Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Expert Review
  • Published:

Molecular windows into the human brain for psychiatric disorders

Abstract

Delineating the pathophysiology of psychiatric disorders has been extremely challenging but technological advances in recent decades have facilitated a deeper interrogation of molecular processes in the human brain. Initial candidate gene expression studies of the postmortem brain have evolved into genome wide profiling of the transcriptome and the epigenome, a critical regulator of gene expression. Here, we review the potential and challenges of direct molecular characterization of the postmortem human brain, and provide a brief overview of recent transcriptional and epigenetic studies with respect to neuropsychiatric disorders. Such information can now be leveraged and integrated with the growing number of genome-wide association databases to provide a functional context of trait-associated genetic variants linked to psychiatric illnesses and related phenotypes. While it is clear that the field is still developing and challenges remain to be surmounted, these recent advances nevertheless hold tremendous promise for delineating the neurobiological underpinnings of mental diseases and accelerating the development of novel medication strategies.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Global Burden of Disease Study C. Global, regional, and national incidence, prevalence, and years lived with disability for 301 acute and chronic diseases and injuries in 188 countries, 1990–2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet. 2015;386:743–800.

    Google Scholar 

  2. Vigo D, Thornicroft G, Atun R. Estimating the true global burden of mental illness. Lancet Psychiatry. 2016;3:171–8.

    PubMed  Google Scholar 

  3. Caceres M, Lachuer J, Zapala MA, Redmond JC, Kudo L, Geschwind DH, et al. Elevated gene expression levels distinguish human from non-human primate brains. Proc Natl Acad Sci USA. 2003;100:13030–5.

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Enard W, Khaitovich P, Klose J, Zollner S, Heissig F, Giavalisco P, et al. Intra- and interspecific variation in primate gene expression patterns. Science. 2002;296:340–3.

    CAS  PubMed  Google Scholar 

  5. Khaitovich P, Muetzel B, She X, Lachmann M, Hellmann I, Dietzsch J, et al. Regional patterns of gene expression in human and chimpanzee brains. Genome Res. 2004;14:1462–73.

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Konopka G, Bomar JM, Winden K, Coppola G, Jonsson ZO, Gao F, et al. Human-specific transcriptional regulation of CNS development genes by FOXP2. Nature. 2009;462:213–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Konopka G, Friedrich T, Davis-Turak J, Winden K, Oldham MC, Gao F, et al. Human-specific transcriptional networks in the brain. Neuron. 2012;75:601–17.

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Oldham MC, Konopka G, Iwamoto K, Langfelder P, Kato T, Horvath S, et al. Functional organization of the transcriptome in human brain. Nat Neurosci. 2008;11:1271–82.

    CAS  PubMed  PubMed Central  Google Scholar 

  9. He Z, Han D, Efimova O, Guijarro P, Yu Q, Oleksiak A, et al. Comprehensive transcriptome analysis of neocortical layers in humans, chimpanzees and macaques. Nat Neurosci. 2017;20:886–95.

    CAS  PubMed  Google Scholar 

  10. Rockman MV, Hahn MW, Soranzo N, Zimprich F, Goldstein DB, Wray GA. Ancient and recent positive selection transformed opioid cis-regulation in humans. PLoS Biol. 2005;3:e387.

    PubMed  PubMed Central  Google Scholar 

  11. Hurd YL, Herman MM, Hyde TM, Bigelow LB, Weinberger DR, Kleinman JE. Prodynorphin mRNA expression is increased in the patch versus matrix compartment of the caudate nucleus in suicide subjects. Mol Psychiatry. 1997;2:495–500.

    CAS  PubMed  Google Scholar 

  12. Hurd YL. Differential messenger RNA expression of prodynorphin and proenkephalin in the human brain. Neuroscience. 1996;72:767–83.

    CAS  PubMed  Google Scholar 

  13. Mansour A, Fox CA, Akil H, Watson SJ. Opioid-receptor mRNA expression in the rat CNS: anatomical and functional implications. Trends Neurosci. 1995;18:22–29.

    CAS  PubMed  Google Scholar 

  14. Peckys D, Landwehrmeyer GB. Expression of mu, kappa, and delta opioid receptor messenger RNA in the human CNS: a 33P in situ hybridization study. Neuroscience. 1999;88:1093–135.

    CAS  PubMed  Google Scholar 

  15. Di Chiara G, Imperato A. Drugs abused by humans preferentially increase synaptic dopamine concentrations in the mesolimbic system of freely moving rats. Proc Natl Acad Sci USA. 1988;85:5274–8.

    PubMed  PubMed Central  Google Scholar 

  16. Luscher C, Malenka RC. Drug-evoked synaptic plasticity in addiction: from molecular changes to circuit remodeling. Neuron. 2011;69:650–63.

    PubMed  PubMed Central  Google Scholar 

  17. Nestler EJ. Is there a common molecular pathway for addiction? Nat Neurosci. 2005;8:1445–9.

    CAS  PubMed  Google Scholar 

  18. D’Souza MS. Glutamatergic transmission in drug reward: implications for drug addiction. Front Neurosci. 2015;9:404.

    PubMed  PubMed Central  Google Scholar 

  19. Egervari G, Landry J, Callens J, Fullard JF, Roussos P, Keller E, et al. Striatal H3K27 acetylation linked to glutamatergic gene dysregulation in human heroin abusers holds promise as therapeutic target. Biol Psychiatry. 2017;81:585–94.

    CAS  PubMed  Google Scholar 

  20. Gipson CD, Kupchik YM, Shen H, Reissner KJ, Thomas CA, Kalivas PW. Relapse induced by cues predicting cocaine depends on rapid, transient synaptic potentiation. Neuron. 2013;77:867–72.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. LaLumiere RT, Kalivas PW. Glutamate release in the nucleus accumbens core is necessary for heroin seeking. J Neurosci. 2008;28:3170–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Lou ZZ, Chen LH, Liu HF, Ruan LM, Zhou WH. Blockade of mGluR5 in the nucleus accumbens shell but not core attenuates heroin seeking behavior in rats. Acta Pharmacol Sin. 2014;35:1485–92.

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Scofield MD, Heinsbroek JA, Gipson CD, Kupchik YM, Spencer S, Smith AC, et al. The nucleus accumbens: mechanisms of addiction across drug classes reflect the importance of glutamate homeostasis. Pharmacol Rev. 2016;68:816–71.

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Shen H, Moussawi K, Zhou W, Toda S, Kalivas PW. Heroin relapse requires long-term potentiation-like plasticity mediated by NMDA2b-containing receptors. Proc Natl Acad Sci USA. 2011;108:19407–12.

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Shen HW, Scofield MD, Boger H, Hensley M, Kalivas PW. Synaptic glutamate spillover due to impaired glutamate uptake mediates heroin relapse. J Neurosci. 2014;34:5649–57.

    PubMed  PubMed Central  Google Scholar 

  26. Smith AC, Kupchik YM, Scofield MD, Gipson CD, Wiggins A, Thomas CA, et al. Synaptic plasticity mediating cocaine relapse requires matrix metalloproteinases. Nat Neurosci. 2014;17:1655–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Gao J, Wang WY, Mao YW, Graff J, Guan JS, Pan L, et al. A novel pathway regulates memory and plasticity via SIRT1 and miR-134. Nature. 2010;466:1105–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Malinow R, Malenka RC. AMPA receptor trafficking and synaptic plasticity. Annu Rev Neurosci. 2002;25:103–26.

    CAS  PubMed  Google Scholar 

  29. Russo SJ, Dietz DM, Dumitriu D, Morrison JH, Malenka RC, Nestler EJ. The addicted synapse: mechanisms of synaptic and structural plasticity in nucleus accumbens. Trends Neurosci. 2010;33:267–76.

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Zhang Y, Venkitaramani DV, Gladding CM, Zhang Y, Kurup P, Molnar E, et al. The tyrosine phosphatase STEP mediates AMPA receptor endocytosis after metabotropic glutamate receptor stimulation. J Neurosci. 2008;28:10561–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Bowers MS, McFarland K, Lake RW, Peterson YK, Lapish CC, Gregory ML, et al. Activator of G protein signaling 3: a gatekeeper of cocaine sensitization and drug seeking. Neuron. 2004;42:269–81.

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Chen L, Huang LY. Sustained potentiation of NMDA receptor-mediated glutamate responses through activation of protein kinase C by a mu opioid. Neuron. 1991;7:319–26.

    PubMed  Google Scholar 

  33. Martin G, Nie Z, Siggins GR. mu-Opioid receptors modulate NMDA receptor-mediated responses in nucleus accumbens neurons. J Neurosci. 1997;17:11–22.

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Xi ZX, Stein EA. Blockade of ionotropic glutamatergic transmission in the ventral tegmental area reduces heroin reinforcement in rat. Psychopharmacology. 2002;164:144–50.

    CAS  PubMed  Google Scholar 

  35. Robison AJ, Nestler EJ. Transcriptional and epigenetic mechanisms of addiction. Nat Rev Neurosci. 2011;12:623–37.

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Wolf ME. The Bermuda triangle of cocaine-induced neuroadaptations. Trends Neurosci. 2010;33:391–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Bach H, Arango V, Kassir SA, Tsaava T, Dwork AJ, Mann JJ, et al. Alcoholics have more tryptophan hydroxylase 2 mRNA and protein in the dorsal and median raphe nuclei. Alcohol Clin Exp Res. 2014;38:1894–901.

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Bannon MJ, Pruetz B, Manning-Bog AB, Whitty CJ, Michelhaugh SK, Sacchetti P, et al. Decreased expression of the transcription factor NURR1 in dopamine neurons of cocaine abusers. Proc Natl Acad Sci USA. 2002;99:6382–5.

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Bannon MJ, Savonen CL, Hartley ZJ, Johnson MM, Schmidt CJ. Investigating the potential influence of cause of death and cocaine levels on the differential expression of genes associated with cocaine abuse. PLoS ONE. 2015;10:e0117580.

    PubMed  PubMed Central  Google Scholar 

  40. Covington HE 3rd, Maze I, Sun H, Bomze HM, DeMaio KD, Wu EY, et al. A role for repressive histone methylation in cocaine-induced vulnerability to stress. Neuron. 2011;71:656–70.

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Damez-Werno DM, Sun H, Scobie KN, Shao N, Rabkin J, Dias C, et al. Histone arginine methylation in cocaine action in the nucleus accumbens. Proc Natl Acad Sci USA. 2016;113:9623–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Engmann O, Labonte B, Mitchell A, Bashtrykov P, Calipari ES, Rosenbluh C, et al. Cocaine-induced chromatin modifications associate with increased expression and three-dimensional looping of Auts2. Biol Psychiatry. 2017;82:794–805.

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Egervari G, Jutras-Aswad D, Landry J, Miller ML, Anderson SA, Michaelides M, et al. A functional 3’UTR polymorphism (rs2235749) of prodynorphin alters microRNA-365 binding in ventral striatonigral neurons to influence novelty seeking and positive reward traits. Neuropsychopharmacology. 2016;41:2512–20.

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Maze I, Shen L, Zhang B, Garcia BA, Shao N, Mitchell A, et al. Analytical tools and current challenges in the modern era of neuroepigenomics. Nat Neurosci. 2014;17:1476–90.

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Drakenberg K, Nikoshkov A, Horvath MC, Fagergren P, Gharibyan A, Saarelainen K, et al. Mu opioid receptor A118G polymorphism in association with striatal opioid neuropeptide gene expression in heroin abusers. Proc Natl Acad Sci USA. 2006;103:7883–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Nikoshkov A, Drakenberg K, Wang X, Horvath MC, Keller E, Hurd YL. Opioid neuropeptide genotypes in relation to heroin abuse: dopamine tone contributes to reversed mesolimbic proenkephalin expression. Proc Natl Acad Sci USA. 2008;105:786–91.

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Nikoshkov A, Hurd YL, Yakovleva T, Bazov I, Marinova Z, Cebers G, et al. Prodynorphin transcripts and proteins differentially expressed and regulated in the adult human brain. FASEB J. 2005;19:1543–5.

    CAS  PubMed  Google Scholar 

  48. Horvath MC, Hurd YL, Rajs J, Keller E. Variations in respiratory distress characterize the acute agonal period during heroin overdose death: relevance to postmortem mRNA studies. Brain Res Bull. 2006;70:251–9.

    CAS  PubMed  Google Scholar 

  49. Koo JW, Mazei-Robison MS, LaPlant Q, Egervari G, Braunscheidel KM, Adank DN, et al. Epigenetic basis of opiate suppression of Bdnf gene expression in the ventral tegmental area. Nat Neurosci. 2015;18:415–22.

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Anderson SA, Michaelides M, Zarnegar P, Ren Y, Fagergren P, Thanos PK, et al. Impaired periamygdaloid-cortex prodynorphin is characteristic of opiate addiction and depression. J Clin Invest. 2013;123:5334–41.

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Okvist A, Fagergren P, Whittard J, Garcia-Osta A, Drakenberg K, Horvath MC, et al. Dysregulated postsynaptic density and endocytic zone in the amygdala of human heroin and cocaine abusers. Biol Psychiatry. 2011;69:245–52.

    PubMed  Google Scholar 

  52. Feng J, Shao N, Szulwach KE, Vialou V, Huynh J, Zhong C, et al. Role of Tet1 and 5-hydroxymethylcytosine in cocaine action. Nat Neurosci. 2015;18:536–44.

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Hemby SE, Tang W, Muly EC, Kuhar MJ, Howell L, Mash DC. Cocaine-induced alterations in nucleus accumbens ionotropic glutamate receptor subunits in human and non-human primates. J Neurochem. 2005;95:1785–93.

    CAS  PubMed  Google Scholar 

  54. Johnson MM, David JA, Michelhaugh SK, Schmidt CJ, Bannon MJ. Increased heat shock protein 70 gene expression in the brains of cocaine-related fatalities may be reflective of postdrug survival and intervention rather than excited delirium. J Forensic Sci. 2012;57:1519–23.

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Kristiansen LV, Bannon MJ, Meador-Woodruff JH. Expression of transcripts for myelin related genes in postmortem brain from cocaine abusers. Neurochem Res. 2009;34:46–54.

    CAS  PubMed  Google Scholar 

  56. Mash DC, Ouyang Q, Pablo J, Basile M, Izenwasser S, Lieberman A, et al. Cocaine abusers have an overexpression of alpha-synuclein in dopamine neurons. J Neurosci. 2003;23:2564–71.

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Moyer RA, Wang D, Papp AC, Smith RM, Duque L, Mash DC, et al. Intronic polymorphisms affecting alternative splicing of human dopamine D2 receptor are associated with cocaine abuse. Neuropsychopharmacology. 2011;36:753–62.

    CAS  PubMed  Google Scholar 

  58. Robison AJ, Vialou V, Mazei-Robison M, Feng J, Kourrich S, Collins M, et al. Behavioral and structural responses to chronic cocaine require a feedforward loop involving DeltaFosB and calcium/calmodulin-dependent protein kinase II in the nucleus accumbens shell. J Neurosci. 2013;33:4295–307.

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Sun H, Damez-Werno DM, Scobie KN, Shao NY, Dias C, Rabkin J, et al. Regulation of BAZ1A and nucleosome positioning in the nucleus accumbens in response to cocaine. Neuroscience. 2017;353:1–6.

    CAS  PubMed  Google Scholar 

  60. Lehrmann E, Colantuoni C, Deep-Soboslay A, Becker KG, Lowe R, Huestis MA, et al. Transcriptional changes common to human cocaine, cannabis and phencyclidine abuse. PLoS ONE. 2006;1:e114.

    PubMed  PubMed Central  Google Scholar 

  61. Mash DC, ffrench-Mullen J, Adi N, Qin Y, Buck A, Pablo J. Gene expression in human hippocampus from cocaine abusers identifies genes which regulate extracellular matrix remodeling. PLoS ONE. 2007;2:e1187.

    PubMed  PubMed Central  Google Scholar 

  62. Zhou Z, Yuan Q, Mash DC, Goldman D. Substance-specific and shared transcription and epigenetic changes in the human hippocampus chronically exposed to cocaine and alcohol. Proc Natl Acad Sci USA. 2011;108:6626–31.

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Sillivan SE, Whittard JD, Jacobs MM, Ren Y, Mazloom AR, Caputi FF, et al. ELK1 transcription factor linked to dysregulated striatal mu opioid receptor signaling network and OPRM1 polymorphism in human heroin abusers. Biol Psychiatry. 2013;74:511–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Albertson DN, Pruetz B, Schmidt CJ, Kuhn DM, Kapatos G, Bannon MJ. Gene expression profile of the nucleus accumbens of human cocaine abusers: evidence for dysregulation of myelin. J Neurochem. 2004;88:1211–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Allen M, Zou F, Chai HS, Younkin CS, Crook J, Pankratz VS, et al. Novel late-onset Alzheimer disease loci variants associate with brain gene expression. Neurology. 2012;79:221–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Bannon MJ, Johnson MM, Michelhaugh SK, Hartley ZJ, Halter SD, David JA, et al. A molecular profile of cocaine abuse includes the differential expression of genes that regulate transcription, chromatin, and dopamine cell phenotype. Neuropsychopharmacology. 2014;39:2191–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Enoch MA, Zhou Z, Kimura M, Mash DC, Yuan Q, Goldman D. GABAergic gene expression in postmortem hippocampus from alcoholics and cocaine addicts; corresponding findings in alcohol-naive P and NP rats. PLoS ONE. 2012;7:e29369.

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Albertson DN, Schmidt CJ, Kapatos G, Bannon MJ. Distinctive profiles of gene expression in the human nucleus accumbens associated with cocaine and heroin abuse. Neuropsychopharmacology. 2006;31:2304–12.

    CAS  PubMed  Google Scholar 

  69. Hurd YL, Herkenham M. Molecular alterations in the neostriatum of human cocaine addicts. Synapse. 1993;13:357–69.

    CAS  PubMed  Google Scholar 

  70. McClintick JN, Xuei X, Tischfield JA, Goate A, Foroud T, Wetherill L, et al. Stress-response pathways are altered in the hippocampus of chronic alcoholics. Alcohol. 2013;47:505–15.

    CAS  PubMed  Google Scholar 

  71. Mamdani M, Williamson V, McMichael GO, Blevins T, Aliev F, Adkins A, et al. Integrating mRNA and miRNA weighted gene co-expression networks with eQTLs in the nucleus accumbens of subjects with alcohol dependence. PLoS ONE. 2015;10:e0137671.

    PubMed  PubMed Central  Google Scholar 

  72. Kryger R, Wilce PA. The effects of alcoholism on the human basolateral amygdala. Neuroscience. 2010;167:361–71.

    CAS  PubMed  Google Scholar 

  73. Farris SP, Arasappan D, Hunicke-Smith S, Harris RA, Mayfield RD. Transcriptome organization for chronic alcohol abuse in human brain. Mol Psychiatry. 2015;20:1438–47.

    CAS  PubMed  Google Scholar 

  74. Gandal MJ, Haney JR, Parikshak NN, Leppa V, Ramaswami G, Hartl C, et al. Shared molecular neuropathology across major psychiatric disorders parallels polygenic overlap. Science. 2018;359:693–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Guan J, Li G. Injury mortality in individuals with autism. Am J Public Health. 2017;107:791–3.

    PubMed  PubMed Central  Google Scholar 

  76. Liu X, Han D, Somel M, Jiang X, Hu H, Guijarro P, et al. Disruption of an evolutionarily novel synaptic expression pattern in autism. PLoS Biol. 2016;14:e1002558.

    PubMed  PubMed Central  Google Scholar 

  77. Ch’ng C, Kwok W, Rogic S, Pavlidis P. Meta-analysis of gene expression in autism spectrum disorder. Autism Res. 2015;8:593–608.

    PubMed  PubMed Central  Google Scholar 

  78. Egervari G, Ciccocioppo R, Jentsch JD, Hurd YL. Shaping vulnerability to addiction—the contribution of behavior, neural circuits and molecular mechanisms. Neurosci Biobehav Rev. 2017;85:117–25.

    PubMed  PubMed Central  Google Scholar 

  79. Voineagu I, Wang X, Johnston P, Lowe JK, Tian Y, Horvath S, et al. Transcriptomic analysis of autistic brain reveals convergent molecular pathology. Nature. 2011;474:380–4.

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Pantazatos SP, Huang YY, Rosoklija GB, Dwork AJ, Arango V, Mann JJ. Whole-transcriptome brain expression and exon-usage profiling in major depression and suicide: evidence for altered glial, endothelial and ATPase activity. Mol Psychiatry. 2017;22:760–73.

    CAS  PubMed  Google Scholar 

  81. Akula N, Barb J, Jiang X, Wendland JR, Choi KH, Sen SK, et al. RNA-sequencing of the brain transcriptome implicates dysregulation of neuroplasticity, circadian rhythms and GTPase binding in bipolar disorder. Mol Psychiatry. 2014;19:1179–85.

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Labonte B, Engmann O, Purushothaman I, Menard C, Wang J, Tan C, et al. Sex-specific transcriptional signatures in human depression. Nat Med. 2017;23:1102–11.

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Qin W, Liu C, Sodhi M, Lu H. Meta-analysis of sex differences in gene expression in schizophrenia. BMC Syst Biol. 2016;10:9.

    PubMed  PubMed Central  Google Scholar 

  84. Mistry M, Gillis J, Pavlidis P. Meta-analysis of gene coexpression networks in the post-mortem prefrontal cortex of patients with schizophrenia and unaffected controls. BMC Neurosci. 2013;14:105.

    PubMed  PubMed Central  Google Scholar 

  85. Fromer M, Roussos P, Sieberts SK, Johnson JS, Kavanagh DH, Perumal TM, et al. Gene expression elucidates functional impact of polygenic risk for schizophrenia. Nat Neurosci. 2016;19:1442–53.

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Hertzberg L, Katsel P, Roussos P, Haroutunian V, Domany E. Integration of gene expression and GWAS results supports involvement of calcium signaling in Schizophrenia. Schizophr Res. 2015;164:92–99.

    CAS  PubMed  Google Scholar 

  87. Roussos P, Katsel P, Davis KL, Siever LJ, Haroutunian V. A system-level transcriptomic analysis of schizophrenia using postmortem brain tissue samples. Arch Gen Psychiatry. 2012;69:1205–13.

    PubMed  Google Scholar 

  88. Haroutunian V, Katsel P, Dracheva S, Stewart DG, Davis KL. Variations in oligodendrocyte-related gene expression across multiple cortical regions: implications for the pathophysiology of schizophrenia. Int J Neuropsychopharmacol. 2007;10:565–73.

    CAS  PubMed  Google Scholar 

  89. Winkler JM, Fox HS. Transcriptome meta-analysis reveals a central role for sex steroids in the degeneration of hippocampal neurons in Alzheimer’s disease. BMC Syst Biol. 2013;7:51.

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Humphries CE, Kohli MA, Nathanson L, Whitehead P, Beecham G, Martin E, et al. Integrated whole transcriptome and DNA methylation analysis identifies gene networks specific to late-onset Alzheimer’s disease. J Alzheimers Dis. 2015;44:977–87.

    CAS  PubMed  Google Scholar 

  91. Humphries C, Kohli MA, Whitehead P, Mash DC, Pericak-Vance MA, Gilbert J. Alzheimer disease (AD) specific transcription, DNA methylation and splicing in twenty AD associated loci. Mol Cell Neurosci. 2015;67:37–45.

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Wang M, Roussos P, McKenzie A, Zhou X, Kajiwara Y, Brennand KJ, et al. Integrative network analysis of nineteen brain regions identifies molecular signatures and networks underlying selective regional vulnerability to Alzheimer’s disease. Genome Med. 2016;8:104.

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Zou F, Chai HS, Younkin CS, Allen M, Crook J, Pankratz VS, et al. Brain expression genome-wide association study (eGWAS) identifies human disease-associated variants. PLoS Genet. 2012;8:e1002707.

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Sweatt JD. The emerging field of neuroepigenetics. Neuron. 2013;80:624–32.

    CAS  PubMed  Google Scholar 

  95. Maze I, Noh KM, Soshnev AA, Allis CD. Every amino acid matters: essential contributions of histone variants to mammalian development and disease. Nat Rev Genet. 2014;15:259–71.

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Varela MA, Roberts TC, Wood MJ. Epigenetics and ncRNAs in brain function and disease: mechanisms and prospects for therapy. Neurotherapeutics. 2013;10:621–31.

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Nord AS, Pattabiraman K, Visel A, Rubenstein JL. Genomic perspectives of transcriptional regulation in forebrain development. Neuron. 2015;85:27–47.

    CAS  PubMed  PubMed Central  Google Scholar 

  98. Fagiolini M, Jensen CL, Champagne FA. Epigenetic influences on brain development and plasticity. Curr Opin Neurobiol. 2009;19:207–12.

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Day JJ, Kennedy AJ, Sweatt JD. DNA methylation and its implications and accessibility for neuropsychiatric therapeutics. Annu Rev Pharmacol Toxicol. 2015;55:591–611.

    CAS  PubMed  Google Scholar 

  100. Nestler EJ, Pena CJ, Kundakovic M, Mitchell A, Akbarian S. Epigenetic basis of mental illness. Neuroscientist. 2016;22:447–63.

    CAS  PubMed  Google Scholar 

  101. Abdolmaleky HM, Zhou JR, Thiagalingam S. An update on the epigenetics of psychotic diseases and autism. Epigenomics. 2015;7:427–49.

    CAS  PubMed  Google Scholar 

  102. Almeida D, Turecki G. A slice of the suicidal brain: what have postmortem molecular studies taught us? Curr Psychiatry Rep. 2016;18:98.

    PubMed  Google Scholar 

  103. Delgado-Morales R . Neuroepigenomics in aging and disease. Advances in experimental medicine and biology. Cham: Springer; 2017. p 1 online resource.

    Google Scholar 

  104. Fullard JF, Halene TB, Giambartolomei C, Haroutunian V, Akbarian S, Roussos P. Understanding the genetic liability to schizophrenia through the neuroepigenome. Schizophr Res. 2016;177:115–24.

    PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  106. Cariaga-Martinez A, Alelu-Paz R. Rethinking the epigenetic framework to unravel the molecular pathology of schizophrenia. Int J Mol Sci. 2017 Apr 7;18(4). pii: E790. doi: 10.3390/ijms18040790

    PubMed Central  Google Scholar 

  107. Geschwind DH, Flint J. Genetics and genomics of psychiatric disease. Science. 2015;349:1489–94.

    CAS  PubMed  PubMed Central  Google Scholar 

  108. Barrera LO, Ren B. The transcriptional regulatory code of eukaryotic cells—insights from genome-wide analysis of chromatin organization and transcription factor binding. Curr Opin Cell Biol. 2006;18:291–8.

    CAS  PubMed  Google Scholar 

  109. Lelli KM, Slattery M, Mann RS. Disentangling the many layers of eukaryotic transcriptional regulation. Annu Rev Genet. 2012;46:43–68.

    CAS  PubMed  PubMed Central  Google Scholar 

  110. Kornienko AE, Guenzl PM, Barlow DP, Pauler FM. Gene regulation by the act of long non-coding RNA transcription. BMC Biol. 2013;11:59.

    PubMed  PubMed Central  Google Scholar 

  111. Consortium EP. An integrated encyclopedia of DNA elements in the human genome. Nature. 2012;489:57–74.

    Google Scholar 

  112. Consortium GT. The Genotype-Tissue Expression (GTEx) project. Nat Genet. 2013;45:580–5.

    Google Scholar 

  113. Roadmap Epigenomics C, Kundaje A, Meuleman W, Ernst J, Bilenky M, Yen A, et al. Integrative analysis of 111 reference human epigenomes. Nature. 2015;518:317–30.

    Google Scholar 

  114. Pletikos M, Sousa AM, Sedmak G, Meyer KA, Zhu Y, Cheng F, et al. Temporal specification and bilaterality of human neocortical topographic gene expression. Neuron. 2014;81:321–32.

    CAS  PubMed  Google Scholar 

  115. Sexton T, Schober H, Fraser P, Gasser SM. Gene regulation through nuclear organization. Nat Struct Mol Biol. 2007;14:1049–55.

    CAS  PubMed  Google Scholar 

  116. Bickmore WA. The spatial organization of the human genome. Annu Rev Genom Hum Genet. 2013;14:67–84.

    CAS  Google Scholar 

  117. Ernst J, Kheradpour P, Mikkelsen TS, Shoresh N, Ward LD, Epstein CB, et al. Mapping and analysis of chromatin state dynamics in nine human cell types. Nature. 2011;473:43–49.

    CAS  PubMed  PubMed Central  Google Scholar 

  118. Stadler MB, Murr R, Burger L, Ivanek R, Lienert F, Scholer A, et al. DNA-binding factors shape the mouse methylome at distal regulatory regions. Nature. 2011;480:490–5.

    CAS  PubMed  Google Scholar 

  119. Wen L, Li XL, Yan LY, Tan YX, Li R, Zhao YY et al. Whole-genome analysis of 5-hydroxymethylcytosine and 5-methylcytosine at base resolution in the human brain. Genome Biol. 2014 Mar 4;15(3):R49. doi: 10.1186/gb-2014-15-3-r49.

    PubMed  PubMed Central  Google Scholar 

  120. Gross JA, Pacis A, Chen GG, Drupals M, Lutz PE, Barreiro LB, et al. Gene-body 5-hydroxymethylation is associated with gene expression changes in the prefrontal cortex of depressed individuals. Transl Psychiatry. 2017;7:e1119.

    CAS  PubMed  PubMed Central  Google Scholar 

  121. Creyghton MP, Cheng AW, Welstead GG, Kooistra T, Carey BW, Steine EJ, et al. Histone H3K27ac separates active from poised enhancers and predicts developmental state. Proc Natl Acad Sci USA. 2010;107:21931–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  122. Rada-Iglesias A, Bajpai R, Swigut T, Brugmann SA, Flynn RA, Wysocka J. A unique chromatin signature uncovers early developmental enhancers in humans. Nature. 2011;470:279–83.

    CAS  PubMed  Google Scholar 

  123. Tie F, Banerjee R, Stratton CA, Prasad-Sinha J, Stepanik V, Zlobin A, et al. CBP-mediated acetylation of histone H3 lysine 27 antagonizes drosophila polycomb silencing. Development. 2009;136:3131–41.

    CAS  PubMed  PubMed Central  Google Scholar 

  124. Simon JA, Kingston RE. Mechanisms of polycomb gene silencing: knowns and unknowns. Nat Rev Mol Cell Biol. 2009;10:697–708.

    CAS  PubMed  Google Scholar 

  125. Schubeler D. Function and information content of DNA methylation. Nature. 2015;517:321–6.

    CAS  PubMed  Google Scholar 

  126. Smith ZD, Meissner A. DNA methylation: roles in mammalian development. Nat Rev Genet. 2013;14:204–20.

    CAS  PubMed  Google Scholar 

  127. Varley KE, Gertz J, Bowling KM, Parker SL, Reddy TE, Pauli-Behn F, et al. Dynamic DNA methylation across diverse human cell lines and tissues. Genome Res. 2013;23:555–67.

    CAS  PubMed  PubMed Central  Google Scholar 

  128. Maunakea AK, Nagarajan RP, Bilenky M, Ballinger TJ, D’Souza C, Fouse SD, et al. Conserved role of intragenic DNA methylation in regulating alternative promoters. Nature. 2010;466:253–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  129. Lister R, Mukamel EA, Nery JR, Urich M, Puddifoot CA, Johnson ND, et al. Global epigenomic reconfiguration during mammalian brain development. Science. 2013;341:1237905.

    PubMed  PubMed Central  Google Scholar 

  130. Spruijt CG, Gnerlich F, Smits AH, Pfaffeneder T, Jansen PW, Bauer C, et al. Dynamic readers for 5-(hydroxy)methylcytosine and its oxidized derivatives. Cell. 2013;152:1146–59.

    CAS  PubMed  Google Scholar 

  131. Yin Y, Morgunova E, Jolma A, Kaasinen E, Sahu B, Khund-Sayeed S, et al. Impact of cytosine methylation on DNA binding specificities of human transcription factors. Science. 2017;356:6337.

    Google Scholar 

  132. Guo JU, Ma DK, Mo H, Ball MP, Jang MH, Bonaguidi MA, et al. Neuronal activity modifies the DNA methylation landscape in the adult brain. Nat Neurosci. 2011;14:1345–51.

    CAS  PubMed  PubMed Central  Google Scholar 

  133. Graff J, Kim D, Dobbin MM, Tsai LH. Epigenetic regulation of gene expression in physiological and pathological brain processes. Physiol Rev. 2011;91:603–49.

    CAS  PubMed  Google Scholar 

  134. Shin J, Ming GL, Song H. DNA modifications in the mammalian brain. Philos Trans R Soc Lond B. 2014;369:1652.

    Google Scholar 

  135. Gusev A, Lee SH, Trynka G, Finucane H, Vilhjalmsson BJ, Xu H, et al. Partitioning heritability of regulatory and cell-type-specific variants across 11 common diseases. Am J Hum Genet. 2014;95:535–52.

    CAS  PubMed  PubMed Central  Google Scholar 

  136. Maurano MT, Humbert R, Rynes E, Thurman RE, Haugen E, Wang H, et al. Systematic localization of common disease-associated variation in regulatory DNA. Science. 2012;337:1190–5.

    CAS  PubMed  PubMed Central  Google Scholar 

  137. Buenrostro JD,Wu B,Chang HY,Greenleaf WJ, ATAC-seq: a method for assaying chromatin accessibility genome-wide. Curr Protoc Mol Biol. 2015;109:21–29.

    PubMed  PubMed Central  Google Scholar 

  138. Corces MR, Trevino AE, Hamilton EG, Greenside PG, Sinnott-Armstrong NA, Vesuna S, et al. An improved ATAC-seq protocol reduces background and enables interrogation of frozen tissues. Nat Methods. 2017;14:959–62.

    CAS  PubMed  PubMed Central  Google Scholar 

  139. Wu J, Huang B, Chen H, Yin Q, Liu Y, Xiang Y, et al. The landscape of accessible chromatin in mammalian preimplantation embryos. Nature. 2016;534:652–7.

    CAS  PubMed  Google Scholar 

  140. Fullard JF, Giambartolomei C, Hauberg ME, Xu K, Voloudakis G, Shao Z, et al. Open chromatin profiling of human postmortem brain infers functional roles for non-coding schizophrenia loci. Hum Mol Genet. 2017;26:1942–51.

    CAS  PubMed  PubMed Central  Google Scholar 

  141. Rivera CM, Ren B. Mapping human epigenomes. Cell. 2013;155:39–55.

    CAS  PubMed  Google Scholar 

  142. Farh KK, Marson A, Zhu J, Kleinewietfeld M, Housley WJ, Beik S, et al. Genetic and epigenetic fine mapping of causal autoimmune disease variants. Nature. 2015;518:337–43.

    CAS  PubMed  Google Scholar 

  143. Trynka G, Sandor C, Han B, Xu H, Stranger BE, Liu XS, et al. Chromatin marks identify critical cell types for fine mapping complex trait variants. Nat Genet. 2013;45:124–30.

    CAS  PubMed  Google Scholar 

  144. Finucane HK, Bulik-Sullivan B, Gusev A, Trynka G, Reshef Y, Loh PR, et al. Partitioning heritability by functional annotation using genome-wide association summary statistics. Nat Genet. 2015;47:1228–35.

    CAS  PubMed  PubMed Central  Google Scholar 

  145. Helm M, Alfonzo JD. Posttranscriptional RNA Modifications: playing metabolic games in a cell’s chemical Legoland. Chem Biol. 2014;21:174–85.

    CAS  PubMed  Google Scholar 

  146. Dominissini D, Moshitch-Moshkovitz S, Schwartz S, Salmon-Divon M, Ungar L, Osenberg S, et al. Topology of the human and mouse m6A RNA methylomes revealed by m6A-seq. Nature. 2012;485:201–6.

    CAS  PubMed  Google Scholar 

  147. Meyer KD, Saletore Y, Zumbo P, Elemento O, Mason CE, Jaffrey SR. Comprehensive analysis of mRNA methylation reveals enrichment in 3’ UTRs and near stop codons. Cell. 2012;149:1635–46.

    CAS  PubMed  PubMed Central  Google Scholar 

  148. Sun WJ, Li JH, Liu S, Wu J, Zhou H, Qu LH, et al. RMBase: a resource for decoding the landscape of RNA modifications from high-throughput sequencing data. Nucleic Acids Res. 2016;44:D259–65.

    CAS  PubMed  Google Scholar 

  149. Schwartz S, Mumbach MR, Jovanovic M, Wang T, Maciag K, Bushkin GG, et al. Perturbation of m6A writers reveals two distinct classes of mRNA methylation at internal and 5’ sites. Cell Rep. 2014;8:284–96.

    CAS  PubMed  PubMed Central  Google Scholar 

  150. Zheng G, Dahl JA, Niu Y, Fedorcsak P, Huang CM, Li CJ, et al. ALKBH5 is a mammalian RNA demethylase that impacts RNA metabolism and mouse fertility. Mol Cell. 2013;49:18–29.

    CAS  PubMed  Google Scholar 

  151. Jia G, Fu Y, Zhao X, Dai Q, Zheng G, Yang Y, et al. N6-methyladenosine in nuclear RNA is a major substrate of the obesity-associated FTO. Nat Chem Biol. 2011;7:885–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  152. Liu J, Yue Y, Han D, Wang X, Fu Y, Zhang L, et al. A METTL3-METTL14 complex mediates mammalian nuclear RNA N6-adenosine methylation. Nat Chem Biol. 2014;10:93–95.

    CAS  PubMed  Google Scholar 

  153. Edupuganti RR, Geiger S, Lindeboom RGH, Shi H, Hsu PJ, Lu Z, et al. N(6)-methyladenosine (m(6)A) recruits and repels proteins to regulate mRNA homeostasis. Nat Struct Mol Biol. 2017;24:870–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  154. Chang M, Lv H, Zhang W, Ma C, He X, Zhao S, et al. Region-specific RNA m(6)A methylation represents a new layer of control in the gene regulatory network in the mouse brain. Open Biol. 2017 Sep;7(9). pii: 170166. doi: 10.1098/rsob.170166.

    PubMed  PubMed Central  Google Scholar 

  155. Zeisel A, Manchado AB, Codeluppi S, Lonnerberg P, La Manno G, Jureus A, et al. Cell types in the mouse cortex and hippocampus revealed by single-cell RNA-seq. Science. 2015;347:1138–42.

    CAS  PubMed  Google Scholar 

  156. Yoon KJ, Ringeling FR, Vissers C, Jacob F, Pokrass M, Jimenez-Cyrus D, et al. Temporal control of mammalian cortical neurogenesis by m(6)A methylation. Cell. 2017;171:877–89.

    CAS  PubMed  PubMed Central  Google Scholar 

  157. Jin F, Li Y, Dixon JR, Selvaraj S, Ye Z, Lee AY, et al. A high-resolution map of the three-dimensional chromatin interactome in human cells. Nature. 2013;503:290–4.

    CAS  PubMed  PubMed Central  Google Scholar 

  158. Lieberman-Aiden E, van Berkum NL, Williams L, Imakaev M, Ragoczy T, Telling A, et al. Comprehensive mapping of long-range interactions reveals folding principles of the human genome. Science. 2009;326:289–93.

    CAS  PubMed  PubMed Central  Google Scholar 

  159. Rao SS, Huntley MH, Durand NC, Stamenova EK, Bochkov ID, Robinson JT, et al. A 3D map of the human genome at kilobase resolution reveals principles of chromatin looping. Cell. 2014;159:1665–80.

    CAS  PubMed  PubMed Central  Google Scholar 

  160. Garcia-Gonzalez E, Escamilla-Del-Arenal M, Arzate-Mejia R, Recillas-Targa F. Chromatin remodeling effects on enhancer activity. Cell Mol Life Sci. 2016;73:2897–910.

    CAS  PubMed  Google Scholar 

  161. Dixon JR, Selvaraj S, Yue F, Kim A, Li Y, Shen Y, et al. Topological domains in mammalian genomes identified by analysis of chromatin interactions. Nature. 2012;485:376–80.

    CAS  PubMed  PubMed Central  Google Scholar 

  162. Gonzalez-Sandoval A, Gasser SM. On TADs and LADs: spatial control over gene expression. Trends Genet. 2016;32:485–95.

    CAS  PubMed  Google Scholar 

  163. Won H, de la Torre-Ubieta L, Stein JL, Parikshak NN, Huang J, Opland CK, et al. Chromosome conformation elucidates regulatory relationships in developing human brain. Nature. 2016;538:523–7.

    PubMed  PubMed Central  Google Scholar 

  164. Jiang Y, Loh YE, Rajarajan P, Hirayama T, Liao W, Kassim BS, et al. The methyltransferase SETDB1 regulates a large neuron-specific topological chromatin domain. Nat Genet. 2017;49:1239–50.

    CAS  PubMed  PubMed Central  Google Scholar 

  165. Cannon M, Jones PB, Murray RM. Obstetric complications and schizophrenia: historical and meta-analytic review. Am J Psychiatry. 2002;159:1080–92.

    PubMed  Google Scholar 

  166. Brown AS, Derkits EJ. Prenatal infection and schizophrenia: a review of epidemiologic and translational studies. Am J Psychiatry. 2010;167:261–80.

    PubMed  PubMed Central  Google Scholar 

  167. Khashan AS, Abel KM, McNamee R, Pedersen MG, Webb RT, Baker PN, et al. Higher risk of offspring schizophrenia following antenatal maternal exposure to severe adverse life events. Arch Gen Psychiatry. 2008;65:146–52.

    PubMed  Google Scholar 

  168. Susser E, Neugebauer R, Hoek HW, Brown AS, Lin S, Labovitz D, et al. Schizophrenia after prenatal famine. Further evidence. Arch Gen Psychiatry. 1996;53:25–31.

    CAS  PubMed  Google Scholar 

  169. Schizophrenia Working Group of the Psychiatric Genomics C. Biological insights from 108 schizophrenia-associated genetic loci. Nature. 2014;511:421–7.

    Google Scholar 

  170. Pardinas AF, Holmans P, Pocklington AJ, Escott-Price V, Ripke S, Carrera N, et al. Common schizophrenia alleles are enriched in mutation-intolerant genes and in regions under strong background selection. Nat Genet. 2018;50:381–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  171. Guidotti A, Grayson DR, Caruncho HJ. Epigenetic RELN dysfunction in schizophrenia and related neuropsychiatric disorders. Front Cell Neurosci. 2016;10:89.

    PubMed  PubMed Central  Google Scholar 

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

    PubMed  Google Scholar 

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

    CAS  Google Scholar 

  174. Numata S, Ye T, Herman M, Lipska BK. DNA methylation changes in the postmortem dorsolateral prefrontal cortex of patients with schizophrenia. Front Genet. 2014;5:280.

    PubMed  PubMed Central  Google Scholar 

  175. Wockner LF, Noble EP, Lawford BR, Young RM, Morris CP, Whitehall VL, et al. Genome-wide DNA methylation analysis of human brain tissue from schizophrenia patients. Transl Psychiatry. 2014;4:e339.

    CAS  PubMed  PubMed Central  Google Scholar 

  176. Wockner LF, Morris CP, Noble EP, Lawford BR, Whitehall VL, Young RM, et al. Brain-specific epigenetic markers of schizophrenia. Transl Psychiatry. 2015;5:e680.

    CAS  PubMed  PubMed Central  Google Scholar 

  177. Alelu-Paz R, Carmona FJ, Sanchez-Mut JV, 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. Front Psychol. 2016;7:1496.

    PubMed  PubMed Central  Google Scholar 

  178. 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. Genome Biol. 2014;15:483.

    PubMed  PubMed Central  Google Scholar 

  179. 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. Hum Mol Genet. 2017;26:210–25.

    CAS  PubMed  Google Scholar 

  180. Spiers H, Hannon E, Schalkwyk LC, Smith R, Wong CC, O’Donovan MC, et al. Methylomic trajectories across human fetal brain development. Genome Res. 2015;25:338–52.

    CAS  PubMed  PubMed Central  Google Scholar 

  181. 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. J Neurosci. 2013;33:11839–51.

    CAS  PubMed  PubMed Central  Google Scholar 

  182. Roussos P, Mitchell AC, Voloudakis G, Fullard JF, Pothula VM, Tsang J, et al. A role for noncoding variation in schizophrenia. Cell Rep. 2014;9:1417–29.

    CAS  PubMed  PubMed Central  Google Scholar 

  183. Vogel Ciernia A, LaSalle J. The landscape of DNA methylation amid a perfect storm of autism aetiologies. Nat Rev Neurosci. 2016;17:411–23.

    PubMed  Google Scholar 

  184. Grayson DR, Guidotti A. Merging data from genetic and epigenetic approaches to better understand autistic spectrum disorder. Epigenomics. 2016;8:85–104.

    CAS  PubMed  PubMed Central  Google Scholar 

  185. Nardone S, Sams DS, Reuveni E, Getselter D, Oron O, Karpuj M, et al. DNA methylation analysis of the autistic brain reveals multiple dysregulated biological pathways. Transl Psychiatry. 2014;4:e433.

    CAS  PubMed  PubMed Central  Google Scholar 

  186. Ladd-Acosta C, Hansen KD, Briem E, Fallin MD, Kaufmann WE, Feinberg AP. Common DNA methylation alterations in multiple brain regions in autism. Mol Psychiatry. 2014;19:862–71.

    CAS  PubMed  Google Scholar 

  187. Ellis SE, Gupta S, Moes A, West AB, Arking DE. Exaggerated CpH methylation in the autism-affected brain. Mol Autism. 2017;8:6.

    PubMed  PubMed Central  Google Scholar 

  188. Kozlenkov A, Roussos P, Timashpolsky A, Barbu M, Rudchenko S, Bibikova M, et al. Differences in DNA methylation between human neuronal and glial cells are concentrated in enhancers and non-CpG sites. Nucleic Acids Res. 2014;42:109–27.

    CAS  PubMed  Google Scholar 

  189. Guo JU, Su Y, Shin JH, Shin J, Li H, Xie B, et al. Distribution, recognition and regulation of non-CpG methylation in the adult mammalian brain. Nat Neurosci. 2014;17:215–22.

    CAS  PubMed  Google Scholar 

  190. Shulha HP, Cheung I, Whittle C, Wang J, Virgil D, Lin CL, et al. Epigenetic signatures of autism: trimethylated H3K4 landscapes in prefrontal neurons. Arch Gen Psychiatry. 2012;69:314–24.

    CAS  PubMed  Google Scholar 

  191. Sun W, Poschmann J, Cruz-Herrera Del Rosario R, Parikshak NN, Hajan HS, Kumar V, et al. Histone acetylome-wide association study of autism spectrum disorder. Cell. 2016;167:1385–97 e1311.

    CAS  PubMed  Google Scholar 

  192. Turecki G. The molecular bases of the suicidal brain. Nat Rev Neurosci. 2014;15:802–16.

    CAS  PubMed  PubMed Central  Google Scholar 

  193. Pishva E, Rutten BPF, van den Hove D. DNA methylation in major depressive disorder. Adv Exp Med Biol. 2017;978:185–96.

    CAS  PubMed  Google Scholar 

  194. Labonte B, Suderman M, Maussion G, Lopez JP, Navarro-Sanchez L, Yerko V, et al. Genome-wide methylation changes in the brains of suicide completers. Am J Psychiatry. 2013;170:511–20.

    PubMed  Google Scholar 

  195. Sabunciyan S, Aryee MJ, Irizarry RA, Rongione M, Webster MJ, Kaufman WE, et al. Genome-wide DNA methylation scan in major depressive disorder. PLoS ONE. 2012;7:e34451.

    CAS  PubMed  PubMed Central  Google Scholar 

  196. Dempster EL, Wong CC, Lester KJ, Burrage J, Gregory AM, Mill J, et al. Genome-wide methylomic analysis of monozygotic twins discordant for adolescent depression. Biol Psychiatry. 2014;76:977–83.

    CAS  PubMed  PubMed Central  Google Scholar 

  197. Nagy C, Suderman M, Yang J, Szyf M, Mechawar N, Ernst C, et al. Astrocytic abnormalities and global DNA methylation patterns in depression and suicide. Mol Psychiatry. 2015;20:320–8.

    CAS  PubMed  Google Scholar 

  198. Murphy TM, Crawford B, Dempster EL, Hannon E, Burrage J, Turecki G, et al. Methylomic profiling of cortex samples from completed suicide cases implicates a role for PSORS1C3 in major depression and suicide. Transl Psychiatry. 2017;7:e989.

    CAS  PubMed  PubMed Central  Google Scholar 

  199. McGowan PO, Sasaki A, D’Alessio AC, Dymov S, Labonte B, Szyf M, et al. Epigenetic regulation of the glucocorticoid receptor in human brain associates with childhood abuse. Nat Neurosci. 2009;12:342–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  200. Lutz PE, Tanti A, Gasecka A, Barnett-Burns S, Kim JJ, Zhou Y, et al. Association of a history of child abuse with impaired myelination in the anterior cingulate cortex: convergent epigenetic, transcriptional, and morphological evidence. Am J Psychiatry. 2017;174:1185–94.

    PubMed  Google Scholar 

  201. Kaminsky Z, Wilcox HC, Eaton WW, Van Eck K, Kilaru V, Jovanovic T, et al. Epigenetic and genetic variation at SKA2 predict suicidal behavior and post-traumatic stress disorder. Transl Psychiatry. 2015;5:e627.

    CAS  PubMed  PubMed Central  Google Scholar 

  202. Deussing JM, Jakovcevski M. Histone modifications in major depressive disorder and related rodent models. Adv Exp Med Biol. 2017;978:169–83.

    CAS  PubMed  Google Scholar 

  203. Robison AJ, Vialou V, Sun HS, Labonte B, Golden SA, Dias C, et al. Fluoxetine epigenetically alters the CaMKIIalpha promoter in nucleus accumbens to regulate DeltaFosB binding and antidepressant effects. Neuropsychopharmacology. 2014;39:1178–86.

    CAS  PubMed  Google Scholar 

  204. Golden SA, Christoffel DJ, Heshmati M, Hodes GE, Magida J, Davis K, et al. Epigenetic regulation of RAC1 induces synaptic remodeling in stress disorders and depression. Nat Med. 2013;19:337–44.

    CAS  PubMed  PubMed Central  Google Scholar 

  205. Chen ES, Ernst C, Turecki G. The epigenetic effects of antidepressant treatment on human prefrontal cortex BDNF expression. Int J Neuropsychopharmacol. 2011;14:427–9.

    CAS  PubMed  Google Scholar 

  206. Cruceanu C, Alda M, Nagy C, Freemantle E, Rouleau GA, Turecki G. H3K4 tri-methylation in synapsin genes leads to different expression patterns in bipolar disorder and major depression. Int J Neuropsychopharmacol. 2013;16:289–99.

    CAS  PubMed  Google Scholar 

  207. Dong E, Grayson DR, Guidotti A, Costa E. Antipsychotic subtypes can be characterized by differences in their ability to modify GABAergic promoter methylation. Epigenomics. 2009;1:201–11.

    CAS  PubMed  Google Scholar 

  208. Ruzicka WB, Subburaju S, Benes FM. Circuit- and diagnosis-specific DNA methylation changes at gamma-aminobutyric acid-related genes in postmortem human hippocampus in schizophrenia and bipolar disorder. JAMA Psychiatry. 2015;72:541–51.

    PubMed  PubMed Central  Google Scholar 

  209. Kaminsky Z, Tochigi M, Jia P, Pal M, Mill J, Kwan A, et al. A multi-tissueanalysis identifies HLA complex group 9 gene methylation differences in bipolar disorder. Mol Psychiatry. 2012;17:728–40.

    CAS  PubMed  Google Scholar 

  210. Bartlett AA, Singh R, Hunter RG. Anxiety and epigenetics. Adv Exp Med Biol. 2017;978:145–66.

    CAS  PubMed  Google Scholar 

  211. Roubroeks JAY, Smith RG, van den Hove DLA, Lunnon K. Epigenetics and DNA methylomic profiling in Alzheimer’s disease and other neurodegenerative diseases. J Neurochem. 2017;143:158–70.

    CAS  PubMed  Google Scholar 

  212. Lunnon K, Smith R, Hannon E, De Jager PL, Srivastava G, Volta M, et al. Methylomic profiling implicates cortical deregulation of ANK1 in Alzheimer’s disease. Nat Neurosci. 2014;17:1164–70.

    CAS  PubMed  PubMed Central  Google Scholar 

  213. De Jager PL, Srivastava G, Lunnon K, Burgess J, Schalkwyk LC, Yu L, et al. Alzheimer’s disease: early alterations in brain DNA methylation at ANK1, BIN1, RHBDF2 and other loci. Nat Neurosci. 2014;17:1156–63.

    PubMed  PubMed Central  Google Scholar 

  214. Nativio R, Donahue G, Berson A, Lan Y, Amlie-Wolf A, Tuzer F, et al. Dysregulation of the epigenetic landscape of normal aging in Alzheimer’s disease. Nat Neurosci. 2018;21:497–505.

    CAS  PubMed  PubMed Central  Google Scholar 

  215. Dang W, Steffen KK, Perry R, Dorsey JA, Johnson FB, Shilatifard A, et al. Histone H4 lysine 16 acetylation regulates cellular lifespan. Nature. 2009;459:802–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  216. Kozak ML, Chavez A, Dang W, Berger SL, Ashok A, Guo X, et al. Inactivation of the Sas2 histone acetyltransferase delays senescence driven by telomere dysfunction. EMBO J. 2010;29:158–70.

    CAS  PubMed  Google Scholar 

  217. Hurd YL. Subjects with major depression or bipolar disorder show reduction of prodynorphin mRNA expression in discrete nuclei of the amygdaloid complex. Mol Psychiatry. 2002;7:75–81.

    CAS  PubMed  Google Scholar 

  218. Michaelides M, Anderson SA, Ananth M, Smirnov D, Thanos PK, Neumaier JF, et al. Whole-brain circuit dissection in free-moving animals reveals cell-specific mesocorticolimbic networks. J Clin Invest. 2013;123:5342–50.

    CAS  PubMed  PubMed Central  Google Scholar 

  219. Michaelides M, Hurd YL. DREAMM: a biobehavioral imaging methodology for dynamic in vivo whole-brain mapping of cell type-specific functional networks. Neuropsychopharmacology. 2015;40:239–40.

    CAS  PubMed  Google Scholar 

  220. O’Donovan SM, Hasselfeld K, Bauer D, Simmons M, Roussos P, Haroutunian V, et al. Glutamate transporter splice variant expression in an enriched pyramidal cell population in schizophrenia. Transl Psychiatry. 2015;5:e579.

    PubMed  PubMed Central  Google Scholar 

  221. Doyle GA, Doucet-O’Hare TT, Hammond MJ, Crist RC, Ewing AD, Ferraro TN, et al. Reading LINEs within the cocaine addicted brain. Brain Behav. 2017;7:e00678.

    PubMed  PubMed Central  Google Scholar 

  222. Ribeiro EA, Scarpa JR, Garamszegi SP, Kasarskis A, Mash DC, Nestler EJ. Gene network dysregulation in dorsolateral prefrontal cortex neurons of humans with cocaine use disorder. Sci Rep. 2017;7:5412.

    PubMed  PubMed Central  Google Scholar 

  223. Jiang Y, Matevossian A, Huang HS, Straubhaar J, Akbarian S. Isolation of neuronal chromatin from brain tissue. BMC Neurosci. 2008;9:42.

    PubMed  PubMed Central  Google Scholar 

  224. Iwamoto K, Bundo M, Ueda J, Oldham MC, Ukai W, Hashimoto E, et al. Neurons show distinctive DNA methylation profile and higher interindividual variations compared with non-neurons. Genome Res. 2011;21:688–96.

    CAS  PubMed  PubMed Central  Google Scholar 

  225. Cheung I, Shulha HP, Jiang Y, Matevossian A, Wang J, Weng Z, et al. Developmental regulation and individual differences of neuronal H3K4me3 epigenomes in the prefrontal cortex. Proc Natl Acad Sci USA. 2010;107:8824–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  226. Kozlenkov A, Wang M, Roussos P, Rudchenko S, Barbu M, Bibikova M, et al. Substantial DNA methylation differences between two major neuronal subtypes in human brain. Nucleic Acids Res. 2016;44:2593–612.

    PubMed  Google Scholar 

  227. Ernst A, Alkass K, Bernard S, Salehpour M, Perl S, Tisdale J, et al. Neurogenesis in the striatum of the adult human brain. Cell. 2014;156:1072–83.

    CAS  PubMed  Google Scholar 

  228. Crist RC, Clarke TK, Ang A, Ambrose-Lanci LM, Lohoff FW, Saxon AJ, et al. An intronic variant in OPRD1 predicts treatment outcome for opioid dependence in African-Americans. Neuropsychopharmacology. 2013;38:2003–10.

    CAS  PubMed  PubMed Central  Google Scholar 

  229. Hancock DB, Levy JL, Gaddis NC, Glasheen C, Saccone NL, Page GP, et al. Cis-expression quantitative trait loci mapping reveals replicable associations with heroin addiction in OPRM1. Biol Psychiatry. 2015;78:474–84.

    CAS  PubMed  PubMed Central  Google Scholar 

  230. Zhong S, Zhang S, Fan X, Wu Q, Yan L, Dong J, et al. A single-cell RNA-seq survey of the developmental landscape of the human prefrontal cortex. Nature. 2018;555:524–8.

    CAS  PubMed  Google Scholar 

  231. Clark SJ, Lee HJ, Smallwood SA, Kelsey G, Reik W. Single-cell epigenomics: powerful new methods for understanding gene regulation and cell identity. Genome Biol. 2016;17:72.

    PubMed  PubMed Central  Google Scholar 

  232. Schwartzman O, Tanay A. Single-cell epigenomics: techniques and emerging applications. Nat Rev Genet. 2015;16:716–26.

    CAS  PubMed  Google Scholar 

  233. Macaulay IC, Ponting CP, Voet T. Single-cell multiomics: multiple measurements from single cells. Trends Genet. 2017;33:155–68.

    CAS  PubMed  PubMed Central  Google Scholar 

  234. Margueron R, Reinberg D. The polycomb complex PRC2 and its mark in life. Nature. 2011;469:343–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  235. Brami-Cherrier K, Anzalone A, Ramos M, Forne I, Macciardi F, Imhof A, et al. Epigenetic reprogramming of cortical neurons through alteration of dopaminergic circuits. Mol Psychiatry. 2014;19:1193–200.

    CAS  PubMed  PubMed Central  Google Scholar 

  236. Akbarian S, Liu C, Knowles JA, Vaccarino FM, Farnham PJ, Crawford GE, et al. The PsychENCODE project. Nat Neurosci. 2015;18:1707–12.

    CAS  PubMed  PubMed Central  Google Scholar 

  237. Consortium GT. Human genomics. The genotype-tissue expression (GTEx) pilot analysis: multitissue gene regulation in humans. Science. 2015;348:648–60.

    Google Scholar 

  238. Webb A, Papp AC, Curtis A, Newman LC, Pietrzak M, Seweryn M, et al. RNA sequencing of transcriptomes in human brain regions: protein-coding and non-coding RNAs, isoforms and alleles. BMC Genom. 2015;16:990.

    Google Scholar 

  239. Bahcall OG. Human genetics: GTEx pilot quantifies eQTL variation across tissues and individuals. Nat Rev Genet. 2015;16:375.

    CAS  PubMed  Google Scholar 

  240. E Stranger, Lori E Brigham, Richard Hasz, Marcus Hunter, Christopher Johns, Mark Johnson, et al. e GP. Enhancing GTEx by bridging the gaps between genotype, gene expression, and disease. Nat Genet. 2017;49:1664–70.

    Google Scholar 

Download references

Acknowledgements

This work was supported by NIH DA15446 (YLH), DA008227 (YLH), DA043247 (SD, YLH), MH103877 (a part of the PsychEncode consortium; SD), and VA BX001829 (SD).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Yasmin L. Hurd.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Electronic supplementary material

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Egervari, G., Kozlenkov, A., Dracheva, S. et al. Molecular windows into the human brain for psychiatric disorders. Mol Psychiatry 24, 653–673 (2019). https://doi.org/10.1038/s41380-018-0125-2

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41380-018-0125-2

This article is cited by

Search

Quick links