Functional polymorphism of −141C Ins/Del in the dopamine D2 receptor gene promoter and schizophrenia

Several studies showed the density of D2 receptors was elevated in postmortem brains from schizophrenics. Genes which operate at the level of gene activation may be associated with the pathogenesis of schizophrenia. Arinami et al. [(1997) Human Molecular Genetics 6, 577-582] found a polymorphism in the 5'-flanking region of the D2 receptor gene designated as -141C Ins/Del. The promoter activity by luciferase assay of a plasmid containing the -141C Ins allele was higher than in the one containing the -141C Del allele. In addition, the -141C Ins allele frequency was significantly higher in schizophrenics than in control subjects. We replicated the -141C Ins/Del polymorphism in 170 schizophrenics and 121 healthy control subjects. The number of schizophrenics with the -141C Ins/Ins genotype was significantly higher than that of control subjects (P = 0.038). The frequency of the -141C Ins allele was significantly increased in the schizophrenics compared with the control subjects (P = 0.042). The mean age of onset for the patients with -141C Ins/Del was significantly lower than that for the patients with -141C Ins/Ins (P = 0.029). There was no association between the genotype and either positive symptoms or the response to antipsychotic medication. Our results suggest that the -141C Ins/Del polymorphism may affect the susceptibility to schizophrenia.

[1]  M. Martres,et al.  Effects of Dopaminergic Transmission Interruption on the D2 Receptor Isoforms in Various Cerebral Tissues , 1992, Journal of neurochemistry.

[2]  G. Pearlson,et al.  Positron emission tomography reveals elevated D2 dopamine receptors in drug-naive schizophrenics. , 1986, Science.

[3]  T. Crow,et al.  Dopaminergic mechanisms in schizophrenia: the antipsychotic effect and the disease process. , 1978, Life sciences.

[4]  S. Stone-Elander,et al.  D2 dopamine receptors in neuroleptic-naive schizophrenic patients. A positron emission tomography study with [11C]raclopride. , 1990, Archives of general psychiatry.

[5]  P Riederer,et al.  Human brain D1 and D2 dopamine receptors in schizophrenia, Alzheimer's, Parkinson's, and Huntington's diseases. , 1987, Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology.

[6]  V. Lehtinen,et al.  Striatal D2 dopamine receptor characteristics in neuroleptic-naive schizophrenic patients studied with positron emission tomography. , 1994, Archives of general psychiatry.

[7]  T. Crow,et al.  DOPAMINE D2 RECEPTORS IN SCHIZOPHRENIA STUDIED IN VIVO , 1986, The Lancet.

[8]  B. Mazoyer,et al.  The Estimated Density of D2 Striatal Receptors in Schizophrenia , 1991, British Journal of Psychiatry.

[9]  J. Baron,et al.  Striatal D2 dopaminergic receptors assessed with positron emission tomography and [76Br]bromospiperone in untreated schizophrenic patients. , 1990, The American journal of psychiatry.

[10]  B. Mazoyer,et al.  Central D2 Receptors and Negative Symptoms of Schizophrenia , 1994, British Journal of Psychiatry.

[11]  E. Vellenga,et al.  EFFECTIVE PROPHYLAXIS WITH ORAL ANTICOAGULANTS AND LOW-DOSE HEPARIN DURING PREGNANCY IN AN ANTITHROMBIN III DEFICIENT WOMAN , 1983, The Lancet.

[12]  T. Arinami,et al.  A functional polymorphism in the promoter region of the dopamine D2 receptor gene is associated with schizophrenia. , 1997, Human molecular genetics.

[13]  J. Endicott,et al.  A diagnostic interview: the schedule for affective disorders and schizophrenia. , 1978, Archives of general psychiatry.

[14]  J. Deakin,et al.  The abundance of mRNA for dopamine D2 receptor isoforms in brain tissue from controls and schizophrenics. , 1994, Brain research. Molecular brain research.

[15]  P. Seeman,et al.  Binding of 3H-neuroleptics and 3H-apomorphine in schizophrenic brains , 1978, Nature.

[16]  T. Crow,et al.  Molecular pathology of schizophrenia: more than one disease process? , 1980, British medical journal.

[17]  M. Poulter,et al.  INCREASED DOPAMINE-RECEPTOR SENSITIVITY IN SCHIZOPHRENIA , 1978, The Lancet.

[18]  P. Seeman,et al.  Elevation of brain neuroleptic/dopamine receptors in schizophrenia. , 1980, The American journal of psychiatry.

[19]  L. Iversen,et al.  DOPAMINE RECEPTORS AND SCHIZOPHRENIA: DRUG EFFECT OR ILLNESS? , 1980, The Lancet.

[20]  J. Goss,et al.  Haloperidol treatment increases D2 dopamine receptor protein independently of RNA levels in mice. , 1991, Life sciences.

[21]  L L Iversen,et al.  Increased brain dopamine and dopamine receptors in schizophrenia. , 1982, Archives of general psychiatry.

[22]  T. Crow.  Positive and Negative Schizophrenia Symptoms and the Role of Dopamine , 1981, British Journal of Psychiatry.

[23]  T. Crow.  Positive and Negative Schizophrenic Symptoms and the Role of Dopamine , 1980, British Journal of Psychiatry.

[24]  K. Ohara,et al.  Intact 5-HT2A receptor exons and the adjoining intron regions in schizophrenia. , 1996, Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology.

[25]  K. Ohara,et al.  Polymorphisms of dopamine D2-like (D2, D3, and D4) receptors in schizophrenia , 1996, Biological Psychiatry.

[26]  T. Kuno,et al.  Decreased serotonin S2 and increased dopamine D2 receptors in chronic schizophrenics , 1986, Biological Psychiatry.

[27]  M. Schumacher,et al.  Regulation by dopaminergic neurotransmission of dopamine D2 mRNA and receptor levels in the striatum and nucleus accumbens of the rat. , 1991, Brain research. Molecular brain research.

[28]  S. Stone-Elander,et al.  No D2 receptor increase in PET study of schizophrenia. , 1987, Archives of general psychiatry.

[29]  S. Snyder,et al.  Antischizophrenic drugs: chronic treatment elevates dopamine receptor binding in brain. , 1977, Science.

[30]  Christer Halldin,et al.  No elevated D2 dopamine receptors in neuroleptic-naive schizophrenic patients revealed by positron emission tomography and [11C]N-methylspiperone , 1995, Psychiatry Research: Neuroimaging.

[31]  I. Creese,et al.  Lack of effect of chronic dopamine receptor blockade on D2 dopamine receptor mRNA level , 1990, Neuroscience Letters.

[32]  K. Ohara,et al.  Dopamine D2-receptor mRNA level in rat striatum after chronic haloperidol treatment , 1991, Neuroscience Research.

[33]  K. Ohara,et al.  Analysis of the 5′-Flanking Promoter Region of the 5-HT2A Receptor Gene in Schizophrenia , 1997, Neuropsychopharmacology.

[34]  K. Hirayasu,et al.  Purification of genomic DNA from human whole blood by isopropanol-fractionation with concentrated Nal and SDS. , 1994, Nucleic acids research.