Hostname: page-component-84b7d79bbc-5lx2p Total loading time: 0 Render date: 2024-07-26T21:19:22.542Z Has data issue: false hasContentIssue false
  • English
  • Français

Methylated Spirits: Epigenetic Hypotheses of Psychiatric Disorders

Published online by Cambridge University Press:  07 November 2014

Stephen M. Stahl
Get access Rights & Permissions [Opens in a new window]

Extract

Our spirits may be regulated by the methylation of our genes. Methylation, acetylation, and other biochemical processes are the molecular switches for turning genes on and off. There is evidence now that certain behaviors, feelings, and psychiatric symptoms may be modified by turning various genes on or off. If classical genetics is the sequence of DNA that is inherited, then epigenetics is a parallel process determining whether a given gene (ie, a sequence of DNA coding for transcription) is expressed into its RNA or is silenced. Epigenetics is now entering psychiatry with the hypothesis that normal genes as well as risk genes can both contribute to a mental disorder. That is, it has long been hypothesized that when “abnormal” genes with an altered sequence of DNA are inherited as risk genes for a mental illness, these risk genes will make an abnormal gene product in neurons, contributing to inefficient information processing in various brain circuits and creating risk for developing a symptom of a mental illness. Now comes the role of epigenetic actions in mental illnesses.

Type
Trends in Psychopharmacology
Information
CNS Spectrums , Volume 15 , Issue 4 , April 2010 , pp. 220 - 230
Copyright
Copyright © Cambridge University Press 2010

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

REFERENCES

1. Waddington, CH. The Strategy of the Genes. New York, NY: MacMillan; 1957.Google Scholar
2. Nestler, EJ. Epigenetic mechanisms in psychiatry. Biol Psychiatry. 2009; 65: 189–190.CrossRefGoogle ScholarPubMed
3. Stahl, SM. Epigenetics and methylomics in psychiatry. J Clin Psychiatry. 2009; 70: 1204–1205.CrossRefGoogle ScholarPubMed
4. Sweatt, JD. Experience-dependent epigenetic modifications in the central nervous system. Biol Psychiatry. 2009; 65: 191–197.CrossRefGoogle ScholarPubMed
5. Slack, A, Cervoni, N, Pinard, M, Szyf, M. Feedback regulation of DNA methyltransferase gene expression by methylation. Eur J Biochem. 1999; 264: 191–199.CrossRefGoogle ScholarPubMed
6. Jamaluddin, Md S, Chen, I et al. , Homocysteine inhibits endothelial cell growth via DNA hypomethylation of the cyclin A gene. Blood. 2007; 110: 3648–3655.CrossRefGoogle ScholarPubMed
7. Wainfan, E, Poirier, LA. Methyl groups in carcinogenesis: effects on DNA methylation and gene expression. Cancer Res. 1992; 52(7 suppl): 2071S–2077S.Google ScholarPubMed
8. Szyf, M. DNA methylation and demethylation as targets for anticancer therapy. Biochemistry (Mosc). 2005; 70: 533–549.CrossRefGoogle ScholarPubMed
9. Stahl, SM. Stahls Essential Psychopharmacology. 3rd edition. New York, NY: Cambridge University Press; 2008.Google Scholar
10. Stahl, SM. Fooling Mother Nature: epigenetics and novel treatments for psychiatric disorders. CNS Spectr. In Press.Google Scholar
11. Friso, S, Choi, S-W. Gene-nutrient interactions in one-carbon metabolism. Curr Drug Metab. 2005; 6: 37–46.CrossRefGoogle ScholarPubMed
12. Friso, S, Choi, S-W. Gene-nutrient interactions and DNA methylation. J Nutr. 2002; 132: 2382S–2387S.CrossRefGoogle ScholarPubMed
13. Stahl, SM. Novel Therapeutics for Depression: L-methylfolate (6 (S)-5 methyltetrahydrofolate or MTHF) as a trimonoamine modulator and antidepressant augmenting agent. CNS Spectr. 2007; 12: 423–428.CrossRefGoogle ScholarPubMed
14. Akbarian, S, Huang, H-S. Epigenetic regulation in human brain: focus on histone lysine methylation. Biol Psychiatry. 2009; 65: 198–203.CrossRefGoogle ScholarPubMed
15. Monteggia, LM, Kavalali, ET. Rett syndrome and the impact of MeCP2 associated transcriptional mechanisms on neurotransmission. Biol Psychiatry. 2009; 65: 204–210.CrossRefGoogle ScholarPubMed
16. Cohen, SM, Nichols, A, Wyatt, R, Pollin, W. The administration of methionine to chronic schizophrenia patients: a review of 10 studies. Biol Psychiatry. 1974; 8: 209–225.Google Scholar
17. Abdolmaleky, HM, Cheng, KH, Faraone, SV et al. , Hypomethylation of MB-COMT promoter is a major risk factor for schizophrenia and bipolar disorder. Hum Mol Genet. 2006; 15: 3132–3145.CrossRefGoogle Scholar
18. Abdolmaleky, HM, Smith, CL, Zhou, RJ, Thiagalingam, S. Epigenetic alterations of dopaminergic system in major psychiatric disorders. In: Yan, Q, ed. Pharmacogenomics in Drug Discovery and Development. New York, NY: Humana Press; 2008: 187–212.CrossRefGoogle Scholar
19. Veldic, M, Caruncho, JH, Liu, WS et al. , DNA-methyltransferase 1 mRNA is selectively overexpressed in telencephalic GABAergic interneurons on schizophrenia brains Proc Natl Acad Sci. 2004; 101: 348–353.CrossRefGoogle ScholarPubMed
20. Costa, E, Dong, E, Grayson, DR, Guidotti, A, Ruzicka, W, Veldic, M. Reviewing the role of DNA (Cytosine-5) methyltransferase overexpression in the cortical GABAergic dysfunction associated with psychosis vulnerability. Epigenetics. 2007; 2: 29–36.Google ScholarPubMed
21. Veldic, M, Kadriu, B, Maloku, E et al. , Epigenetic mechanisms expressed in basal ganglia GABAergic neurons differentiate schizophrenia from bipolar disorder. Schizophr Res. 2007; 91: 51–61.CrossRefGoogle ScholarPubMed
22. Tremolizzo, L, Caraboni, G, Ruzicka, WB et al. , An epigenetic mouse model for molecular and behavioral neuropathologies related to schizophrenia vulnerability. Proc Natl Acad Sci. 2002; 99: 17095–17100.CrossRefGoogle ScholarPubMed
23. Abdolmaleky, HM, Cheng, KH, Russo, A et al. , Hypermethylation of the Reelin RELN promoter in the brain of schizophrenic patients: a preliminary report. Am J Med Genet B Neuropsychiatr Genet. 2005; 134: 60–66.CrossRefGoogle Scholar
24. Abdolmaleky, HM, Smith, CL, Zhou, J-R, Thiagalingam, S. Epigenetic modulation of reelin function in schizophrenia and bipolar disorder. In: SH, Fatem, ed. Reelin Glycoprotein: Structure, Biology and Roles in Health and Disease. New York, NY: Springer; 2008: 365–384.CrossRefGoogle Scholar
25. Noh, JS, Sharma, RP, Veldic, M et al. , DNA methyltransferase 1 regulates reelin mRNA expression in mouse primary cortical cultures. Proc Natl Acad Sci. 2005; 102: 1749–1754.CrossRefGoogle ScholarPubMed
26. Grayson, DR, Jia, X, Chen, Y et al. , Reelin promoter hypermethylation in schizophrenia. Proc Natl Acad Sci. 2005; 102: 9341–9346.CrossRefGoogle ScholarPubMed
27. Mill, J, Tang, T, Kaminsky, Z et al. , Epigenomic profiling reveals DNA methylation changes associated with major psychosis. Am J Human Genet. 2008; 82: 696–711.CrossRefGoogle ScholarPubMed
28. Murphy, BC, O'Reilly, RL, Singh, SM. Site specific cytosine methylation in S-COMT promoter in 31 brain regions with implications for studies involving schizophrenia. Am J Med Genet B Neuropsychiatr Genet. 2005; 133: 37–42.CrossRefGoogle Scholar
29. Tochigi, M, Iwamoto, K, Bundo, M et al. , Methylation status of the reelin promoter region in the brain of schizophrenic patients. Biol Psychiatry. 2008; 63: 530–533.CrossRefGoogle ScholarPubMed
30. Abdolmaleky, HM, Smith, CL, Farone, SV et al. , Methylomics in psychiatry: modulation of gene-environment interactions may be through DNA methylation. Am J Med Genet B Neuropsychiatr Genet. 2004; 127B: 51–59.CrossRefGoogle ScholarPubMed
31. Stadler, F, Kolb, G, Bubusch, L, Baker, SP, Jones, EG, Akbarian, S. Histone methylation at gene promoters is associated with developmental regulation and region-specific expression of ionotropic and metabotropic glutamate receptors in human brain. J Neurochem. 2005; 94: 324–336.CrossRefGoogle ScholarPubMed
32. Huang, HS, Matevossian, A, Whittle, C et al. , Prefrontal dysfunction in schizophrenia involves mixed-lineage leukemia 1-regulated histone methylation at GABAergic gene promoters. J Neurosci. 2007; 27: 11254–11262.CrossRefGoogle ScholarPubMed
33. Shimabukuro, M, Sasaki, T, Imamura, A et al. , Global hypomethylation of peripheral leukocyte DNA in male patients with schizophrenia: a potential link between epigenetics and schizophrenia. J Psychiatr Res. 2007; 41: 1042–1046.CrossRefGoogle ScholarPubMed
34. Connor, CM, Akbarian, S. DNA methylation changes in schizophrenia and bipolar disorder. Epigenetics. 2008; 3: 55–58.CrossRefGoogle ScholarPubMed
35. Freeman, JM, Finkelstein, JM, Mudd, SH. Folate-responsive homocysteinuria and “schizophrenia.” A defect in methylation due to deficient 5, 10-methylenetetrahydrofolate reductase activity. N Eng J Med. 1975; 292: 491–496.CrossRefGoogle Scholar
36. Fiso, S, Choi, S-W, Girelli, D et al. , A common mutation in the 5, 10-methylenetetrahydrofolate reductase gene affects genomic DNA methylation through an interaction with folate status. Proc Natl Acad Sci. 2002; 99: 5606–5611.Google Scholar
37. Gilbody, S, Lewis, S, Lightfoot, T. Methylenetetrahydrofolate reductase (MTHFR) genetic polymorphisms and psychiatric disorders: A HuGE Review. Am J Epidemiol. 2007; 165: 1–13.CrossRefGoogle ScholarPubMed
38. Goff, DC, Bottiglieri, T, Arning, E et al. , Folate, homocysteine and negative symptoms of schizophrenia. Am J Psychiatry. 2004; 161: 1705–1708.CrossRefGoogle Scholar
39. Godfrey, PSA, Toone, BK, Carney, MWB et al. , Enhancement of recovery from psychiatric illness by methylfolate. Lancet. 1990; 336: 392–395.CrossRefGoogle ScholarPubMed
40. Levine, J. Stahl, Z, Sela, B-A et al. , Homocysteine-reducing strategies improve symptoms in chronic schizophrenic patients with hyperhomocysteinemia. Biol Psychiatry. 2006; 60: 265–269.CrossRefGoogle ScholarPubMed
41. Roffman, JL, Weiss, AP, Deckersbach, T et al. , Effects of the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism on executive function in schizophrenia. Schizophr Res. 2007; 92: 181–188.CrossRefGoogle ScholarPubMed
42. Roffman, JL, Weiss, AP, Purcell, S et al. , Contribution of methylenetetrahydrofolate reductase (MTHFR) polymorphisms to negative symptoms in schizophrenia. Biol Psychiatry. 2008; 63: 42–48.CrossRefGoogle ScholarPubMed
43. Muntjewerff, J-W. Gellekink, H, den Heijer, M et al. , Polymorphisms in catechol-O-methyltransferase and methylenetetrahydrofolate reductase in relation to the risk of schizophrenia. Eur Neuropsychopharmacol. 2008; 18: 99–106.CrossRefGoogle Scholar
44. Muntjewerff, JW, Kahn, RS, Blom, HJ, den Heijer, M. Homocysteine, methylenetetrahydrofolate reductase and risk of schizophrenia: a meta analysis. Mol Psychiatr. 2006; 11: 143–149.CrossRefGoogle ScholarPubMed
45. Lewis, SJ, Zammit, S, Gunnell, D, Smith, GD. A meta analysis of the MTHFR C677T polymorphism and schizophrenia risk, Am J Med Genetics Part B. Neuropsychiatric Genetics. 2005; 135B: 2–4.CrossRefGoogle Scholar
46. Arinami, T, Yamada, N, Yamakawa-Kobayashi, K, Hamaguchi, H, Toru, M. Methylenete trahydrofolate reductase variant and schizophrenia/depression. Am J Med Genet B Neuropsychiatr Genet. 1997; 74: 526–528.3.0.CO;2-E>CrossRefGoogle Scholar
47. Roffman, JL, Gollub, RL, Calhoun, VD et al. , MTHFR 677C to T genotype disrupts prefrontal function in schizophrenia through an interactions with COMT 158 val to met. Proc Natl Acad Sci. 2008; 105: 17573–17578.CrossRefGoogle Scholar
48. Roffman, JL, Weiss, AP, Decersbach, T et al. , Interactive effects of COMT val108/158Met and MTHFR C677T on executive function in schizophrenia. Am J Med Genet B Neuropsychiatr Genet. 2008; 147B: 990–995.CrossRefGoogle ScholarPubMed
49. Kempisty, B, Skiora, J, Lianeri, M et al. , MTHFD 1958G>A and MTR 2756A>G polymorphisms are associated with bipolar disorder and schizophrenia. Psychiatr Genet. 2007; 17: 177–181.CrossRefGoogle Scholar
50. Picker, JD, Coyle, JT. Do maternal folate and homocysteine levels play a role in neurodevelopmental processes that increase risk for schizophrenia? Harvard Rev Psychiatry. 2005; 13: 197–205.CrossRefGoogle ScholarPubMed
51. Brown, AD, Susser, ES. Prenatal nutritional deficiency and risk of adult schizophrenia. Schiz Bull. 2008; 34: 1054–1063.CrossRefGoogle ScholarPubMed
52. Brown, AS, Bottiglieri, T, Schaefer, CA et al. , Elevated prenatal homocysteine levels as a risk factor for schizophrenia. Arch Gen Psychiatry. 2007; 64: 31–39.CrossRefGoogle ScholarPubMed
53. Jiang, Y, Sun, T, Xiong, J, Cao, J, Li, G, Wang, S. Hyperhomocysteinemia-mediated DNA hypomethylation and its potential epigenetic role in rats. Acta Biochim Biophys Sin (Shanghai). 2007; 39: 657–667.CrossRefGoogle ScholarPubMed
54. Fan, G, Beard, C, Chen, RZ et al. , DNA hypomethylation perturbs the function and survival of CNS neurons in postnatal animals. J Neurosci. 2001; 21: 788–797.CrossRefGoogle ScholarPubMed
55. Ingrosso, D, Cimmino, A, Perna, AF et al. , Folate treatment and unbalanced methylation and changes of allelic expression induced by hyperhomocyseinemia in patients with uraemia. Lancet. 2003; 361: 1693–1699.CrossRefGoogle Scholar
56. Obeid, R, McCaddon, A, Herrmann, W. The role of hyperhomocysteinemia and B-vitamin deficiency in neurological and psychiatric diseases. Clin Chem Lab Med. 2007; 45: 1590–1606.CrossRefGoogle ScholarPubMed
57. Blount, BC, Mack, MM, Wehr, CM et al. , Folate deficiency causes uracil misincorporation into DNA and chromosome breakage: implications for cancer and neuronal damage. Proc Natl Acad Sci. 1997; 94: 3290–3295.CrossRefGoogle ScholarPubMed
58. Nagothu, KK, Rishi, AK, Jaszewski, R, Kucuk, O, Najumdar, APN. Folic acid-mediated inhibition of serum-induced activation of EGFR promoter in colon cancer cells. Am J Phusiol Gastrointest Liver Physiol. 2004; 287: G541–G546.CrossRefGoogle ScholarPubMed
59. Henning, SM, Swendseid, ME, Coulson, WF. Male rats fed methyl- and folate-deficient diets with or without niacin develop hepatic carcinomas associated with decreased tissue NAD concentrations and altered poly (ADP-ribose) polymerase activity. J Nutr. 1997; 127: 30–36.CrossRefGoogle ScholarPubMed
60. Pogribny, IP, James, SJ. De Novo methylation of the; 16INK4A gene in early preneoplastic liver and tumors induced by folate/methyl deficiency in rats. Cancer Lett. 2002; 187: 69–75.CrossRefGoogle Scholar
61. Pogribny, IP, Poirier, LA, James, SJ. Differential sensitivity to loss of cytosine methyl groups within the hepatic p53 gene of folate/methyl deficient rats. Carcinogenesis. 1995; 16: 2863–2867.CrossRefGoogle ScholarPubMed