monozygotic twins discordant for childhood psychotic symptoms.
      )
       14 converters and 25 nonconverters to psychosisWhole blood450K arrayNRPI1, CHL1, EPHNA3, IL17RE, AKT1(
      • Kebir O.
      • Chaumette B.
      • Rivollier F.
      • Miozzo F.
      • Lemieux Perreault L.P.
      • Barhdadi A.
      • et al.
      Methylomic changes during conversion to psychosis.
      )
       767 subjects with psychotic episodes at 12 and 18 years of age (ALSPAC cohort)Cord blood and whole blood at 7 and 15 to 17 years of age450K arrayBAIAP2, F2RL1, FAM19A5, FGFR3, LFNG, LPR5, MAD1L1, OLFML2A, RNH1 (detected in more than one comparison)(
      • Roberts S.
      • Suderman M.
      • Zammit S.
      • Watkins S.H.
      • Hannon E.
      • Mill J.
      • et al.
      Longitudinal investigation of DNA methylation changes preceding adolescent psychotic experiences.
      )
      Biomarker Studies
       759 SZ and 738 CTR discovery cohort; 178 SZ and 182 CTR replication cohort 1; 561 SZ and 582 CTR replication cohort 2Whole bloodMBD-seqFAM63B, ARHGAP26, CTAGE11P, TBC1D22A, RELN (replicated in all cohorts)(
      • Aberg K.A.
      • McClay J.L.
      • Nerella S.
      • Clark S.
      • Kumar G.
      • Chen W.
      • et al.
      Methylome-wide association study of schizophrenia: Identifying blood biomarker signatures of environmental insults.
      )
       353 SZ and 322 CTR discovery cohort; 414 SZ and 433 CTR replication cohortWhole blood450K arrayFAM126A, PPTC7, GYG1, SIK3, USP36 (part of 25 DMPs replicated also in the second cohort)(
      • Hannon E.
      • Dempster E.
      • Viana J.
      • Burrage J.
      • Smith A.R.
      • Macdonald R.
      • et al.
      An integrated genetic-epigenetic analysis of schizophrenia: Evidence for co-localization of genetic associations and differential DNA methylation.
      )
       689 SZ and 645 CTR discovery cohort; 247 SZ and 250 CTR replication cohortWhole blood450K arrayRPS6KA1, MGRN1, S100A2, NCOR, KIAA0355 (part of the top 15 replicated in all cohorts)(
      • Montano C.
      • Taub M.A.
      • Jaffe A.
      • Briem E.
      • Feinberg J.I.
      • Trygvadottir R.
      • et al.
      Association of DNA methylation differences with schizophrenia in an epigenome-wide association study.
      )
       130 adolescents at risk for psychiatric disorders, discovery cohort; 93 adolescents, replication cohortWhole blood450K array305,147 CpG loci investigated in relation to 37 SNPs associated with psychiatric disorders. 5 SNPs (in HCRTR1, GAD1, HDAC3, and FKBP5) associated with 7 DMPs (closest gene PEF1, GAD1, DIAPH1, PCDHGC3, TULP1, and C11orf9)(
      • Ciuculete D.M.
      • Bostrom A.E.
      • Voisin S.
      • Philipps H.
      • Titova O.E.
      • Bandstein M.
      • et al.
      A methylome-wide mQTL analysis reveals associations of methylation sites with GAD1 and HDAC3 SNPs and a general psychiatric risk score.
      )
      The table summarizes the main findings from studies assessing genome-wide DNA methylation profiles in peripheral tissues of patients with schizophrenia (SZ) relative to matched control subjects (CTR) and/or in subjects at high risk for psychosis relative to control subjects. The table specifies the study sample, type of peripheral tissue, method used to assess DNA methylation profiles, and genes and loci with the most significant DNA methylation changes.
      ALSPAC, Avon Longitudinal Study of Parents and Children; DMP, differentially methylated position; MBD-seq, methyl-CpG binding domain protein-enriched genome sequencing; MZ, monozygotic; SNP, single nucleotide polymorphism.
      The assay for transposase-accessible chromatin using sequencing (ATAC-seq) is a powerful addition to the genome-wide DNAm profiling approaches because it allows researchers to assess genome-wide chromatin accessibility and overall changes in epigenetic landscapes and corresponding gene signatures (
      • Buenrostro J.D.
      • Giresi P.G.
      • Zaba L.C.
      • Chang H.Y.
      • Greenleaf W.J.
      Transposition of native chromatin for fast and sensitive epigenomic profiling of open chromatin, DNA-binding proteins and nucleosome position.
      ). ATAC-seq has recently been implemented in schizophrenia research (
      • Bryois J.
      • Garrett M.E.
      • Song L.
      • Safi A.
      • Giusti-Rodriguez P.
      • Johnson G.D.
      • et al.
      Evaluation of chromatin accessibility in prefrontal cortex of individuals with schizophrenia.
      ,
      • Hoffman G.E.
      • Bendl J.
      • Voloudakis G.
      • Montgomery K.S.
      • Sloofman L.
      • Wang Y.C.
      • et al.
      CommonMind Consortium provides transcriptomic and epigenomic data for schizophrenia and bipolar disorder.
      ) and has already provided preliminary evidence for altered chromatin accessibility in schizophrenia cases compared with control cases. For example, performing ATAC-seq on adult PFC brain samples from 135 individuals with schizophrenia and 137 control subjects, Bryois et al. (
      • Bryois J.
      • Garrett M.E.
      • Song L.
      • Safi A.
      • Giusti-Rodriguez P.
      • Johnson G.D.
      • et al.
      Evaluation of chromatin accessibility in prefrontal cortex of individuals with schizophrenia.
      ) found that chromatin accessibility in schizophrenia differs in three specific genomic regions. Moreover, the authors identified 118,152 ATAC-seq peaks in PFC tissue, many of which were found to be enriched for schizophrenia single nucleotide polymorphism heritability (
      • Bryois J.
      • Garrett M.E.
      • Song L.
      • Safi A.
      • Giusti-Rodriguez P.
      • Johnson G.D.
      • et al.
      Evaluation of chromatin accessibility in prefrontal cortex of individuals with schizophrenia.
      ). Further use of ATAC-seq is expected to provide imperative new knowledge regarding the molecular mechanisms of altered gene expression in schizophrenia and beyond.

      Histone Modifications

      Several lines of evidence suggest that histone posttranslational modifications (PTMs) play a role in the etiology and pathophysiology of schizophrenia. Initial support for this notion stemmed from the observation that valproate, a mood stabilizer with frequent off-label use in schizophrenia (
      • Horowitz E.
      • Bergman L.C.
      • Ashkenazy C.
      • Moscona-Hurvitz I.
      • Grinvald-Fogel H.
      • Magnezi R.
      Off-label use of sodium valproate for schizophrenia.
      ), is a histone deacetylase (HDAC) inhibitor when administered at therapeutic doses (
      • Sharma R.P.
      • Rosen C.
      • Kartan S.
      • Guidotti A.
      • Costa E.
      • Grayson D.R.
      • et al.
      Valproic acid and chromatin remodeling in schizophrenia and bipolar disorder: Preliminary results from a clinical population.
      ). Based on the findings showing beneficial effects of valproate on clinical symptoms in some patients with schizophrenia (
      • Wang Y.
      • Xia J.
      • Helfer B.
      • Li C.
      • Leucht S.
      Valproate for schizophrenia.
      ), various studies explored whether schizophrenia is linked to specific histone PTMs and associated alterations in the enzymes that catalyze such modifications. The existing evidence for such alterations includes the presence of high levels of H3R17 methylation (
      • Akbarian S.
      • Ruehl M.G.
      • Bliven E.
      • Luiz L.A.
      • Peranelli A.C.
      • Baker S.P.
      • et al.
      Chromatin alterations associated with down-regulated metabolic gene expression in the prefrontal cortex of subjects with schizophrenia.
      ), increased cortical levels of HDAC1 (
      • Bahari-Javan S.
      • Varbanov H.
      • Halder R.
      • Benito E.
      • Kaurani L.
      • Burkhardt S.
      • et al.
      HDAC1 links early life stress to schizophrenia-like phenotypes.
      ,
      • Sharma R.P.
      • Grayson D.R.
      • Gavin D.P.
      Histone deactylase 1 expression is increased in the prefrontal cortex of schizophrenia subjects: Analysis of the National Brain Databank microarray collection.
      ), and histone methyltransferases (
      • Chase K.A.
      • Gavin D.P.
      • Guidotti A.
      • Sharma R.P.
      Histone methylation at H3K9: Eidence for a restrictive epigenome in schizophrenia.
      ,
      • Chase K.A.
      • Rosen C.
      • Rubin L.H.
      • Feiner B.
      • Bodapati A.S.
      • Gin H.
      • et al.
      Evidence of a sex-dependent restrictive epigenome in schizophrenia.
      ), but reduced cortical levels of HDAC2 (
      • Schroeder F.A.
      • Gilbert T.M.
      • Feng N.
      • Taillon B.D.
      • Volkow N.D.
      • Innis R.B.
      • et al.
      Expression of HDAC2 but not HDAC1 transcript is reduced in dorsolateral prefrontal cortex of patients with schizophrenia.
      ) in postmortem samples of cases with schizophrenia. The latter finding was recently corroborated by an in vivo positron emission tomography study using a radiotracer version of the potent HDAC inhibitor [11C]Martinostat, showing lower in vivo HDAC levels in cases with schizophrenia as compared with matched control subjects (
      • Gilbert T.M.
      • Zurcher N.R.
      • Wu C.J.
      • Bhanot A.
      • Hightower B.G.
      • Kim M.
      • et al.
      PET neuroimaging reveals histone deacetylase dysregulation in schizophrenia.
      ). Furthermore, this study revealed a positive correlation between cortical HDAC levels and cognitive performance independent of diagnostic groups (
      • Gilbert T.M.
      • Zurcher N.R.
      • Wu C.J.
      • Bhanot A.
      • Hightower B.G.
      • Kim M.
      • et al.
      PET neuroimaging reveals histone deacetylase dysregulation in schizophrenia.
      ), highlighting a general involvement of HDACs in cognitive functions.
      Imperative new research efforts, mainly fueled by the PsychENCODE initiative (
      • Akbarian S.
      • Liu C.
      • Knowles J.A.
      • Vaccarino F.M.
      • Farnham P.J.
      • et al.
      PsychENCODE Consortium
      The PsychENCODE project.
      ), are also being made to comprehensively map histone PTMs across the genome in different brain regions, cell types, and psychiatric disorders. This initiative aims at providing a public resource of genomic data (including histone PTMs) originating from tissue and cell-specific samples of 1866 individuals (558 of whom were diagnosed with schizophrenia). Based on the practical guidelines for chromatin immunoprecipitation sequencing followed by deep sequencing suggested by Kundakovic et al. (
      • Kundakovic M.
      • Jiang Y.
      • Kavanagh D.H.
      • Dincer A.
      • Brown L.
      • Pothula V.
      • et al.
      Practical guidelines for high-resolution epigenomic profiling of nucleosomal histones in postmortem human brain tissue.
      ), which ensure a high degree of standardization across studies, two studies investigated genome-wide histone PTMs in health and disease. In a first study, Girdhar et al. (
      • Girdhar K.
      • Hoffman G.E.
      • Jiang Y.
      • Brown L.
      • Kundakovic M.
      • Hauberg M.E.
      • et al.
      Cell-specific histone modification maps in the human frontal lobe link schizophrenia risk to the neuronal epigenome.
      ) profiled open chromatin-associated modifications in neuronal and nonneuronal cells isolated from the dorsolateral PFC and the anterior cingulate cortex of healthy subjects. These investigations aimed at generating reference maps for two histone marks (H3K4me3 and H3K27ac) that are associated with active promoters and enhancers, which in turn can be used as a resource to map histone PTMs in a cell-type-specific manner. The results obtained by Girdhar et al. (
      • Girdhar K.
      • Hoffman G.E.
      • Jiang Y.
      • Brown L.
      • Kundakovic M.
      • Hauberg M.E.
      • et al.
      Cell-specific histone modification maps in the human frontal lobe link schizophrenia risk to the neuronal epigenome.
      ) show that neuronal and nonneuronal cell types strongly differ with regard to histone modification profiles, highlighting the critical role of cell-type-specific epigenetic signatures in cortical tissue. Moreover, the study found that risk variants for schizophrenia were overrepresented in neuronal versus nonneuronal H3K4me3 and H3K27ac landscapes (
      • Girdhar K.
      • Hoffman G.E.
      • Jiang Y.
      • Brown L.
      • Kundakovic M.
      • Hauberg M.E.
      • et al.
      Cell-specific histone modification maps in the human frontal lobe link schizophrenia risk to the neuronal epigenome.
      ), emphasizing the need to focus on neuronal populations for future investigations of histone PTMs in this disorder.
      In a second study, Wang et al. (
      • Wang D.
      • Liu S.
      • Warrell J.
      • Won H.
      • Shi X.
      • Navarro F.C.P.
      • et al.
      Comprehensive functional genomic resource and integrative model for the human brain.
      ) annotated active enhancers (defined as open chromatin regions depleted in H3K4me3 and enriched in H3K27ac) in neuronal and nonneuronal nuclei originating from healthy individuals and patients with schizophrenic. This impressive dataset was used to calculate chromatin quantitative trait loci and integrated with other genomic data to obtain regulatory networks linking enhancers, transcription factors, and target genes. These regulatory networks were then further used to link schizophrenia genome-wide association study variants to genes (uncovering a set of 321 novel high-confidence schizophrenia-associated genes) and finally embedded into a deep learning model to predict psychiatric phenotypes from genomic data, which provides a 6-fold increased improvement in prediction over additive polygenic risk scores (PRSs) (
      • Wang D.
      • Liu S.
      • Warrell J.
      • Won H.
      • Shi X.
      • Navarro F.C.P.
      • et al.
      Comprehensive functional genomic resource and integrative model for the human brain.
      ).
      A few studies further identified altered histone PTMs in peripheral tissues from patients with schizophrenia. For example, reduced acetylated H3 levels (
      • Gavin D.P.
      • Kartan S.
      • Chase K.
      • Grayson D.R.
      • Sharma R.P.
      Reduced baseline acetylated histone 3 levels, and a blunted response to HDAC inhibition in lymphocyte cultures from schizophrenia subjects.
      ) and higher levels of H3K9me2 (
      • Gavin D.P.
      • Rosen C.
      • Chase K.
      • Grayson D.R.
      • Tun N.
      • Sharma R.P.
      Dimethylated lysine 9 of histone 3 is elevated in schizophrenia and exhibits a divergent response to histone deacetylase inhibitors in lymphocyte cultures.
      ) were found in lymphocytes obtained from patients relative to control subjects. Intriguingly, increased H3K9me2 levels were also found in the parietal cortex of schizophrenia cases (
      • Chase K.A.
      • Gavin D.P.
      • Guidotti A.
      • Sharma R.P.
      Histone methylation at H3K9: Eidence for a restrictive epigenome in schizophrenia.
      ,
      • Chase K.A.
      • Rosen C.
      • Rubin L.H.
      • Feiner B.
      • Bodapati A.S.
      • Gin H.
      • et al.
      Evidence of a sex-dependent restrictive epigenome in schizophrenia.
      ), suggesting that there is a certain correspondence between altered histone PTMs in peripheral and central tissues.

      Noncoding RNAs

      The majority of studies examining the possible involvement of ncRNAs in schizophrenia have focused on microRNAs (miRNAs) as opposed to other ncRNAs (
      • Zhao H.
      • Xu J.
      • Pang L.
      • Zhang Y.
      • Fan H.
      • Liu L.
      • et al.
      Genome-wide DNA methylome reveals the dysfunction of intronic microRNAs in major psychosis.
      ,
      • Ragan C.
      • Patel K.
      • Edson J.
      • Zhang Z.H.
      • Gratten J.
      • Mowry B.
      Small non-coding RNA expression from anterior cingulate cortex in schizophrenia shows sex specific regulation.
      ,
      • Liu Y.
      • Chang X.
      • Hahn C.G.
      • Gur R.E.
      • Sleiman P.A.M.
      • Hakonarson H.
      Non-coding RNA dysregulation in the amygdala region of schizophrenia patients contributes to the pathogenesis of the disease.
      ). A likely reason for the strong focus on miRNAs is that a microdeletion at chromosome 22q11.2, which is a genetic variation conferring high risk of schizophrenia and other neurodevelopmental disorders, includes a gene (DGCR8) encoding for an miRNA processing protein (
      • Van L.
      • Boot E.
      • Bassett A.S.
      Update on the 22q11.2 deletion syndrome and its relevance to schizophrenia.
      ). This discovery led to the hypothesis that miRNA dysfunctionalities, whether induced by genetic or environmental factors, are involved in the etiology and pathophysiology of schizophrenia (
      • Perkins D.O.
      • Jeffries C.
      • Sullivan P.
      Expanding the “central dogma”: The regulatory role of nonprotein coding genes and implications for the genetic liability to schizophrenia.
      ). Since the seminal findings of Perkins et al. (
      • Perkins D.O.
      • Jeffries C.D.
      • Jarskog L.F.
      • Thomson J.M.
      • Woods K.
      • Newman M.A.
      • et al.
      microRNA expression in the prefrontal cortex of individuals with schizophrenia and schizoaffective disorder.
      ), who were the first to identify altered miRNA profiles in postmortem PFC from patients with schizophrenia, a number of studies revealed altered cortical and subcortical expression of various miRNAs, including mir130 (
      • Burmistrova O.A.
      • Goltsov A.Y.
      • Abramova L.I.
      • Kaleda V.G.
      • Orlova V.A.
      • Rogaev E.I.
      microRNA in schizophrenia: Genetic and expression analysis of miR-130b (22q11).
      ), mir181b (
      • Beveridge N.J.
      • Tooney P.A.
      • Carroll A.P.
      • Gardiner E.
      • Bowden N.
      • Scott R.J.
      • et al.
      Dysregulation of miRNA 181b in the temporal cortex in schizophrenia.
      ), mir497 (
      • Banigan M.G.
      • Kao P.F.
      • Kozubek J.A.
      • Winslow A.R.
      • Medina J.
      • Costa J.
      • et al.
      Differential expression of exosomal microRNAs in prefrontal cortices of schizophrenia and bipolar disorder patients.
      ), mir185 (
      • Forstner A.J.
      • Degenhardt F.
      • Schratt G.
      • Nothen M.M.
      microRNAs as the cause of schizophrenia in 22q11.2 deletion carriers, and possible implications for idiopathic disease: A mini-review.
      ), mir9 (
      • Topol A.
      • Zhu S.
      • Hartley B.J.
      • English J.
      • Hauberg M.E.
      • Tran N.
      • et al.
      Dysregulation of miRNA-9 in a subset of schizophrenia patient-derived neural progenitor cells.
      ), mir195, mir301a (
      • Alacam H.
      • Akgun S.
      • Akca H.
      • Ozturk O.
      • Kabukcu B.B.
      • Herken H.
      miR-181b-5p, miR-195-5p and miR-301a-3p are related with treatment resistance in schizophrenia.
      ), mir132, mir1307 (
      • Liu Y.
      • Chang X.
      • Hahn C.G.
      • Gur R.E.
      • Sleiman P.A.M.
      • Hakonarson H.
      Non-coding RNA dysregulation in the amygdala region of schizophrenia patients contributes to the pathogenesis of the disease.
      ), and mir137 (
      • Sakamoto K.
      • Crowley J.J.
      A comprehensive review of the genetic and biological evidence supports a role for microRNA-137 in the etiology of schizophrenia.
      ). Notably, mir137 was found to be linked to schizophrenia in an early genome-wide association study (
      Schizophrenia Psychiatric Genome-Wide Association Study Consortium
      Genome-wide association study identifies five new schizophrenia loci.
      ), a finding that was confirmed in the largest genome-wide association study of schizophrenia existing to date (
      Schizophrenia Working Group of the Psychiatric Genomics Consortium
      Biological insights from 108 schizophrenia-associated genetic loci.
      ). In further support of its involvement in schizophrenia, mir137 represents an important signaling node in various gene networks relevant to brain development and functions, including axon guidance signaling, ephrin receptor signaling, and synaptic activity (
      • Wright C.
      • Calhoun V.D.
      • Ehrlich S.
      • Wang L.
      • Turner J.A.
      • Bizzozero N.I.
      Meta gene set enrichment analyses link miR-137-regulated pathways with schizophrenia risk.
      ,
      • Collins A.L.
      • Kim Y.
      • Bloom R.J.
      • Kelada S.N.
      • Sethupathy P.
      • Sullivan P.F.
      Transcriptional targets of the schizophrenia risk gene MIR137.
      ), all of which are known to be disrupted in schizophrenia and related disorders (
      • Owen M.J.
      • Sawa A.
      • Mortensen P.B.
      Schizophrenia.
      ,
      • Prata D.P.
      • Costa-Neves B.
      • Cosme G.
      • Vassos E.
      Unravelling the genetic basis of schizophrenia and bipolar disorder with GWAS: A systematic review.
      ,
      Schizophrenia Working Group of the Psychiatric Genomics Consortium
      Biological insights from 108 schizophrenia-associated genetic loci.
      ,
      • Landek-Salgado M.A.
      • Faust T.E.
      • Sawa A.
      Molecular substrates of schizophrenia: Homeostatic signaling to connectivity.
      ).
      miRNAs have also been profiled in the blood of patients with schizophrenia (
      • Lai C.Y.
      • Yu S.L.
      • Hsieh M.H.
      • Chen C.H.
      • Chen H.Y.
      • Wen C.C.
      • et al.
      microRNA expression aberration as potential peripheral blood biomarkers for schizophrenia.
      ), with the main aim of identifying blood biomarkers of the disease. In a recent genome-wide expression study, Du et al. (
      • Du Y.
      • Yu Y.
      • Hu Y.
      • Li X.W.
      • Wei Z.X.
      • Pan R.Y.
      • et al.
      Genome-wide, integrative analysis implicates exosome-derived microRNA dysregulation in schizophrenia.
      ) found that several miRNAs were differentially expressed in serum exosomes of patients with first-episode, drug-free schizophrenia relative to matched control subjects. Importantly, among the differentially expressed miRNAs, 11 could be used to dissociate schizophrenia samples from control samples with 75% to 90% accuracy (
      • Du Y.
      • Yu Y.
      • Hu Y.
      • Li X.W.
      • Wei Z.X.
      • Pan R.Y.
      • et al.
      Genome-wide, integrative analysis implicates exosome-derived microRNA dysregulation in schizophrenia.
      ). Despite this remarkable precision, however, blood miRNA profiling tends to produce equivocal results in the context of schizophrenia, with biomarker candidates varying across independent studies (
      • Liu S.
      • Zhang F.
      • Shugart Y.Y.
      • Yang L.
      • Li X.
      • Liu Z.
      • et al.
      The early growth response protein 1-miR-30a-5p-neurogenic differentiation factor 1 axis as a novel biomarker for schizophrenia diagnosis and treatment monitoring.
      ,
      • Liu S.
      • Zhang F.
      • Wang X.
      • Shugart Y.Y.
      • Zhao Y.
      • Li X.
      • et al.
      Diagnostic value of blood-derived microRNAs for schizophrenia: Results of a meta-analysis and validation.
      ,
      • Wu S.
      • Zhang R.
      • Nie F.
      • Wang X.
      • Jiang C.
      • Liu M.
      • et al.
      microRNA-137 inhibits EFNB2 expression affected by a genetic variant and is expressed aberrantly in peripheral blood of schizophrenia patients.
      ). While this variability may arise from various cofounding effects, including differences in the type of tissue, low sample size, and smoking-related epigenetic effects (
      • Kaur G.
      • Begum R.
      • Thota S.
      • Batra S.
      A systematic review of smoking-related epigenetic alterations.
      ), it may also mirror the disorder’s etiological (and phenotypic) heterogeneity (
      • Tsuang M.T.
      • Faraone S.V.
      The case for heterogeneity in the etiology of schizophrenia.
      ,
      • Tsuang M.T.
      • Lyons M.J.
      • Faraone S.V.
      Heterogeneity of schizophrenia: Conceptual models and analytic strategies.
      ).

      Epigenetic Modifications as Molecular Scars of Environmental Exposures

      While certain epigenetic modifications in schizophrenia may have a genetic origin (
      • Hannon E.
      • Dempster E.
      • Viana J.
      • Burrage J.
      • Smith A.R.
      • Macdonald R.
      • et al.
      An integrated genetic-epigenetic analysis of schizophrenia: Evidence for co-localization of genetic associations and differential DNA methylation.
      ,
      • Montano C.
      • Taub M.A.
      • Jaffe A.
      • Briem E.
      • Feinberg J.I.
      • Trygvadottir R.
      • et al.
      Association of DNA methylation differences with schizophrenia in an epigenome-wide association study.
      ,
      • Ciuculete D.M.
      • Bostrom A.E.
      • Voisin S.
      • Philipps H.
      • Titova O.E.
      • Bandstein M.
      • et al.
      A methylome-wide mQTL analysis reveals associations of methylation sites with GAD1 and HDAC3 SNPs and a general psychiatric risk score.
      ,
      • Tao R.
      • Davis K.N.
      • Li C.
      • Shin J.H.
      • Gao Y.
      • Jaffe A.E.
      • et al.
      GAD1 alternative transcripts and DNA methylation in human prefrontal cortex and hippocampus in brain development, schizophrenia.
      ), converging evidence suggests that a substantial portion of epigenetic alterations may be acquired through environmental factors (
      • Bale T.L.
      Epigenetic and transgenerational reprogramming of brain development.
      ,
      • Jirtle R.L.
      • Skinner M.K.
      Environmental epigenomics and disease susceptibility.
      ,
      • Szyf M.
      The early life social environment and DNA methylation: DNA methylation mediating the long-term impact of social environments early in life.
      ,
      • Zhang T.Y.
      • Meaney M.J.
      Epigenetics and the environmental regulation of the genome and its function.
      ). Hence, epigenetic modifications in schizophrenia may represent molecular scars of exposures to certain environmental adversities, especially when encountered during sensitive developmental periods (
      • Grayson D.R.
      • Guidotti A.
      The dynamics of DNA methylation in schizophrenia and related psychiatric disorders.
      ,
      • Hollins S.L.
      • Cairns M.J.
      microRNA: Small RNA mediators of the brains genomic response to environmental stress.
      ,
      • Morishita H.
      • Kundakovic M.
      • Bicks L.
      • Mitchell A.
      • Akbarian S.
      Interneuron epigenomes during the critical period of cortical plasticity: Implications for schizophrenia.
      ,
      • Nestler E.J.
      • Pena C.J.
      • Kundakovic M.
      • Mitchell A.
      • Akbarian S.
      Epigenetic basis of mental illness.
      ,
      • Rutten B.P.
      • Mill J.
      Epigenetic mediation of environmental influences in major psychotic disorders.
      ). Consistent with this notion, a recent study showed that blood HDAC1 levels were increased in patients with schizophrenia who had been exposed to early-life stress as compared with patients with schizophrenia who had not been exposed to early-life stress exposure (
      • Bahari-Javan S.
      • Varbanov H.
      • Halder R.
      • Benito E.
      • Kaurani L.
      • Burkhardt S.
      • et al.
      HDAC1 links early life stress to schizophrenia-like phenotypes.
      ). A plethora of findings derived from animal models, in which causal links among environmental factors, epigenetic modifications, and pathological traits can be studied against the background of genetic homogeneity, provide additional evidence for the lasting impact of environmental factors on the epigenetic machinery (
      • Grayson D.R.
      • Guidotti A.
      DNA methylation in animal models of psychosis.
      ). As summarized in Table S1, many of these models are based on environmental factors implicated in the etiology of schizophrenia and related disorders (
      • Meyer U.
      • Feldon J.
      Epidemiology-driven neurodevelopmental animal models of schizophrenia.
      ), including exposure to prenatal or postnatal stress, inhibitors of fetal neurogenesis, infectious and noninfectious maternal immune activation (MIA) during pregnancy, gestational and postpartum nutritional deficiencies or exposure to drugs of abuse and toxicants, reduced postpartum maternal care, and chronic cannabis intake during adolescence. Not only do these models capture a broad spectrum of behavioral and neurobiological alterations pertinent to schizophrenia and other psychotic disorders, but they also show lasting abnormalities in various epigenetic profiles (Table S1).
      While these models are relevant for other brain disorders as well (
      • Reisinger S.
      • Khan D.
      • Kong E.
      • Berger A.
      • Pollak A.
      • Pollak D.D.
      The poly(I:C)-induced maternal immune activation model in preclinical neuropsychiatric drug discovery.
      ), they contribute to our understanding of how exposure to environmental factors in early life can change neurodevelopmental trajectories and cause long-term brain dysfunctions implicated in schizophrenia (
      • Meyer U.
      • Feldon J.
      Epidemiology-driven neurodevelopmental animal models of schizophrenia.
      ,
      • Ayhan Y.
      • McFarland R.
      • Pletnikov M.V.
      Animal models of gene-environment interaction in schizophrenia: A dimensional perspective.
      ) and beyond (
      • Reisinger S.
      • Khan D.
      • Kong E.
      • Berger A.
      • Pollak A.
      • Pollak D.D.
      The poly(I:C)-induced maternal immune activation model in preclinical neuropsychiatric drug discovery.
      ). Within the context of schizophrenia, a key feature of these models is that they allow epigenetic screens against multiple and coexisting schizophrenia-related dysfunctions while incorporating the disease-relevant concept of abnormal brain development under stringent experimental conditions. Furthermore, they can be used to explore whether pharmacological or nonpharmacological interventions targeting the epigenetic machinery are capable of attenuating abnormalities in brain development and functions (
      • Grayson D.R.
      • Guidotti A.
      DNA methylation in animal models of psychosis.
      ,
      • Gapp K.
      • Bohacek J.
      • Grossmann J.
      • Brunner A.M.
      • Manuella F.
      • Nanni P.
      • et al.
      Potential of environmental enrichment to prevent transgenerational effects of paternal trauma.
      ,
      • Matrisciano F.
      • Tueting P.
      • Dalal I.
      • Kadriu B.
      • Grayson D.R.
      • Davis J.M.
      • et al.
      Epigenetic modifications of GABAergic interneurons are associated with the schizophrenia-like phenotype induced by prenatal stress in mice.
      ,
      • Tremolizzo L.
      • Doueiri M.S.
      • Dong E.
      • Grayson D.R.
      • Davis J.
      • Pinna G.
      • et al.
      Valproate corrects the schizophrenia-like epigenetic behavioral modifications induced by methionine in mice.
      ).
      Although exposure to distinct environmental factors can induce a specific set of epigenetic alterations (Table S1), there is also notable convergence between the epigenetic effects of individual environmental (and genetic) factors. Epigenetic remodeling of the gene regulatory region of GAD1, which encodes the 67-kDa isoform of the GABA-synthesizing enzyme glutamic acid decarboxylase (GAD67), is an illustrative example of such convergence (Figure 2). In animal models, altered DNAm in the gene regulatory region of Gad1 and corresponding GAD67 expression deficits have been found following exposure to various environmental adversities, including exposure to MIA (
      • Labouesse M.A.
      • Dong E.
      • Grayson D.R.
      • Guidotti A.
      • Meyer U.
      Maternal immune activation induces GAD1 and GAD2 promoter remodeling in the offspring prefrontal cortex.
      ), maternal stress (
      • Matrisciano F.
      • Tueting P.
      • Dalal I.
      • Kadriu B.
      • Grayson D.R.
      • Davis J.M.
      • et al.
      Epigenetic modifications of GABAergic interneurons are associated with the schizophrenia-like phenotype induced by prenatal stress in mice.
      ,
      • Matrisciano F.
      • Tueting P.
      • Maccari S.
      • Nicoletti F.
      • Guidotti A.
      Pharmacological activation of group-II metabotropic glutamate receptors corrects a schizophrenia-like phenotype induced by prenatal stress in mice.
      ), and low postpartum maternal care (
      • Zhang T.Y.
      • Hellstrom I.C.
      • Bagot R.C.
      • Wen X.
      • Diorio J.
      • Meaney M.J.
      Maternal care and DNA methylation of a glutamic acid decarboxylase 1 promoter in rat hippocampus.
      ). Intriguingly, these epigenetic and transcriptional changes correlate with the deficits in sociability and working memory occurring after MIA (
      • Labouesse M.A.
      • Dong E.
      • Grayson D.R.
      • Guidotti A.
      • Meyer U.
      Maternal immune activation induces GAD1 and GAD2 promoter remodeling in the offspring prefrontal cortex.
      ), emphasizing a possible functional impact of Gad1 promoter remodeling on schizophrenia-relevant behavioral and cognitive functions. Taken together, experimental research in animal models of early-life adversities suggests that various environmental factors, which have each been implicated in the etiology of schizophrenia and related disorders, can converge on the same molecular pathways affecting GABAergic development and functions (Figure 2).
      Figure thumbnail gr2
      Figure 2Convergence between environmental and genetic factors in methylation-related remodeling of the GAD1 gene regulatory region. (A) Schematic illustration of a simplified version of the GAD1 gene regulatory and coding regions that encodes the 67-kDa isoform of GAD (GAD67) mRNA. The GAD1 gene regulatory region contains numerous CpG islands that facilitate methylation at position 5′ in the cytosine ring (5mC). (B) Several environmental factors, including maternal stress during pregnancy, maternal immune activation during pregnancy, and low postpartum maternal care, can cause hypermethylation of the GAD1 gene regulatory region. Hypermethylation of the GAD1 gene regulatory region can also be caused by certain genetic variants (e.g., rs3749034, a schizophrenia-risk single nucleotide polymorphism). In schizophrenia and disease-relevant model systems, epigenetic remodeling of the GAD1 gene regulatory region further includes increased binding of DNMTs and MeCP2 at GAD1 promoter regions. Together, these epigenetic changes can lead to reduced transcription of GAD67 mRNA, which in turn has been associated with impaired neuronal synchronization and inhibition and the subsequent emergence of behavioral and cognitive deficits. DNMT, DNA methyltransferase; GAD67, glutamic acid decarboxylase; MeCP2, methyl-CpG binding protein 2; mRNA, messenger RNA; TSS, transcription start site.
      Even though schizophrenia has been repeatedly associated with reduced GAD67 expression in cortical and hippocampal areas, it remains elusive whether this GABAergic deficit stems from altered DNAm in the gene regulatory region of GAD1 (
      • Huang H.S.
      • Akbarian S.
      GAD1 mRNA expression and DNA methylation in prefrontal cortex of subjects with schizophrenia.
      ,
      • Ruzicka W.B.
      • Subburaju S.
      • Benes F.M.
      Circuit- and diagnosis-specific DNA methylation changes at gamma-aminobutyric acid-related genes in postmortem human hippocampus in schizophrenia and bipolar disorder.
      ,
      • Wockner L.F.
      • Noble E.P.
      • Lawford B.R.
      • Young R.M.
      • Morris C.P.
      • Whitehall V.L.
      • et al.
      Genome-wide DNA methylation analysis of human brain tissue from schizophrenia patients.
      ,
      • Wockner L.F.
      • Morris C.P.
      • Noble E.P.
      • Lawford B.R.
      • Whitehall V.L.
      • Young R.M.
      • et al.
      Brain-specific epigenetic markers of schizophrenia.
      ,
      • Grayson D.R.
      • Guidotti A.
      The dynamics of DNA methylation in schizophrenia and related psychiatric disorders.
      ,
      • Akbarian S.
      • Huang H.S.
      Molecular and cellular mechanisms of altered GAD1/GAD67 expression in schizophrenia and related disorders.
      ). Several schizophrenia postmortem studies, however, show altered expression and/or promoter binding of enzymes that are critical for the maintenance of the DNA methylation/demethylation equilibrium of cytosines positioned within a CG context, including DNMTs, TET proteins, and MeCP2 (
      • Dong E.
      • Gavin D.P.
      • Chen Y.
      • Davis J.
      Upregulation of TET1 and downregulation of APOBEC3A and APOBEC3C in the parietal cortex of psychotic patients.
      ,
      • Dong E.
      • Ruzicka W.B.
      • Grayson D.R.
      • Guidotti A.
      DNA-methyltransferase1 (DNMT1) binding to CpG rich GABAergic and BDNF promoters is increased in the brain of schizophrenia and bipolar disorder patients.
      ,
      • Mitchell A.C.
      • Jiang Y.
      • Peter C.
      • Akbarian S.
      Transcriptional regulation of GAD1 GABA synthesis gene in the prefrontal cortex of subjects with schizophrenia.
      ,
      • Zhubi A.
      • Chen Y.
      • Dong E.
      • Cook E.H.
      • Guidotti A.
      • Grayson D.R.
      Increased binding of MeCP2 to the GAD1 and RELN promoters may be mediated by an enrichment of 5-hmC in autism spectrum disorder (ASD) cerebellum.
      ). In addition, other epigenetic changes may contribute to GAD1 promoter remodeling in schizophrenia as well, including reduced repressive chromatin-associated DNAm at the promoter, decreased H3K4 trimethylation (a marker of active transcription), and changes in the 3D configuration of the linear sequence containing the GAD1 locus (
      • Huang H.S.
      • Akbarian S.
      GAD1 mRNA expression and DNA methylation in prefrontal cortex of subjects with schizophrenia.
      ,
      • Dong E.
      • Ruzicka W.B.
      • Grayson D.R.
      • Guidotti A.
      DNA-methyltransferase1 (DNMT1) binding to CpG rich GABAergic and BDNF promoters is increased in the brain of schizophrenia and bipolar disorder patients.
      ,
      • Huang H.S.
      • Matevossian A.
      • Whittle C.
      • Kim S.Y.
      • Schumacher A.
      • Baker S.P.
      • et al.
      Prefrontal dysfunction in schizophrenia involves mixed-lineage leukemia 1-regulated histone methylation at GABAergic gene promoters.
      ,
      • Bharadwaj R.
      • Jiang Y.
      • Mao W.
      • Jakovcevski M.
      • Dincer A.
      • Krueger W.
      • et al.
      Conserved chromosome 2q31 conformations are associated with transcriptional regulation of GAD1 GABA synthesis enzyme and altered in prefrontal cortex of subjects with schizophrenia.
      ).
      While exposure to environmental adversities may readily contribute to epigenetically driven deficits in GABAergic gene transcription (Figure 2), several gene variants appear to do so as well (
      • Ciuculete D.M.
      • Bostrom A.E.
      • Voisin S.
      • Philipps H.
      • Titova O.E.
      • Bandstein M.
      • et al.
      A methylome-wide mQTL analysis reveals associations of methylation sites with GAD1 and HDAC3 SNPs and a general psychiatric risk score.
      ,
      • Tao R.
      • Davis K.N.
      • Li C.
      • Shin J.H.
      • Gao Y.
      • Jaffe A.E.
      • et al.
      GAD1 alternative transcripts and DNA methylation in human prefrontal cortex and hippocampus in brain development, schizophrenia.
      ,
      • Curie A.
      • Lesca G.
      • Bussy G.
      • Manificat S.
      • Arnaud V.
      • Gonzalez S.
      • et al.
      Asperger syndrome and early-onset schizophrenia associated with a novel MECP2 deleterious missense variant.
      ,
      • McCarthy S.E.
      • Gillis J.
      • Kramer M.
      • Lihm J.
      • Yoon S.
      • Berstein Y.
      • et al.
      De novo mutations in schizophrenia implicate chromatin remodeling and support a genetic overlap with autism and intellectual disability.
      ). The latter effects are consistent with the considerable genetic influence on schizophrenia risk (
      • Owen M.J.
      • Sawa A.
      • Mortensen P.B.
      Schizophrenia.
      ,
      • Landek-Salgado M.A.
      • Faust T.E.
      • Sawa A.
      Molecular substrates of schizophrenia: Homeostatic signaling to connectivity.
      ). Future studies are warranted, however, to explore how specific environmental and genetic factors can have additive or interactive effects on molecular pathways affecting GABAergic gene transcription in schizophrenia and related disorders.

      Epigenetic Modifications as Source of Phenotypic Variability

      Schizophrenia is known to be highly heterogeneous in terms of both its clinical presentation and its etiology. Even though they are practical for clinicians, the diagnostic systems currently used are not well equipped to capture the clinical heterogeneity of the disorder(s) that Bleuler initially referred to as the “group of schizophrenias” [see (
      • Liang S.G.
      • Greenwood T.A.
      The impact of clinical heterogeneity in schizophrenia on genomic analyses.
      )]. The clinical heterogeneity of schizophrenia is also mirrored by the underlying genetic risk, which appears to be polygenic and highly heterogeneous. While both common and rare genetic variants shape the risk of developing schizophrenia (
      • Prata D.P.
      • Costa-Neves B.
      • Cosme G.
      • Vassos E.
      Unravelling the genetic basis of schizophrenia and bipolar disorder with GWAS: A systematic review.
      ,
      Schizophrenia Working Group of the Psychiatric Genomics Consortium
      Biological insights from 108 schizophrenia-associated genetic loci.
      ), the disorder’s common genetic risk is usually indexed by the PRS, which reflects the cumulative sum of risk-associated alleles at common variants across the entire genome (
      Schizophrenia Working Group of the Psychiatric Genomics Consortium
      Biological insights from 108 schizophrenia-associated genetic loci.
      ).
      Under certain conditions, the PRS of schizophrenia may be useful for estimating individual disease risk (
      • Vassos E.
      • Di Forti M.
      • Coleman J.
      • Iyegbe C.
      • Prata D.
      • Euesden J.
      • et al.
      An examination of polygenic score risk prediction in individuals with first-episode psychosis.
      ), treatment response (
      • Zhang J.P.
      • Robinson D.
      • Yu J.
      • Gallego J.
      • Fleischhacker W.W.
      • Kahn R.S.
      • et al.
      Schizophrenia polygenic risk score as a predictor of antipsychotic efficacy in first-episode psychosis.
      ), and certain symptoms (
      • Toulopoulou T.
      • Zhang X.
      • Cherny S.
      • Dickinson D.
      • Berman K.F.
      • Straub R.E.
      • et al.
      Polygenic risk score increases schizophrenia liability through cognition-relevant pathways.
      ), but it might not be capable of fully seizing the biological basis of the disorder’s clinical and etiological heterogeneity (
      • Wang D.
      • Liu S.
      • Warrell J.
      • Won H.
      • Shi X.
      • Navarro F.C.P.
      • et al.
      Comprehensive functional genomic resource and integrative model for the human brain.
      ). For example, in a recent brain imaging study, it was found that the PRS was unrelated to the substantial brain structural heterogeneity present in schizophrenia (
      • Alnaes D.
      • Kaufmann T.
      • van der Meer D.
      • Cordova-Palomera A.
      • Rokicki J.
      • Moberget T.
      • et al.
      Brain heterogeneity in schizophrenia and its association with polygenic risk.
      ). These findings suggest that brain variability in schizophrenia results from interactions between environmental and genetic factors that are not captured by the PRS.
      To what extent may epigenetic modifications contribute to phenotypic heterogeneity in schizophrenia? We deem this a very likely possibility for various reasons. First, environmental factors can influence the phenotypic presentation of schizophrenia even if they do not interact with common genetic risk of the disorder. One example is prenatal exposure to infectious or noninfectious MIA, which has been shown to influence structural brain abnormalities and executive functioning in schizophrenia (
      • Brown A.S.
      • Vinogradov S.
      • Kremen W.S.
      • Poole J.H.
      • Deicken R.F.
      • Penner J.D.
      • et al.
      Prenatal exposure to maternal infection and executive dysfunction in adult schizophrenia.
      ,
      • Ellman L.M.
      • Deicken R.F.
      • Vinogradov S.
      • Kremen W.S.
      • Poole J.H.
      • Kern D.M.
      • et al.
      Structural brain alterations in schizophrenia following fetal exposure to the inflammatory cytokine interleukin-8.
      ). While direct involvement of epigenetic modifications still awaits examination in these epidemiological associations, findings from animal models show that such modifications provide a key mechanism mediating the effects of MIA on schizophrenia-related structural and functional brain anomalies in the offspring (
      • Labouesse M.A.
      • Dong E.
      • Grayson D.R.
      • Guidotti A.
      • Meyer U.
      Maternal immune activation induces GAD1 and GAD2 promoter remodeling in the offspring prefrontal cortex.
      ,
      • Richetto J.
      • Massart R.
      • Weber-Stadlbauer U.
      • Szyf M.
      • Riva M.A.
      • Meyer U.
      Genome-wide DNA methylation changes in a mouse model of infection-mediated neurodevelopmental disorders.
      ,
      • Richetto J.
      • Chesters R.
      • Cattaneo A.
      • Labouesse M.A.
      • Gutierrez A.M.C.
      • Wood T.C.
      • et al.
      Genome-wide transcriptional profiling and structural magnetic resonance imaging in the maternal immune activation model of neurodevelopmental disorders.
      ) (see also Table S1). Interestingly, the specificity of epigenetic modifications and behavioral abnormalities induced by MIA are dependent on the precise prenatal stage at which MIA occurs (
      • Richetto J.
      • Massart R.
      • Weber-Stadlbauer U.
      • Szyf M.
      • Riva M.A.
      • Meyer U.
      Genome-wide DNA methylation changes in a mouse model of infection-mediated neurodevelopmental disorders.
      ), highlighting that epigenetic variability mirrors phenotypic variability, at least in the context of MIA. Second, genetic variants that are not considered as common in the genetics of schizophrenia may nevertheless be etiologically relevant and contribute to phenotypic heterogeneity by interacting with environmentally acquired epigenetic modifications. The interaction between DISC1 and adolescent stress exposure, which is mediated by stress-induced epigenetic modifications in the mesocortical dopamine system (
      • Niwa M.
      • Jaaro-Peled H.
      • Tankou S.
      • Seshadri S.
      • Hikida T.
      • Matsumoto Y.
      • et al.
      Adolescent stress-induced epigenetic control of dopaminergic neurons via glucocorticoids.
      ), is an illustrative example of this notion. Third, in healthy subjects, the broad interindividual variability in PFC development and functions is mirrored by variable epigenetic profiles, which partly interact with genetic factors (
      • Cheung I.
      • Shulha H.P.
      • Jiang Y.
      • Matevossian A.
      • Wang J.
      • Weng Z.
      • et al.
      Developmental regulation and individual differences of neuronal H3K4me3 epigenomes in the prefrontal cortex.
      ,
      • Gusev F.E.
      • Reshetov D.A.
      • Mitchell A.C.
      • Andreeva T.V.
      • Dincer A.
      • Grigorenko A.P.
      • et al.
      Epigenetic-genetic chromatin footprinting identifies novel and subject-specific genes active in prefrontal cortex neurons.
      ). Fourth, even if some epigenetic modifications can be stable and perpetuate across generations, others are highly dynamic and reversible (
      • Gavin D.P.
      • Chase K.A.
      • Sharma R.P.
      Active DNA demethylation in post-mitotic neurons: A reason for optimism.
      ). The latter not only provides a rationale for epigenetically acting treatments (
      • Gapp K.
      • Bohacek J.
      • Grossmann J.
      • Brunner A.M.
      • Manuella F.
      • Nanni P.
      • et al.
      Potential of environmental enrichment to prevent transgenerational effects of paternal trauma.
      ,
      • Matrisciano F.
      • Tueting P.
      • Dalal I.
      • Kadriu B.
      • Grayson D.R.
      • Davis J.M.
      • et al.
      Epigenetic modifications of GABAergic interneurons are associated with the schizophrenia-like phenotype induced by prenatal stress in mice.
      ,
      • Tremolizzo L.
      • Doueiri M.S.
      • Dong E.
      • Grayson D.R.
      • Davis J.
      • Pinna G.
      • et al.
      Valproate corrects the schizophrenia-like epigenetic behavioral modifications induced by methionine in mice.
      ,
      • Guidotti A.
      • Grayson D.R.
      DNA methylation and demethylation as targets for antipsychotic therapy.
      ) but also provides a parsimonious explanation for the variable and often irreproducible epigenetic findings in schizophrenia (Tables 1 and 2). Taken together, epigenetic modifications not only may help to explain missing heritability in schizophrenia but also are a likely source of the disorder’s phenotypic heterogeneity (Figure 3).
      Figure thumbnail gr3
      Figure 3Hypothetical model of the epigenetic influence on phenotypic trait variability. (A) Using the bean machine (Galton Board) as a simplified metaphor for the specification of developmental trajectories, each developmental step is influenced by stochastic events occurring at distinct stages of development. With the pegs representing developmental specification nodes, developmental steps can bounce either left or right when hitting the pegs. The phenotypic traits associated with the developmental trajectories are spread according to a certain probability distribution. The current example shows a normal distribution of phenotypic traits, which would occur when running a large number of identical balls through a leveled device with unbiased pegs. (B) In this hypothetical model, environmentally and/or genetically driven epigenetic modifications targeting the pegs (i.e., the developmental specification nodes) can bias them toward one direction, which in turn changes the probability distribution of the eventual phenotypic traits. Note that the influence of epigenetic modifications on biasing the developmental trajectories would depend on its developmental timing and its specificity as well as on the nature of the developmental specification node it targets (not shown). (C) Pharmacological or nonpharmacological interventions targeting epigenetic modifications at accessible developmental specification nodes may reshape the probability distribution of phenotypic traits.

      Limitations and Future Directions

      Even though the evidence for a role of abnormal epigenetic processes in schizophrenia has rapidly accumulated over recent years (
      • Smigielski L.
      • Jagannath V.
      • Rössler W.
      • Walitza S.
      • Grünblatt E.
      Epigenetic mechanisms in schizophrenia and other psychotic disorders: A systematic review of empirical human findings.
      ), there is as yet no clear picture of the precise disease mechanisms involved. Indeed, different genome-wide studies have limited overlap in terms of their results, and these unbiased approaches could replicate only a small fraction of the initial findings that were obtained from targeted (hypothesis-driven) epigenetic studies. The lack of reproducibility is most likely accounted for by a number of factors, including small sample size and study population bias (
      • Nishioka M.
      • Bundo M.
      • Kasai K.
      • Iwamoto K.
      DNA methylation in schizophrenia: Progress and challenges of epigenetic studies.
      ), influence of chronic pharmacotherapy (
      • Swathy B.
      • Banerjee M.
      Understanding epigenetics of schizophrenia in the backdrop of its antipsychotic drug therapy.
      ), and other confounders such as smoking (
      • Marzi S.J.
      • Sugden K.
      • Arseneault L.
      • Belsky D.W.
      • Burrage J.
      • Corcoran D.L.
      • et al.
      Analysis of DNA methylation in young people: Limited evidence for an association between victimization stress and epigenetic variation in blood.
      ), methodological differences in epigenetic screening (
      • Dempster E.
      • Viana J.
      • Pidsley R.
      • Mill J.
      Epigenetic studies of schizophrenia: Progress, predicaments, and promises for the future.
      ), and heterogeneity of cell populations studied (
      • Jaffe A.E.
      • Irizarry R.A.
      Accounting for cellular heterogeneity is critical in epigenome-wide association studies.
      ). The latter has emerged as an important source of data variability at both the gene transcriptional and epigenetic levels (
      • Jaffe A.E.
      • Irizarry R.A.
      Accounting for cellular heterogeneity is critical in epigenome-wide association studies.
      ), which in turn can mask diagnostic differences or lead to spurious and irreproducible findings. Accounting for cell heterogeneity in epigenetic studies will require the implementation of single-cell technologies (
      • Kelsey G.
      • Stegle O.
      • Reik W.
      Single-cell epigenomics: Recording the past and predicting the future.
      ) and/or the use of statistical methods that compute the relative proportions of cell types from heterogeneous bulk tissues (
      • Houseman E.A.
      • Accomando W.P.
      • Koestler D.C.
      • Christensen B.C.
      • Marsit C.J.
      • Nelson H.H.
      • et al.
      DNA methylation arrays as surrogate measures of cell mixture distribution.
      ). The establishment of large databases and publicly available resources of multidimensional genomic and epigenetic data obtained from tissue-specific and cell type–specific samples, such as those provided by the PsychENCODE initiative (
      • Akbarian S.
      • Liu C.
      • Knowles J.A.
      • Vaccarino F.M.
      • Farnham P.J.
      • et al.
      PsychENCODE Consortium
      The PsychENCODE project.
      ), will critically help unravel the complex nature of genetic and epigenetic abnormalities in schizophrenia and other chronic brain disorders. Such initiatives also underline the importance of incorporating multiple and coexisting epigenetic anomalies in molecular disease models of schizophrenia and related disorders rather than relying on single genes such as GAD1 (Figure 3). Indeed, similar to the polygenic architecture of schizophrenia (
      • Owen M.J.
      • Sawa A.
      • Mortensen P.B.
      Schizophrenia.
      ,
      • Landek-Salgado M.A.
      • Faust T.E.
      • Sawa A.
      Molecular substrates of schizophrenia: Homeostatic signaling to connectivity.
      ,
      • Vassos E.
      • Di Forti M.
      • Coleman J.
      • Iyegbe C.
      • Prata D.
      • Euesden J.
      • et al.
      An examination of polygenic score risk prediction in individuals with first-episode psychosis.
      ,
      • Zhang J.P.
      • Robinson D.
      • Yu J.
      • Gallego J.
      • Fleischhacker W.W.
      • Kahn R.S.
      • et al.
      Schizophrenia polygenic risk score as a predictor of antipsychotic efficacy in first-episode psychosis.
      ,
      • Toulopoulou T.
      • Zhang X.
      • Cherny S.
      • Dickinson D.
      • Berman K.F.
      • Straub R.E.
      • et al.
      Polygenic risk score increases schizophrenia liability through cognition-relevant pathways.
      ), a multitude of genes are likely to be epigenetically dysregulated in this disorder and in response to environmental risk factors such as prenatal infection (
      • Richetto J.
      • Massart R.
      • Weber-Stadlbauer U.
      • Szyf M.
      • Riva M.A.
      • Meyer U.
      Genome-wide DNA methylation changes in a mouse model of infection-mediated neurodevelopmental disorders.
      ).
      Most of the available epigenetic findings in schizophrenia are based on analyses of postmortem brain samples, which imposes the additional challenge of retrieving a reliable patient history or antemortem diagnosis (
      • Hill C.
      • Keks N.
      • Roberts S.
      • Opeskin K.
      • Dean B.
      • MacKinnon A.
      • et al.
      Problem of diagnosis in postmortem brain studies of schizophrenia.
      ). The use of postmortem samples also precludes the identification of dynamic changes in epigenetic signatures that may occur in response to certain clinical manifestations (e.g., acute exacerbation of psychotic symptoms) or pharmacological treatments. Another limitation of postmortem analyses is that they are unlikely to provide a satisfactory answer to the question of whether epigenetic anomalies are the cause or consequence of the disease. Addressing this question in the context of schizophrenia warrants the use of longitudinal studies in which epigenetic signatures can be followed-up in the same subjects from premorbid and high-risk states to the eventual onset of full-blown psychosis. Such longitudinal investigations, however, will require the use of easily accessible tissues such as peripheral blood, saliva, and olfactory epithelium (
      • Lavoie J.
      • Sawa A.
      • Ishizuka K.
      Application of olfactory tissue and its neural progenitors to schizophrenia and psychiatric research.
      ). Even if epigenetic signatures in peripheral tissues might not necessarily capture disease-associated epigenetic changes occurring in the CNS (Tables 1 and 2), they can provide valuable information regarding the clinical course of schizophrenia, including conversion from a high-risk state to first-onset psychosis (
      • Kebir O.
      • Chaumette B.
      • Rivollier F.
      • Miozzo F.
      • Lemieux Perreault L.P.
      • Barhdadi A.
      • et al.
      Methylomic changes during conversion to psychosis.
      ). The complementary use of animal models will further aid the interpretation of epigenetic findings obtained from longitudinal studies in humans. Indeed, not only do animal models allow for a comparison of epigenetic signatures in peripheral and CNS tissues at various stages of development (
      • Richetto J.
      • Massart R.
      • Weber-Stadlbauer U.
      • Szyf M.
      • Riva M.A.
      • Meyer U.
      Genome-wide DNA methylation changes in a mouse model of infection-mediated neurodevelopmental disorders.
      ), but they also enable experimental testing of target sequences affected by chromatin alterations and their effects on brain development and functions (
      • Javidfar B.
      • Park R.
      • Kassim B.S.
      • Bicks L.K.
      • Akbarian S.
      The epigenomics of schizophrenia, in the mouse.
      ).

      Conclusions

      Despite the current limitations in the field, it is increasingly recognized that epigenetic modifications may play a critical role in the etiology and pathophysiology of schizophrenia. Recent findings suggest that certain schizophrenia risk loci can influence stochastic variation in gene expression through epigenetic processes, highlighting the intricate interaction between the genetic control and epigenetic control of developmental trajectories in schizophrenia. In addition, a substantial portion of epigenetic alterations in schizophrenia may be acquired through environmental factors and remain stable as molecular scars. Some of these scars may influence brain functions throughout the entire lifespan and may even be transmitted across generations via epigenetic germline inheritance (see Supplement). Moreover, epigenetic modifications are a plausible molecular source of phenotypic heterogeneity and offer a target for therapeutic interventions. The further elucidation of epigenetic modifications may thus increase our knowledge regarding schizophrenia’s heterogeneous etiology and pathophysiology and, in the long term, may advance personalized treatments through the use of biomarker-guided epigenetic interventions.

      Acknowledgments and Disclosures

      JR receives financial support from the Swiss National Science Foundation (Grant No. PZ00P3_18009 ) and the Brain & Behavior Research Foundation (NARSAD Young Investigator Grant No. 28662 ). UM receives financial support from the Swiss National Science Foundation (Grant No. 310030_188524 ) and the University of Zurich .
      Unrelated to the current article, UM has received financial support from Boehringer Ingelheim Pharma and Wren Therapeutics. JR reports no biomedical financial interests or potential conflicts of interest.

      Supplementary Material

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