Genetics and epigenetics in major psychiatric disorders - Dilemmas, achievements, applications, and future scope

被引:98
作者
Abdolmaleky, HM
Thiagalingam, S
Wilcox, M
机构
[1] Boston Univ, Sch Med & Publ Hlth, Dept Med, Genet Program, Boston, MA 02118 USA
[2] Boston Univ, Sch Med & Publ Hlth, Dept Biostat, Boston, MA 02118 USA
[3] Boston Univ, Sch Med & Publ Hlth, Dept Epidemiol, Boston, MA 02118 USA
[4] Boston Univ, Sch Med & Publ Hlth, Div Grad Med Sci, Boston, MA 02118 USA
[5] Harvard Univ, Sch Med, Massachusetts Mental Hlth Ctr, Dept Psychiat, Boston, MA 02115 USA
[6] Harvard Univ, Inst Psychiat Epidemiol & Genet, Boston, MA 02115 USA
[7] Boston Univ, Sch Med, Dept Genet, Boston, MA 02215 USA
[8] Boston Univ, Sch Med, Dept Pathol & Lab Med, Boston, MA 02215 USA
[9] Boston Univ, Sch Med, Dept Genom, Boston, MA 02215 USA
[10] Iran Univ Med Sci, Tehran Psychiat Inst, Dept Psychiat, Tehran, Iran
关键词
D O I
10.2165/00129785-200505030-00002
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
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 (GRIN], 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 D-2 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 D-1/D-2 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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页码:149 / 160
页数:12
相关论文
共 132 条
  • [51] Sequence variants of the brain-derived neurotrophic factor (BDNF) gene are strongly associated with obsessive-compulsive disorder
    Hall, D
    Dhilla, A
    Charalambous, A
    Gogos, JA
    Karayiorgou, M
    [J]. AMERICAN JOURNAL OF HUMAN GENETICS, 2003, 73 (02) : 370 - 376
  • [52] Schizophrenia genes, gene expression, and neuropathology: on the matter of their convergence
    Harrison, PJ
    Weinberger, DR
    [J]. MOLECULAR PSYCHIATRY, 2005, 10 (01) : 40 - 68
  • [53] Harrison TS, 2004, DRUGS, V64, P1715
  • [54] Interaction of disabled-1 and the GTPase activating protein Dab2IP in mouse brain
    Homayouni, R
    Magdaleno, S
    Keshvara, L
    Rice, DS
    Curran, T
    [J]. MOLECULAR BRAIN RESEARCH, 2003, 115 (02): : 121 - 129
  • [55] Genetic evidence for the bidirectional modulation of synaptic plasticity in the prefrontal cortex by D1 receptors
    Huang, YY
    Simpson, E
    Kellendonk, C
    Kandel, ER
    [J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2004, 101 (09) : 3236 - 3241
  • [56] Systematic mutation analysis of the human glutamate receptor, ionotropic, N-methyl-D-aspartate 1 gene (GRIN1) in schizophrenic patients
    Hung, CC
    Chen, HY
    Chen, CH
    [J]. PSYCHIATRIC GENETICS, 2002, 12 (04) : 225 - 230
  • [57] A decrease of reelin expression as a putative vulnerability factor in schizophrenia
    Impagnatiello, F
    Guidotti, AR
    Pesold, C
    Dwivedi, Y
    Caruncho, H
    Pisu, MG
    Uzunov, DP
    Smalheiser, NR
    Davis, JM
    Pandey, GN
    Pappas, GD
    Tueting, P
    Sharma, RP
    Costa, E
    [J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1998, 95 (26) : 15718 - 15723
  • [58] Genetic analysis of a functional GRIN2A promoter (GT)n repeat in bipolar disorder pedigrees in humans
    Itokawa, M
    Yamada, K
    Iwayama-Shigeno, Y
    Ishitsuka, Y
    Detera-Wadleigh, S
    Yoshikawa, T
    [J]. NEUROSCIENCE LETTERS, 2003, 345 (01) : 53 - 56
  • [59] A microsatellite repealt in the promoter of the N-methyl-D-aspartate receptor 2A subunit (GRIN2A) gene suppresses transcriptional activity and correlates with chronic outcome in schizophrenia
    Itokawa, M
    Yamada, K
    Yoshitsugu, K
    Toyota, T
    Suga, T
    Ohba, H
    Watanabe, A
    Hattori, E
    Shimizu, H
    Kumakura, T
    Ebihara, M
    Meerabux, JMA
    Toru, M
    Yoshikawa, T
    [J]. PHARMACOGENETICS, 2003, 13 (05): : 271 - 278
  • [60] 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
    Jardemark, K
    Marcus, MM
    Konradsson, Å
    Svensson, TH
    [J]. INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY, 2005, 8 (02) : 157 - 162