Abstract
During the last two decades, diverse epigenetic modifications including DNA methylation, histone modifications, RNA editing and miRNA dysregulation have been associated with psychiatric disorders. A few years ago, in a review we outlined the most common epigenetic alterations in major psychiatric disorders (e.g., aberrant DNA methylation of DTNBP1, HTR2A, RELN, MB-COMT and PPP3CC, and increased expression of miR-34a and miR-181b). Recent follow-up studies have uncovered other DNA methylation aberrations affecting several genes in mental disorders, in addition to dysregulation of many miRNAs. Here, we provide an update on new epigenetic findings and highlight potential origin of the diversity and inconsistencies, focusing on drug effects, tissue/cell specificity of epigenetic landscape and discuss shortcomings of the current diagnostic criteria in mental disorders.
Papers of special note have been highlighted as: • of interest; •• of considerable interest
References
- 1. . An update on the epigenetics of psychotic disorders and autism. Epigenomics 7(3), 427–449 (2015).
- 2. . Microbiome, inflammation, epigenetic alterations, and mental disorders. Am. J. Med. Genet. B Neuropsychiatr. Genet. 174(6), 651–660 (2017).
- 3. Hypermethylation of the reelin (RELN) promoter in the brain of schizophrenic patients: a preliminary report. Am. J. Med. Genet. B Neuropsychiatr. Genet. 134B(1), 60–66 (2005).
- 4. Reelin promoter hypermethylation in schizophrenia. Proc. Natl Acad. Sci. USA 102(26), 9341–9346 (2005).
- 5. Methylome-wide association study of schizophrenia: identifying blood biomarker signatures of environmental insults. JAMA Psychiatry 71(3), 255–264 (2014). • Among the largest whole-genome DNA methylation profiling of blood cell using the technology of next-generation sequencing in schizophrenia (SCZ).
- 6. Reelin (RELN) DNA methylation in the peripheral blood of schizophrenia. J. Psychiatr. Res. 88, 28–37 (2017).
- 7. Quantitative DNA methylation analysis of DLGAP2 gene using pyrosequencing in schizophrenia with Tardive Dyskinesia: a linear mixed model approach. Sci. Rep. 8(1), 17466 (2018).
- 8. GAD1 alternative transcripts and DNA methylation in human prefrontal cortex and hippocampus in brain development, schizophrenia. Mol. Psychiatry 23(6), 1496–1505 (2018).
- 9. Hypomethylation of MB-COMT promoter is a major risk factor for schizophrenia and bipolar disorder. Hum. Mol. Genet. 15(21), 3132–3145 (2006).
- 10. DNA hypomethylation of MB-COMT promoter in the DNA derived from saliva in schizophrenia and bipolar disorder. J. Psychiatr. Res. 45(11), 1432–1438 (2011).
- 11. MB-COMT promoter DNA methylation is associated with working-memory processing in schizophrenia patients and healthy controls. Epigenetics 9(8), 1101–1107 (2014).
- 12. . DNA methylation of membrane-bound catechol-O-methyltransferase in Malaysian schizophrenia patients. Psychiatry Clin. Neurosci. 72(4), 266–279 (2018).
- 13. Aberrant transcriptomes and DNA methylomes define pathways that drive pathogenesis and loss of brain laterality/asymmetry in schizophrenia and bipolar disorder. Am. J. Med. Genet. B Neuropsychiatr. Genet. 180(2), 138–149 (2019).
- 14. Differential methylation of enhancer at IGF2 is associated with abnormal dopamine synthesis in major psychosis. Nat. Commun. 10(1), 2046 (2019). • An interesting epigenetic study showing DNA hypomethylation of IGF2 is linked to increase in dopamine synthesis in psychotic disorders.
- 15. DNA Methylation and Gene Expression of Matrix Metalloproteinase 9 Gene in Deficit and Non-deficit Schizophrenia. Front. Genet. 11(9), 646 (2018).
- 16. DNA methylation and gene expression of the chemokine (C-X-C motif) ligand 1 in patients with deficit and non-deficit schizophrenia. Psychiatry Res. 268, 82–86 (2018).
- 17. Reduced DNA methylation of the oxytocin receptor gene is associated with anhedonia-asociality in women with recent-onset schizophrenia and ultra-high risk for psychosis. Schizophr. Bull. 45(6), 1279–1290 (2019).
- 18. GRIN2B promoter methylation deficits in early-onset schizophrenia and its association with cognitive function. Epigenomics 11(4), 401–410 (2019).
- 19. Decreased DNA methylation in the Shati/Nat8l promoter in both patients with schizophrenia and a methamphetamine-induced murine model of schizophrenia-like phenotype. PLoS ONE 11(6), e0157959 (2016).
- 20. . Epigenetic profiling of human brain differential DNA methylation networks in schizophrenia. BMC Med. Genomics. 9(Suppl. 3), 68 (2016).
- 21. Differentially methylated regions in bipolar disorder and suicide. Am. J Med. Genet. B Neuropsychiatr. Genet. 180(7), 496–507 (2019).
- 22. Hypomethylation of LINE-1 elements in schizophrenia and bipolar disorder. J. Psychiatr. Res. 107, 68–72 (2018).
- 23. Altered DNA methylation of the AluY subfamily in schizophrenia and bipolar disorder. Epigenomics 11(6), 581–586 (2019).
- 24. DNA methylation analyses of the candidate genes identified by a methylome-wide association study revealed common epigenetic alterations in schizophrenia and bipolar disorder. Psychiatry Clin. Neurosci. 72(4), 245–254 (2018).
- 25. An integrated genetic-epigenetic analysis of schizophrenia: evidence for co-localization of genetic associations and differential DNA methylation. Genome Biol. 17(1), 176 (2016). •• One of the largest genome-wide DNA methylation analysis of three cohorts suggesting polygenic nature of DNA methylation alterations in SCZ and bipolar disorder.
- 26. Functional DNA methylation signatures for autism spectrum disorder genomic risk loci: 16p11.2 deletions and CHD8 variants. Clin. Epigenetics. 11(1), 103 (2019).
- 27. Differential SLC1A2 promoter methylation in bipolar disorder with or without addiction. Front. Cell Neurosci. 11, 217 (2017).
- 28. Association of human serotonin receptor 4 promoter methylation with autism spectrum disorder. Medicine (Baltimore) 99(4), e18838 (2020).
- 29. DNA Methylation of the Oxytocin Receptor Across Neurodevelopmental Disorders. J. Autism Dev. Disord.
Doi: 10.1007/s10803-020-04792-x (2021) (Epub ahead of print). - 30. Placental DNA methylation levels at CYP2E1 and IRS2 are associated with child outcome in a prospective autism study. Hum. Mol. Genet. 28(16), 2659–2674 (2019).
- 31. Correspondence of DNA methylation between blood and brain tissue and its application to schizophrenia research. Schizophr. Bull. 42(2), 406–414 (2016).
- 32. Mood stabilizers and the influence on global leukocyte DNA methylation in bipolar disorder. Mol. Neuropsychiatry. 1(2), 76–81 (2015).
- 33. A DNA methylation signature discriminates between excellent and non-response to lithium in patients with bipolar disorder type 1. Sci. Rep. 10(1), 12239 (2020).
- 34. DNA methylation and expression of KCNQ3 in bipolar disorder. Bipolar Disord. 17(2), 150–159 (2015).
- 35. . Study on the epigenetic methylation modification of bipolar disorder major genes. Eur. Rev. Med. Pharmacol. Sci. 22(5), 1421–1425 (2018).
- 36. . Association of DNA methylation with acute mania and inflammatory markers. PLoS ONE 10(7), e0132001 (2015).
- 37. . Antipsychotic drugs attenuate aberrant DNA methylation of DTNBP1 (dysbindin) promoter in saliva and post-mortem brain of patients with schizophrenia and bipolar disorder. Am. J Med. Genet. B Neuropsychiatr. Genet. 168, 687–696 (2015).
- 38. DNA hypermethylation of serotonin transporter gene promoter in drug naïve patients with schizophrenia. Schizophr. Res. 152(2–3), 373–380 (2014).
- 39. Promoter activity-based case-control association study on SLC6A4 highlighting hypermethylation and altered amygdala volume in male patients with schizophrenia. Schizophr. Bull. 46(6), 1577–1586 (2020).
- 40. Effect of clozapine on DNA methylation in peripheral leukocytes from patients with treatment-resistant schizophrenia. Int. J. Mol. Sci. 18(3), 632 (2017).
- 41. First-episode schizophrenia is associated with a reduction of HERV-K methylation in peripheral blood. Psychiatry Res. 271, 459–463 (2019).
- 42. . The inherited methylome landscape is directly altered with paternal aging and associated with offspring neurodevelopmental disorders. Aging Cell 19(8), e13178 (2020).
- 43. Accelerated epigenetic aging and mitochondrial DNA copy number in bipolar disorder. Transl. Psychiatry. 7(12), 1283 (2017).
- 44. Temporal dynamics of miRNAs in human DLPFC and its association with miRNA dysregulation in schizophrenia. Transl. Psychiatry 9(1), 196 (2019).
- 45. . Schizophrenia-associated MicroRNA–gene interactions in the dorsolateral prefrontal cortex. Genomics Proteomics Bioinformatics 17(6), 623–634 (2019).
- 46. Exosomal secretion of a psychosis-altered miRNA that regulates glutamate receptor expression is affected by antipsychotics. Neuropsychopharmacology 45(4), 656–665 (2020).
- 47. Altered expression of microRNA-223 in the plasma of patients with first-episode schizophrenia and its possible relation to neuronal migration-related genes. Transl. Psychiatry 9(1), 289 (2019).
- 48. Screening of schizophrenia associated miRNAs and the regulation of miR-320a-3p on integrin β1. Medicine (Baltimore) 98(8), e14332 (2019).
- 49. Detection of circulating miRNA levels in schizophrenia. Am. J. Psychiatry 172(11), 1141–1147 (2015). • One of relatively large studies proposing plasma biomarker for SCZ diagnosis.
- 50. Identification of serum microRNAs as diagnostic biomarkers for schizophrenia. Hereditas 156, 23 (2019).
- 51. Genome-wide, integrative analysis implicates exosome-derived MicroRNA dysregulation in schizophrenia. Schizophr. Bull. 45(6), 1257–1266 (2019).
- 52. Schizophrenia risk variants affecting microRNA function and site-specific regulation of NT5C2 by miR-206. Eur. Neuropsychopharmacol. 26(9), 1522–1526 (2016).
- 53. Diagnostic value of blood-derived microRNAs for schizophrenia: results of a meta-analysis and validation. Sci. Rep. 7(1), 15328 (2017). • A meta-analysis of six studies introducing blood mononuclear miRNAs with high sensitivity and specificity for SCZ diagnosis.
- 54. Identification of miR-22-3p, miR-92a-3p, and miR-137 in peripheral blood as biomarker for schizophrenia. Psychiatry Res. 265, 70–76 (2018).
- 55. Rs1625579 polymorphism in the MIR137 gene is associated with the risk of schizophrenia: updated meta-analysis. Neurosci. Lett. 713, 134535 (2019).
- 56. MIR137 schizophrenia-associated locus controls synaptic function by regulating synaptogenesis, synapse maturation and synaptic transmission. Hum. Mol. Genet. 27(11), 1879–1891 (2018).
- 57. Inhibition of the schizophrenia-associated MicroRNA miR-137 disrupts Nrg1α neurodevelopmental signal transduction. Cell Rep. 20(1), 1–12 (2017).
- 58. . A direct regulatory link between microRNA-137 and SHANK2: implications for neuropsychiatric disorders. J. Neurodev. Disord. 10(1), 15 (2018).
- 59. Alteration of miRNA-mRNA interactions in lymphocytes of individuals with schizophrenia. J. Psychiatr. Res. 112, 89–98 (2019).
- 60. Identification of a miRNAs signature associated with exposure to stress early in life and enhanced vulnerability for schizophrenia: new insights for the key role of miR-125b-1-3p in neurodevelopmental processes. Schizophr. Res. 205, 63–75 (2019).
- 61. . Evaluation of miRNA expression profiles in schizophrenia using principal-component analysis-based unsupervised feature extraction method. J. Comput. Biol. 27(8), 1253–1263 (2020).
- 62. miR-149 and miR-29c as candidates for bipolar disorder biomarkers. Am. J. Med. Genet. B Neuropsychiatr. Genet. 174(3), 315–323 (2017).
- 63. Differential expression of exosomal microRNAs in prefrontal cortices of schizophrenia and bipolar disorder patients. PLoS ONE 8(1), e48814 (2013).
- 64. Preliminary investigation of miRNA expression in individuals at high familial risk of bipolar disorder. J. Psychiatr. Res. 62, 48–55 (2015).
- 65. MicroRNA dysregulation in manic and euthymic patients with bipolar disorder. J. Affect. Disord. 15(261), 84–90 (2020).
- 66. A miRNome analysis of drug-free manic psychotic bipolar patients versus healthy controls. Eur. Arch. Psychiatry Clin. Neurosci. 270(7), 893–900 (2020).
- 67. Transcriptome changes in relation to manic episode. Front. Psychiatry. 10, 280 (2019).
- 68. Dysregulation of miR-499, miR-708 and miR-1908 during a depression episode in bipolar disorders. Neurosci. Lett. 27(654), 117–119 (2017).
- 69. Genome-wide analysis implicates microRNAs and their target genes in the development of bipolar disorder. Transl. Psychiatry 5(11), e678 (2015).
- 70. . Circulating exosomal microRNAs in bipolar disorder. J. Affect. Disord. 262, 99–107 (2020).
- 71. Whole genome expression analyses of miRNAs and mRNAs suggest the involvement of miR-320a and miR-155-3p and their targeted genes in lithium response in bipolar disorder. Int. J Mol. Sci. 20(23), 6040 (2019).
- 72. Comparison of plasma MicroRNA levels in drug naive, first episode depressed patients and healthy controls. J. Psychiatr. Res. 69, 67–71 (2015).
- 73. Circulating microRNA 134 sheds light on the diagnosis of major depressive disorder. Transl. Psychiatry. 10(1), 95 (2020).
- 74. Serum miRNA as a possible biomarker in the diagnosis of bipolar II disorder. Sci. Rep. 10(1), 1131 (2020).
- 75. . Serum microRNAs in ASD: association with monocyte cytokine profiles and mitochondrial respiration. Front. Psychiatry 10(10), 614 (2019).
- 76. Saliva MicroRNA differentiates children with autism from peers with typical and atypical development. J. Am. Acad. Child Adolesc. Psychiatry 59(2), 296–308 (2020).
- 77. . Serum miRNA expression profiling reveals miR-486-3p may play a significant role in the development of autism by targeting ARID1B. Neuroreport 29(17), 1431–1436 (2018).
- 78. . Increased expression of miR-155p5 in amygdala of children with autism spectrum disorder. Autism Res. 13(1), 18–23 (2020).
- 79. . MicroRNA profiling in adults with high-functioning autism spectrum disorder. Mol. Brain. 12(1), 82 (2019).
- 80. Disruption of melatonin synthesis is associated with impaired 14-3-3 and miR-451 levels in patients with autism spectrum disorders. Sci. Rep. 7(1), 2096 (2017).
- 81. Genome-wide DNA methylation analysis reveals epigenetic pattern of SH2B1 in Chinese monozygotic twins discordant for autism spectrum disorder. Front. Neurosci. 13, 712 (2019).
- 82. Cord blood DNA methylome in newborns later diagnosed with autism spectrum disorder reflects early dysregulation of neurodevelopmental and X-linked genes. Genome Med. 12(1), 88 (2020).
- 83. Genome-wide DNA methylation profiling identifies convergent molecular signatures associated with idiopathic and syndromic autism in post-mortem human brain tissue. Hum. Mol. Genet. 28(13), 2201–2211 (2019).
- 84. Elevated polygenic burden for autism is associated with differential DNA methylation at birth. Genome Med. 10, 19 (2018). • A large-scale genome-wide DNA methylation analysis of blood samples indicating polygenic nature of DNA methylation alterations in autism.
- 85. Case–control meta-analysis of blood DNA methylation and autism spectrum disorder. Mol. Autism. 28(9), 40 (2018).
- 86. . Genome-wide, integrative analysis implicates microRNA dysregulation in autism spectrum disorder. Nat. Neurosci. 19(11), 1463–1476 (2016).
- 87. . Knowledge-guided bioinformatics model for identifying autism spectrum disorder diagnostic MicroRNA biomarkers. Sci. Rep. 6, 39663 (2016).
- 88. Cell type-specific epigenetic links to schizophrenia risk in the brain. Genome Biol. 20(1), 135 (2019).
- 89. Proximal recolonization by self-renewing microglia re-establishes microglial homeostasis in the adult mouse brain. PLoS Biol. 17(2), e3000134 (2019).
- 90. Cell type-specific epigenetic links to schizophrenia risk in the brain. Genome Biol. 20(1), 135 (2019).
- 91. . Multiplexed imaging of high-density libraries of RNAs with MERFISH and expansion microscopy. Sci. Rep. 8(1), 4847 (2018).
- 92. Multiplex digital spatial profiling of proteins and RNA in fixed tissue. Nat. Biotechnol. 38(5), 586–599 (2020).
- 93. Genome-wide significant associations in schizophrenia to ITIH3/4, CACNA1C and SDCCAG8, and extensive replication of associations reported by the Schizophrenia PGC. Mol. Psychiatry 18(6), 708–712 (2013).
- 94. Genome-wide association study identifies 30 loci associated with bipolar disorder. Nat. Genet. 51(5), 793–803 (2019).
- 95. . Human gut colonisation may be initiated in utero by distinct microbial communities in the placenta and amniotic fluid. Sci. Rep. 6, 23129 (2016).