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Genetics and Epigenetics in Major Psychiatric Disorders

Dilemmas, Achievements, Applications, and Future Scope

American Journal of Pharmacogenomics volume 5, pages 149–160 (2005)Cite this article

Abstract

No specific gene has been identified for any major psychiatric disorder, including schizophrenia, in spite of strong evidence supporting a genetic basis for these complex and devastating disorders. There are several likely reasons for this failure, ranging from poor study design with low statistical power to genetic mechanisms such as polygenic inheritance, epigenetic interactions, and pleiotropy. Most study designs currently in use are inadequate to uncover these mechanisms. However, to date, genetic studies have provided some valuable insight into the causes and potential therapies for psychiatric disorders.

There is a growing body of evidence suggesting that the understanding of the genetic etiology of psychiatric illnesses, including schizophrenia, will be more successful with integrative approaches considering both genetic and epigenetic factors. For example, several genes including those encoding dopamine receptors (DRD2, DRD3, and DRD4), serotonin receptor 2A (HTR2A) and catechol-O-methyltransferase (COMT) have been implicated in the etiology of schizophrenia and related disorders through meta-analyses and large, multicenter studies. There is also growing evidence for the role of DRD1, NMDA receptor genes (GRIN1, GRIN2A, GRIN2B), brain-derived neurotrophic factor (BDNF), and dopamine transporter (SLC6A3) in both schizophrenia and bipolar disorder. Recent studies have indicated that epigenetic modification of reelin (RELN), BDNF, and the DRD2 promoters confer susceptibility to clinical psychiatric conditions.

Pharmacologic therapy of psychiatric disorders will likely be more effective once the molecular pathogenesis is known. For example, the hypoactive alleles of DRD2 and the hyperactive alleles of COMT, which degrade the dopamine in the synaptic cleft, are associated with schizophrenia. It is likely that insufficient dopaminergic transmission in the frontal lobe plays a role in the development of negative symptoms associated with this disorder. Antipsychotic therapies with a partial dopamine D2 receptor agonist effect may be a plausible alternative to current therapies, and would be effective in symptom reduction in psychotic individuals. It is also possible that therapies employing dopamine D1/D2 receptor agonists or COMT inhibitors will be beneficial for patients with negative symptoms in schizophrenia and bipolar disorder. The complex etiology of schizophrenia, and other psychiatric disorders, warrants the consideration of both genetic and epigenetic systems and the careful design of experiments to illumine the genetic mechanisms conferring liability for these disorders and the benefit of existing and new therapies.

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References

  1. Pyeritz RE. Pleiotropy revisited: molecular explanations of a classic concept. Am J Med Genet 1989 Sep; 34(1): 124–34

    Article  PubMed  CAS  Google Scholar 

  2. Bird A. DNA methylation patterns and epigenetic memory. Genes Dev 2002; 16: 6–21

    Article  PubMed  CAS  Google Scholar 

  3. Blum K, Noble E. Psychiatric genetics. New York: CRP Press, 1997

    Google Scholar 

  4. Golimbet VE, Aksenova MG, Nosikov VV, et al. Analysis of the linkage of the Taq1A and Taq1B loci of the dopamine D2 receptor gene with schizophrenia in patients and their siblings. Neurosci Behav Physiol 2003 Mar; 33(3): 223–5

    Article  PubMed  CAS  Google Scholar 

  5. Zhou W, Cunningham KA, Thomas ML. Estrogen regulation of gene expression in the brain: a possible mechanism altering the response to psychostimulants in female rats. Brain Res Mol Brain Res 2002 Apr 30; 100(1–2): 75–83

    Article  PubMed  CAS  Google Scholar 

  6. Shifman S, Bronstein M, Sternfeld M, et al. A highly significant association between a COMT haplotype and schizophrenia. Am J Hum Genet 2002 Dec; 71(6): 1296–302

    Article  PubMed  CAS  Google Scholar 

  7. Jiang H, Xie T, Ramsden DB, et al. Human catechol-O-methyltransferase down-regulation by estradiol. Neuropharmacology 2003 Dec; 45(7): 1011–8

    Article  PubMed  CAS  Google Scholar 

  8. Wilcox MA, Faraone SV, Ju J, et al. Genome scan of three quantitative traits in schizophrenia pedigrees. Biol Psychiatry 2002; 52: 847–54

    Article  PubMed  CAS  Google Scholar 

  9. Nestadt G, Addington A, Samuels J, et al. The identification of OCD-related subgroups based on comorbidity. Biol Psychiatry 2003 May 15; 53(10): 914–20

    Article  PubMed  Google Scholar 

  10. Eichstedt JA, Arnold SL. Childhood-onset obsessive-compulsive disorder: a ticrelated subtype of OCD? Clin Psychol Rev 2001 Feb; 21(1): 137–57

    Article  PubMed  CAS  Google Scholar 

  11. Jiang YH, Bressler J, Beaudet AL. Epigenetics and human disease. Annu Rev Genomics Hum Genet 2004; 5: 479–510

    Article  PubMed  CAS  Google Scholar 

  12. Saddock B, Saddock V. Kaplan and Sadock’s comprehensive textbook of psychiatry. 7th ed. Vol. 1. Philadelphia (PA): Lippincott Williams & Wilkins, 2000: 3344

    Google Scholar 

  13. Bester TH. The DNA methyltransferases of mammals. Hum Mol Genet 2000; 9: 2395–402

    Article  Google Scholar 

  14. Abdolmaleky HM, Smith CL, Faraone SV, et al. Methylomics in psychiatry: modulation of gene-environment interactions may be through DNA methylation. Am J Med Genet 2004 May 15; 127B(1): 51–9

    Article  PubMed  Google Scholar 

  15. Comings DE, Blum K. Reward deficiency syndrome: genetic aspects of behavioral disorders. Prog Brain Res 2000; 126: 325–41

    Article  PubMed  CAS  Google Scholar 

  16. Williams NM, Norton N, Williams H, et al. A systematic genomewide linkage study in 353 sib pairs with schizophrenia. Am J Hum Genet 2003 Dec; 73(6): 1355–67

    Article  PubMed  CAS  Google Scholar 

  17. Takahashi S, Ohtsuki T, Yu SY, et al. Significant linkage to chromosome 22q for exploratory eye movement dysfunction in schizophrenia. Am J Med Genet 2003 Nov 15; 123B(1): 27–32

    Article  PubMed  Google Scholar 

  18. Chen X, Wang X, O’Neill AF, et al. Variants in the catechol-o-methyltransferase (COMT) gene are associated with schizophrenia in Irish high-density families. Mol Psychiatry 2004; 9(10): 962–7

    Article  PubMed  CAS  Google Scholar 

  19. Rosa A, Peralta V, Cuesta MJ, et al. New evidence of association between COMT gene and prefrontal neurocognitive function in healthy individuals from sibling pairs discordant for psychosis. Am J Psychiatry 2004 Jun; 161(6): 1110–2

    Article  PubMed  Google Scholar 

  20. Eley TC, Tahir E, Angleitner A, et al. Association analysis of MAOA and COMT with neuroticism assessed by peers. Am J Med Genet 2003 Jul 1; 120B(1): 90–6

    Article  PubMed  Google Scholar 

  21. Lachman HM, Papolos DF, Saito T, et al. Human catechol-O-methyltransferase pharmacogenetics: description of a functional polymorphism and its potential application to neuropsychiatric disorders. Pharmacogenetics 1996 Jun; 6(3): 243–50

    Article  PubMed  CAS  Google Scholar 

  22. Glatt SJ, Faraone SV, Tsuang MT. Association between a functional catechol O-methyltransferase gene polymorphism and schizophrenia: meta-analysis of case-control and family-based studies. Am J Psychiatry 2003 Mar; 160(3): 469–76

    Article  PubMed  Google Scholar 

  23. Azzam A, Mathews CA. Meta-analysis of the association between the catecho-lamine-O-methyl-transferase gene and obsessive-compulsive disorder. Am J Med Genet 2003 Nov 15; 123B(1): 64–9

    Article  PubMed  Google Scholar 

  24. Massat I, Souery D, Del-Favero J, et al. Association between COMT (Val (158)Met) functional polymorphism and early onset in patients with major depressive disorder in a European multicenter genetic association study. Mol Psychiatry 2004 Dec 07, [Epub ahead of print]

    Google Scholar 

  25. Matsumoto M, Weickert CS, Beltaifa S, et al. Catechol O-methyltransferase (COMT) mRNA expression in the dorsolateral prefrontal cortex of patients with schizophrenia. Neuropsychopharmacology 2003 Aug; 28(8): 1521–30

    Article  PubMed  CAS  Google Scholar 

  26. Tunbridge E, Burnet PW, Sodhi MS, et al. Catechol-o-methyltransferase (COMT) and proline dehydrogenase (PRODH) mRNAs in the dorsolateral prefrontal cortex in schizophrenia, bipolar disorder, and major depression. Synapse 2004 Feb; 51(2): 112–8

    Article  PubMed  CAS  Google Scholar 

  27. Egan MF, Goldberg TE, Kolachana BS, et al. Effect of COMT Val108/158 Met genotype on frontal lobe function and risk for schizophrenia. Proc Natl Acad Sci U S A 2001 Jun 5; 98(12): 6917–22

    Article  PubMed  CAS  Google Scholar 

  28. Kasper S, Barnas C, Heiden A, et al. Pramipexole as adjunct to haloperidol in schizophrenia: safety and efficacy. Eur Neuropsychopharmacol 1997 Feb; 7(1): 65–70

    Article  PubMed  CAS  Google Scholar 

  29. Greenwood TA, Alexander M, Keck PE, et al. Evidence for linkage disequilibrium between the dopamine transporter and bipolar disorder. Am J Med Genet 2001 Mar 8; 105(2): 145–51

    Article  PubMed  CAS  Google Scholar 

  30. Georgieva L, Dimitrova A, Nikolov I, et al. Dopamine transporter gene (DAT1) VNTR polymorphism in major psychiatric disorders: family-based association study in the Bulgarian population. Acta Psychiatr Scand 2002 May; 105(5): 396–9

    Article  PubMed  CAS  Google Scholar 

  31. Khodayari N, Garshasbi M, Fadai F, et al. Association of the dopamine transporter gene (DAT1) core promoter polymorphism-67T variant with schizophrenia. Am J Med Genet B Neuropsychiatr Genet 2004 Aug 15; 129B(1): 10–2

    Article  PubMed  CAS  Google Scholar 

  32. Huang YY, Simpson E, Kellendonk C, et al. Genetic evidence for the bidirectional modulation of synaptic plasticity in the prefrontal cortex by D1 receptors. Proc Natl Acad Sci U S A 2004 Mar 2; 101(9): 3236–41

    Article  PubMed  CAS  Google Scholar 

  33. Centonze D, Grande C, Saulle E, et al. Distinct roles of D1 and D5 dopamine receptors in motor activity and striatal synaptic plasticity. J Neurosci 2003 Sep 17; 23(24): 8506–12

    PubMed  CAS  Google Scholar 

  34. Chen G, Greengard P, Yan Z. Potentiation of NMDA receptor currents by dopamine D1 receptors in prefrontal cortex. Proc Natl Acad Sci U S A 2004 Feb 24; 101(8): 2596–600

    Article  PubMed  CAS  Google Scholar 

  35. Fang H, Chartier J, Sodja C, et al. Transcriptional activation of the human brain-derived neurotrophic factor gene promoter III by dopamine signaling in NT2/N neurons. J Biol Chem 2003; 278(29): 26401–9

    Article  PubMed  CAS  Google Scholar 

  36. Ni X, Trakalo JM, Mundo E, et al. Linkage disequilibrium between dopamine D1 receptor gene (DRD1) and bipolar disorder. Biol Psychiatry 2002 Dec 15; 52(12): 1144–50

    Article  PubMed  CAS  Google Scholar 

  37. Goldberg JF, Burdick KE, Endick CJ. Preliminary randomized, double-blind, placebo-controlled trial of pramipexole added to mood stabilizers for treatment-resistant bipolar depression. Am J Psychiatry 2004 Mar; 161(3): 564–6

    Article  PubMed  Google Scholar 

  38. Zarate CA, Payne JL, Singh J, et al. Pramipexole for bipolar II depression: a placebo-controlled proof of concept study. Biol Psychiatry 2004 Jul 1; 56(1): 54–60

    Article  PubMed  CAS  Google Scholar 

  39. Tallerico T, Novak G, Liu IS, et al. Schizophrenia: elevated mRNA for dopamine D2 (Longer) receptors in frontal cortex. Brain Res Mol Brain Res 2001 Mar 5; 87(2): 160–5

    Article  PubMed  CAS  Google Scholar 

  40. Lewis CM, Levinson DF, Wise LH, et al. Genome scan meta-analysis of schizophrenia and bipolar disorder: part II. Schizophrenia. Am J Hum Genet 2003 Jul; 73(1): 34–48

    Article  PubMed  CAS  Google Scholar 

  41. Glatt SJ, Faraone SV, Tsuang MT. Meta-analysis identifies an association between the dopamine D2 receptor gene and schizophrenia. Mol Psychiatry 2003 Nov; 8(11): 911–5

    Article  PubMed  CAS  Google Scholar 

  42. Popendikyte V, Laurinavicius A, Paterson AD, et al. DNA methylation at the putative promoter region of the human dopamine D2 receptor gene. Neuroreport 1999; 10: 1249–55

    Article  PubMed  CAS  Google Scholar 

  43. Petronis A, Gottesman II, Kan P, et al. Monozygotic twins exhibit numerous epigenetic differences: clues to twin discordance? Schizophr Bull 2003; 29(1): 169–78

    Article  PubMed  Google Scholar 

  44. Li J, Guo Y, Schroeder FA, et al. Dopamine D2-like antagonists induce chromatin remodeling in striatal neurons through cyclic AMP-protein kinase A and NMDA receptor signaling. J Neurochem 2004 Sep; 90(5): 1117–31

    Article  PubMed  CAS  Google Scholar 

  45. Dubertret C, Gorwood P, Ades J, et al. Meta-analysis of DRD3 gene and schizophrenia: ethnic heterogeneity and significant association in Caucasians. Am J Med Genet 1998 Jul 10; 81(4): 318–22

    Article  PubMed  CAS  Google Scholar 

  46. Jonsson EG, Flyckt L, Burgert E, et al. Dopamine D3 receptor gene Ser9Gly variant and schizophrenia: association study and meta-analysis. Psychiatr Genet 2003 Mar; 13(1): 1–12

    Article  PubMed  Google Scholar 

  47. Jonsson EG, Sedvall GC, Nothen MM, et al. Dopamine D4 receptor gene (DRD4) variants and schizophrenia: meta-analyses. Schizophr Res 2003 May 1; 61(1): 111–9

    Article  PubMed  Google Scholar 

  48. Glatt SJ, Faraone SV, Tsuang MT. Schizophrenia is not associated with DRD4 48-base-pair-repeat length or individual alleles: results of a meta-analysis. Biol Psychiatry 2003 Sep 15; 54(6): 629–35

    Article  PubMed  CAS  Google Scholar 

  49. Serretti A, Lilli R, Lorenzi C, et al. DRD4 exon 3 variants associated with delusional symptomatology in major psychoses: a study on 2,011 affected subjects. Am J Med Genet 2001; 105: 283–90

    Article  PubMed  CAS  Google Scholar 

  50. Maher BS, Marazita ML, Ferrell RE, et al. Dopamine system genes and attention deficit hyperactivity disorder: a meta-analysis. Psychiatr Genet 2002 Dec; 12(4): 207–15

    Article  PubMed  Google Scholar 

  51. Faraone SV, Doyle AE, Mick E, et al. Meta-analysis of the association between the 7-repeat allele of the dopamine D (4) receptor gene and attention deficit hyperactivity disorder. Am J Psychiatry 2001 Jul; 158(7): 1052–7

    Article  PubMed  CAS  Google Scholar 

  52. Ghosh A, Carnahan J, Greenberg ME. Requirement for BDNF in activity-dependent survival of cortical neurons. Science 1994 Mar 18; 263(5153): 1618–23

    Article  PubMed  CAS  Google Scholar 

  53. Chen B, Dowlatshahi D, MacQueen GM, et al. Increased hippocampal BDNF immunoreactivity in subjects treated with antidepressant medication. Biol Psychiatry 2001 Aug 15; 50(4): 260–5

    Article  PubMed  CAS  Google Scholar 

  54. Neves-Pereira M, Mundo E, Muglia P, et al. The brain-derived neurotrophic factor gene confers susceptibility to bipolar disorder: evidence from a family-based association study. Am J Hum Genet 2002 Sep; 71(3): 651–5

    Article  PubMed  CAS  Google Scholar 

  55. Sklar P, Gabriel SB, Mclnnis MG, et al. Family-based association study of 76 candidate genes in bipolar disorder: BDNF is a potential risk locus: brain-derived neutrophic factor. Mol Psychiatry 2002; 7(6): 579–93

    Article  PubMed  CAS  Google Scholar 

  56. Hall D, Dhilla A, Charalambous A, et al. Sequence variants of the brain-derived neurotrophic factor (BDNF) gene are strongly associated with obsessive-compulsive disorder. Am J Hum Genet 2003 Aug; 73(2): 370–6

    Article  PubMed  CAS  Google Scholar 

  57. Lang UE, Hellweg R, Kalus P, et al. Association of a functional BDNF polymorphism and anxiety-related personality traits. Psychopharmacology (Berl) 2005 Jan 26, [Epub ahead of print]

    Google Scholar 

  58. Roceri M, Hendriks W, Racagni G, et al. Early maternal deprivation reduces the expression of BDNF and NMDA receptor subunits in rat hippocampus. Mol Psychiatry 2002; 7(6): 609–16

    Article  PubMed  CAS  Google Scholar 

  59. Fanous AH, Neale MC, Straub RE, et al. Clinical features of psychotic disorders and polymorphisms in HT2A, DRD2, DRD4, SLC6A3 (DAT1), and BDNF: a family based association study. Am J Med Genet 2004 Feb 15; 125B(1): 69–78

    Article  PubMed  Google Scholar 

  60. Szekeres G, Juhasz A, Rimanoczy A, et al. The C270T polymorphism of the brain-derived neurotrophic factor gene is associated with schizophrenia. Schizophr Res 2003 Dec 1; 65(1): 15–8

    Article  PubMed  Google Scholar 

  61. Shirayama Y, Chen AC, Nakagawa S, et al. Brain-derived neurotrophic factor produces antidepressant effects in behavioral models of depression. J Neurosci 2002 Apr 15; 22(8): 3251–61

    PubMed  CAS  Google Scholar 

  62. Altar CA. Neurotrophins and depression. Trends Pharmacol Sci 1999 Feb; 20(2): 59–61

    Article  PubMed  CAS  Google Scholar 

  63. Luo C, Xu H, Li XM. Post-stress changes in BDNF and Bcl-2 immunoreactivities in hippocampal neurons: effect of chronic administration of olanzapine. Brain Res 2004 Oct 29; 1025(1–2): 194–202

    Article  PubMed  CAS  Google Scholar 

  64. Fumagalli F, Molteni R, Roceri M, et al. Effect of antipsychotic drugs on brain-derived neurotrophic factor expression under reduced N-methyl-D-aspartate receptor activity. J Neurosci Res 2003 Jun 1; 72(5): 622–8

    Article  PubMed  CAS  Google Scholar 

  65. Chen WG, Chang Q, Lin Y, et al. Depression of BDNF transcription involves calcium-dependent phosphorylation of MeCP2. Science 2003 Oct 31; 302(5646): 885–9

    Article  PubMed  CAS  Google Scholar 

  66. Fatemi SH, Earle JA, McMenomy T. Reduction in Reelin immunoreactivity in hippocampus of subjects with schizophrenia, bipolar disorder and major depression. Mol Psychiatry 2000; 5: 654–63, 571

    Article  PubMed  CAS  Google Scholar 

  67. Fatemi SH. Reelin glycoprotein: structure, biology and roles in health and disease. Mol Psychiatry 2004 Dec 7, [Epub ahead of print]

    Google Scholar 

  68. Pesold C, Liu WS, Guidotti A, et al. Cortical bitufted, horizontal, and Martinotti cells preferentially express and secrete reelin into perineuronal nets, nonsynaptically modulating gene expression. Proc Natl Acad Sci U S A 1999 Mar 16; 96(6): 3217–22

    Article  PubMed  CAS  Google Scholar 

  69. Homayouni R, Magdaleno S, Keshvara L, et al. Interaction of disabled-1 and the GTPase activating protein Dab2IP in mouse brain. Brain Res Mol Brain Res 2003 Jul 23; 115(2): 121–9

    Article  PubMed  CAS  Google Scholar 

  70. DeSilva U, D’Arcangelo G, Braden VV, et al. The human reelin gene: isolation, sequencing, and mapping on chromosome 7. Genome Res 1997 Feb; 7(2): 157–64

    Article  PubMed  CAS  Google Scholar 

  71. Chen Y, Sharma RP, Costa RH, et al. On the epigenetic regulation of the human reelin promoter. Nucleic Acids Res 2002; 30: 2930–9

    Article  PubMed  CAS  Google Scholar 

  72. Tremolizzo L, Carboni G, Ruzicka WB, et al. An epigenetic mouse model for molecular and behavioral neuropathologies related to schizophrenia vulnerability. Proc Natl Acad Sci U S A 2002 Dec 24; 99(26): 17095–100

    Article  PubMed  CAS  Google Scholar 

  73. Impagnatiello F, Guidotti AR, Pesold C, et al. A decrease of reelin expression as a putative vulnerability factor in schizophrenia. Proc Natl Acad Sci U S A 1998 Dec 22; 95(26): 15718–23

    Article  PubMed  CAS  Google Scholar 

  74. Guidotti A, Auta J, Davis JM, et al. Decrease in reelin and glutamic acid decarboxylase67 (GAD67) expression in schizophrenia and bipolar disorder: a postmortem brain study. Arch Gen Psychiatry 2000 Nov; 57(11): 1061–9

    Article  PubMed  CAS  Google Scholar 

  75. Manev H, Uz T. DNA hypomethylating agents 5-aza-2′-deoxycytidine and valproate increase neuronal 5-lipoxygenase mRNA. Eur J Pharmacol 2002 Jun 7; 445(1–2): 149–50

    Article  PubMed  CAS  Google Scholar 

  76. Veldic M, Caruncho HJ, Liu WS, et al. DNA-methyltransferase 1 mRNA is selectively overexpressed in telencephalic GABAergic interneurons of schizophrenia brains. Proc Natl Acad Sci U S A 2004 Jan 6; 101(1): 348–53

    Article  PubMed  CAS  Google Scholar 

  77. Abdolmaleky HM, Cheng K-H, Russo A, et al. Hypermethylation of the Reelin (RELN) promoter in the brain of schizophrenic patients: a preliminary report. Am J Med Genet 2005 Feb. Epub ahead of print

    Google Scholar 

  78. Zhu WG, Otterson GA. The interaction of histone deacetylase inhibitors and DNA methyltransferase inhibitors in the treatment of human cancer cells. Curr Med Chem Anti-Cane Agents 2003 May; 3(3): 187–99

    Article  CAS  Google Scholar 

  79. Fang MZ, Wang Y, Ai N, et al. Tea polyphenol (−)-epigallocatechin-3-gallate inhibits DNA methyltransferase and reactivates methylation-silenced genes in cancer cell lines. Cancer Res 2003 Nov 15; 63(22): 7563–70

    PubMed  CAS  Google Scholar 

  80. Kandel ER. The molecular biology of memory storage: a dialogue between genes and synapses. Science 2001; 294: 1030–8

    Article  PubMed  CAS  Google Scholar 

  81. Gershon ES, Badner JA. Progress toward discovery of susceptibility genes for bipolar manic-depressive illness and schizophrenia. CNS Spectr 2002 Dec; 7(12): 965–8

    Google Scholar 

  82. Williams J, McGuffin P, Nothen M, et al. Meta-analysis of association between the 5-HT2a receptor T102C polymorphism and schizophrenia [letter]. EMASS Collaborative Group. European Multicentre Association Study of Schizophrenia. Lancet 1997 Apr 26; 349(9060): 1221

    Article  PubMed  CAS  Google Scholar 

  83. Khait VD, Huang YY, Zalsman G, et al. Association of serotonin 5-HT2A receptor binding and the T102C polymorphism in depressed and healthy Caucasian subjects. Neuropsychopharmacology 2005 Jan; 30(1): 166–72

    Article  PubMed  CAS  Google Scholar 

  84. Polesskaya OO, Sokolov BP. Differential expression of the “C” and “T” alleles of the 5-HT2A receptor gene in the temporal cortex of normal individuals and schizophrenics. J Neurosci Res 2002; 67: 812–22

    Article  PubMed  CAS  Google Scholar 

  85. Arranz M, Collier D, Sodhi M, et al. Association between clozapine response and allelic variation in 5-HT2A receptor gene. Lancet 1995 Jul 29; 346(8970): 281–2

    Article  PubMed  CAS  Google Scholar 

  86. Yu YW, Tsai SJ, Yang KH, et al. Evidence for an association between polymorphism in the serotonin-2A receptor variant (102T/C) and increment of N100 amplitude in schizophrenics treated with clozapine. Neuropsychobiology 2001; 43(2): 79–82

    Article  PubMed  CAS  Google Scholar 

  87. Petronis A. The genes for major psychosis: aberrant sequence or regulation? Neuropsychopharmacology 2000; 23: 1–12

    Article  PubMed  CAS  Google Scholar 

  88. Attwood JT, Yung RL, Richardson BC. DNA methylation and the regulation of gene transcription. Cell Mol Life Sci 2002; 59: 241–57

    Article  PubMed  CAS  Google Scholar 

  89. Watson RE, Goodman JI. Epigenetics and DNA methylation come of age in toxicology. Toxicol Sci 2002; 67: 11–6

    Article  PubMed  CAS  Google Scholar 

  90. Ngo V, Gourdji D, Laverriere JN. Site-specific methylation of the rat prolactin and growth hormone promoters correlates with gene expression. Mol Cell Biol 1996; 16: 3245–54

    PubMed  CAS  Google Scholar 

  91. Duan J, Wainwright MS, Comeron JM, et al. Synonymous mutations in the human dopamine receptor D2 (DRD2) affect mRNA stability and synthesis of the receptor. Hum Mol Genet 2003 Feb 1; 12(3): 205–16

    Article  PubMed  CAS  Google Scholar 

  92. Joober R, Benkelfat C, Brisebois K, et al. T102C polymorphism in the 5HT2A gene and schizophrenia: relation to phenotype and drug response variability. J Psychiatry Neurosci 1999 Mar; 24(2): 141–6

    PubMed  CAS  Google Scholar 

  93. Tan EC, Chong SA, Mahendran R, et al. Susceptibility to neuroleptic-induced tardive dyskinesia and the T102C polymorphism in the serotonin type 2A receptor. Biol Psychiatry 2001 Jul 15; 50(2): 144–7

    Article  PubMed  CAS  Google Scholar 

  94. Segman RH, Heresco-Levy U, Finkel B, et al. Association between the serotonin 2A receptor gene and tardive dyskinesia in chronic schizophrenia. Mol Psychiatry 2001 Mar; 6(2): 225–9

    Article  PubMed  CAS  Google Scholar 

  95. Abdolmaleky HM, Faraone SV, Glatt SJ, et al. Meta-analysis of association between the T102C polymorphism of the 5HT2a receptor gene and schizophrenia. Schizophr Res 2004 Mar 1; 67(1): 53–62

    Article  PubMed  Google Scholar 

  96. Bunzel R, Blumcke I, Cichon S, et al. Polymorphic imprinting of the serotonin-2A (5-HT2A) receptor gene in human adult brain. Brain Res Mol Brain Res 1998 Aug 15; 59(1): 90–2

    Article  PubMed  CAS  Google Scholar 

  97. Nocjar C, Roth BL, Pehek EA. Localization of 5-HT (2A) receptors on dopamine cells in subnuclei of the midbrain A10 cell group. Neuroscience 2002; 111(1): 163–76

    Article  PubMed  CAS  Google Scholar 

  98. Martucci L, Wong AH, Trakalo J, et al. N-methyl-D-aspartate receptor NR1 subunit gene (GRIN1) in schizophrenia: TDT and case-control analyses. Am J Med Genet 2003 May 15; 119B(1): 24–7

    Article  PubMed  Google Scholar 

  99. Mohn AR, Gainetdinov RR, Caron MG, et al. Mice with reduced NMDA receptor expression display behaviors related to schizophrenia. Cell 1999 Aug 20; 98(4): 427–36

    Article  PubMed  CAS  Google Scholar 

  100. Rice SR, Niu N, Berman DB, et al. Identification of single nucleotide polymorphisms (SNPs) and other sequence changes and estimation of nucleotide diversity in coding and flanking regions of the NMDAR1 receptor gene in schizophrenic patients. Mol Psychiatry 2001 May; 6(3): 274–84

    Article  PubMed  CAS  Google Scholar 

  101. Nishiguchi N, Shirakawa O, Ono H, et al. Novel polymorphism in the gene region encoding the carboxyl-terminal intracellular domain of the NMDA receptor 2B subunit: analysis of association with schizophrenia. Am J Psychiatry 2000 Aug; 157(8): 1329–31

    Article  PubMed  CAS  Google Scholar 

  102. Hung CC, Chen HY, Chen CH. Systematic mutation analysis of the human glutamate receptor, ionotropic, N-methyl-D-aspartate 1 gene (GRIN1) in schizophrenic patients. Psychiatr Genet 2002 Dec; 12(4): 225–30

    Article  PubMed  Google Scholar 

  103. Ohtsuki T, Sakurai K, Dou H, et al. Mutation analysis of the NMDAR2B (GRIN2B) gene in schizophrenia. Mol Psychiatry 2001 Mar; 6(2): 211–6

    Article  PubMed  CAS  Google Scholar 

  104. Di Maria E, Gulli R, Begni S, et al. Variations in the NMDA receptor subunit 2B gene (GRIN2B) and schizophrenia: a case-control study. Am J Med Genet 2004 Jul 1; 128B(1): 27–9

    Article  PubMed  Google Scholar 

  105. Itokawa M, Yamada K, Yoshitsugu K, et al. A microsatellite repeat in the promoter of the N-methyl-D-aspartate receptor 2A subunit (GRIN2A) gene suppresses transcriptional activity and correlates with chronic outcome in schizophrenia. Pharmacogenetics 2003 May; 13(5): 271–8

    Article  PubMed  CAS  Google Scholar 

  106. Itokawa M, Yamada K, Iwayama-Shigeno Y, et al. Genetic analysis of a functional GRIN2A promoter (GT)n repeat in bipolar disorder pedigrees in humans. Neurosci Lett 2003 Jul 10; 345(1): 53–6

    Article  PubMed  CAS  Google Scholar 

  107. Mundo E, Tharmalingham S, Neves-Pereira M, et al. Evidence that the N-methyl-D-aspartate subunit 1 receptor gene (GRIN1) confers susceptibility to bipolar disorder. Mol Psychiatry 2003 Feb; 8(2): 241–5

    Article  PubMed  CAS  Google Scholar 

  108. Coyle JT, Tsai G, Goff DC. Ionotropic glutamate receptors as therapeutic targets in schizophrenia. Curr Drug Targets CNS Neurol Disord 2002 Apr; 1(2): 183–9

    Article  PubMed  CAS  Google Scholar 

  109. Lee FJ, Liu F. Direct interactions between NMDA and D1 receptors: a tale of tails. Biochem Soc Trans 2004 Dec; 32 (Pt 6): 1032–6

    Article  PubMed  CAS  Google Scholar 

  110. Chung YC, Li Z, Dai J, et al. Clozapine increases both acetylcholine and dopamine release in rat ventral hippocampus: role of 5-HT1A receptor agonism. Brain Res 2004 Oct 8; 1023(1): 54–63

    Article  PubMed  CAS  Google Scholar 

  111. Vanable PA, Carey MP, Carey KB, et al. Smoking among psychiatric outpatients: relationship to substance use, diagnosis, and illness severity. Psychol Addict Behav 2003 Dec; 17(4): 259–65

    Article  PubMed  Google Scholar 

  112. Jardemark K, Marcus MM, Konradsson A, et al. The combination of nicotine with the D2 antagonist raclopride or the weak D4 antagonist L-745,870 generates a clozapine-like facilitation of NMDA receptor-mediated neurotransmission in pyramidal cells of the rat medial prefrontal cortex. Int J Neuropsychopharmacol 2005 Jan; 8(2): 157–62

    Article  PubMed  CAS  Google Scholar 

  113. Shinkai T, Ohmori O, Hori H, et al. Allelic association of the neuronal nitric oxide synthase (NOS1) gene with schizophrenia. Mol Psychiatry 2002; 7(6): 560–3

    Article  PubMed  CAS  Google Scholar 

  114. Mimmack ML, Ryan M, Baba H, et al. Gene expression analysis in schizophrenia: reproducible up-regulation of several members of the apolipoprotein L family located in a high-susceptibility locus for schizophrenia on chromosome 22. Proc Natl Acad Sci U S A 2002 Apr 2; 99(7): 4680–5

    Article  PubMed  CAS  Google Scholar 

  115. Stefansson H, Sigurdsson E, Steinthorsdottir V, et al. Neuregulin 1 and susceptibility to schizophrenia. Am J Hum Genet 2002 Oct; 71(4): 877–92

    Article  PubMed  Google Scholar 

  116. Yang Y, Xiao Z, Chen W, et al. Tumor suppressor gene TP53 is genetically associated with schizophrenia in the Chinese population. Neurosci Lett 2004 Oct 14; 369(2): 126–31

    Article  PubMed  CAS  Google Scholar 

  117. Harrison PJ, Weinberger DR. Schizophrenia genes, gene expression, and neuropathology: on the matter of their convergence. Mol Psychiatry 2005 Jan; 10(1): 40–68

    Article  PubMed  CAS  Google Scholar 

  118. Mizoguchi K, Ishige A, Takeda S, et al. Endogenous glucocorticoids are essential for maintaining prefrontal cortical cognitive function. J Neurosci 2004 Jun 16; 24(24): 5492–9

    Article  PubMed  CAS  Google Scholar 

  119. Akil M, Kolachana BS, Rothmond DA, et al. Catechol-O-methyltransferase genotype and dopamine regulation in the human brain. J Neurosci 2003 Mar 15; 23(6): 2008–13

    PubMed  CAS  Google Scholar 

  120. Perugi G, Toni C, Ruffolo G, et al. Adjunctive dopamine agonists in treatment-resistant bipolar II depression: an open case series. Pharmacopsychiatry. 2001 Jul; 34(4): 137–41

    Article  PubMed  CAS  Google Scholar 

  121. Kupsch A, Trottenberg T, Bremen D. Levodopa therapy with entacapone in daily clinical practice: results of a post-marketing surveillance study. Curr Med Res Opin 2004 Jan; 20(1): 115–20

    Article  PubMed  CAS  Google Scholar 

  122. Moreau JL, Borgulya J, Jenck F, et al. Tolcapone: a potential new antidepressant detected in a novel animal model of depression. Behav Pharmacol 1994 Jun; 5(3): 344–50

    Article  PubMed  CAS  Google Scholar 

  123. Tunbridge EM, Bannerman DM, Sharp T, et al. Catechol-O-methyltransferase inhibition improves set-shifting performance and elevates stimulated dopamine release in the rat prefrontal cortex. J Neurosci 2004 Jun 9; 24(23): 5331–5

    Article  PubMed  CAS  Google Scholar 

  124. Fava M, Rosenbaum JF, Kolsky AR, et al. Open study of the catechol-O-methyltransferase inhibitor tolcapone in major depressive disorder. J Clin Psychopharmacol 1999 Aug; 19(4): 329–35

    Article  PubMed  CAS  Google Scholar 

  125. Moroz G, Magni G, Fava M. Update on “open study of the catechol-O-methyltransferase inhibitor tolcapone in major depressive disorder”. J Clin Psychopharmacol 2000 Apr; 20(2): 285

    Article  PubMed  CAS  Google Scholar 

  126. Szegedi A, Rujescu D, Tadic A, et al. The catechol-O-methyltransferase Val108/158Met polymorphism affects short-term treatment response to mirtazapine, but not to paroxetine in major depression. Pharmacogenomics J 2005; 5(1): 49–53

    Article  PubMed  CAS  Google Scholar 

  127. Bertolino A, Caforio G, Blasi G, et al. Interaction of COMT (Val (108/158)Met) genotype and olanzapine treatment on prefrontal cortical function in patients with schizophrenia. Am J Psychiatry 2004 Oct; 161(10): 1798–805

    Article  PubMed  Google Scholar 

  128. Mattay VS, Goldberg TE, Fera F, et al. Catechol-O-methyltransferase val158-met genotype and individual variation in the brain response to amphetamine. Proc Natl Acad Sci U S A 2003 May 13; 100(10): 6186–91

    Article  PubMed  CAS  Google Scholar 

  129. Goodnick PJ, Jerry JM. Aripiprazole: profile on efficacy and safety. Expert Opin Pharmacother 2002 Dec; 3(12): 1773–81

    Article  PubMed  CAS  Google Scholar 

  130. Swainston Harrison T, Perry CM. Aripiprazole: a review of its use in schizophrenia and schizoaffective disorder. Drugs 2004; 64(15): 1715–36

    Article  PubMed  Google Scholar 

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Acknowledgments

We thank Dr Stephen J. Glatt for his critical review of this manuscript.

This work was supported by grants from NIMH (R25MH60485) and NIH (ES10377 and CA101773).

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Authors and Affiliations

  1. Department of Psychiatry, Harvard Medical School at Massachusetts Mental Health Center, Boston, Massachusetts, USA

    Hamid M. Abdolmaleky & Marsha Wilcox

  2. Harvard Institute of Psychiatric Epidemiology and Genetics, Boston, Massachusetts, USA

    Hamid M. Abdolmaleky

  3. Departments of Genetics, and Pathology and Laboratory Medicine, Genomics, Boston University School of Medicine, Boston, Massachusetts, USA

    Hamid M. Abdolmaleky & Sam Thiagalingam

  4. Department of Psychiatry, Tehran Psychiatric Institute, Iran University of Medical Sciences, Tehran, Iran

    Hamid M. Abdolmaleky

  5. Division of Graduate Medical Sciences and Departments of Medicine (Genetics Program), Biostatistics, and Epidemiology, Boston University Schools of Medicine and Public Health, Boston, Massachusetts, USA

    Marsha Wilcox

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  1. Hamid M. Abdolmaleky
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  2. Sam Thiagalingam
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  3. Marsha Wilcox
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Correspondence to Hamid M. Abdolmaleky.

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Abdolmaleky, H.M., Thiagalingam, S. & Wilcox, M. Genetics and Epigenetics in Major Psychiatric Disorders. Am J Pharmacogenomics 5, 149–160 (2005). https://doi.org/10.2165/00129785-200505030-00002

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