The C/C genotype of the C957T polymorphism of the dopamine D2 receptor is associated with schizophrenia

The T allele of the human dopamine D2 receptor (DRD2) gene C957T polymorphism is associated with reduced mRNA translation and stability. This results in decreased dopamine induced DRD2 upregulation and decreased in vivo D2 dopamine binding. Conversely, the C allele of the C957T polymorphism is not associated with such changes in mRNA leading to increased DRD2 expression. PET and postmortem binding studies show that schizophrenia is often associated with increased DRD2 availability. We report that on the basis of comparing the frequencies of the C/C and T/T genotypes of 153 patients with schizophrenia and 148 controls that schizophrenia is associated with the C/C genotype. The C957T shows a population attributable risk for schizophrenia of 24% and an attributable risk in those with schizophrenia of 42%. Increased expression of D2 receptors associated with the C allele is likely to be important in the underlying pathophysiology of at least some forms of schizophrenia. Enhanced understanding of schizophrenia afforded by this finding may lead to advances in treatment and prevention.

[1]  Laurent Gouya,et al.  The 3′ region of the DRD2 gene is involved in genetic susceptibility to schizophrenia , 2004, Schizophrenia Research.

[2]  F. Yasuno,et al.  Low dopamine d(2) receptor binding in subregions of the thalamus in schizophrenia. , 2004, The American journal of psychiatry.

[3]  M. Laruelle,et al.  Glutamate, dopamine, and schizophrenia: from pathophysiology to treatment. , 2003, Annals of the New York Academy of Sciences.

[4]  Lei Wang,et al.  Hippocampal deformities in the unaffected siblings of schizophrenia subjects , 2003, Biological Psychiatry.

[5]  A. Lane,et al.  Schizophrenia: Solving the puzzle , 2003, Irish journal of medical science.

[6]  P. Riederer,et al.  Insertion/deletion variant (−141C Ins/Del) in the 5′ regulatory region of the dopamine D2 receptor gene: lack of association with schizophrenia and bipolar affective disorder , 1998, Journal of Neural Transmission.

[7]  S. Kapur,et al.  Half a century of antipsychotics and still a central role for dopamine D2 receptors , 2003, Progress in Neuro-Psychopharmacology and Biological Psychiatry.

[8]  D StClair,et al.  -141 C del/ins polymorphism of the dopamine receptor 2 gene is associated with schizophrenia in a British population. , 1999, American journal of medical genetics.

[9]  A. Bassett,et al.  Genetic Counselling for Schizophrenia in the Era of Molecular Genetics , 2001, Canadian journal of psychiatry. Revue canadienne de psychiatrie.

[10]  R. V. Van Heertum,et al.  Increased baseline occupancy of D2 receptors by dopamine in schizophrenia. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[11]  N. Saitou,et al.  Synonymous mutations in the human dopamine receptor D2 (DRD2) affect mRNA stability and synthesis of the receptor. , 2003, Human molecular genetics.

[12]  Jacob Cohen.  Statistical Power Analysis for the Behavioral Sciences , 1969, The SAGE Encyclopedia of Research Design.

[13]  Yuhei Nakamura,et al.  Functional polymorphism of −141C Ins/Del in the dopamine D2 receptor gene promoter and schizophrenia , 1998, Psychiatry Research.

[14]  B. Orser,et al.  A D2 Class Dopamine Receptor Transactivates a Receptor Tyrosine Kinase to Inhibit NMDA Receptor Transmission , 2002, Neuron.

[15]  M. Itokawa,et al.  Association of dopamine D2 receptor molecular variant with schizophrenia , 1994, The Lancet.

[16]  Paul J. Harrison,et al.  Schizophrenia genes, gene expression, and neuropathology: on the matter of their convergence , 2005, Molecular Psychiatry.

[17]  P. Sullivan,et al.  Schizophrenia as a complex trait: evidence from a meta-analysis of twin studies. , 2003, Archives of general psychiatry.

[18]  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.

[19]  M. Morari,et al.  Striatal dopamine–NMDA receptor interactions in the modulation of glutamate release in the substantia nigra pars reticulata in vivo: opposite role for D1 and D2 receptors , 2002, Journal of neurochemistry.

[20]  T. Shinkai,et al.  Association analysis between two functional dopamine D2 receptor gene polymorphisms and schizophrenia. , 2001, American journal of medical genetics.

[21]  M. Kaneshima,et al.  An association study between the Cys311 variant of dopamine D2 receptor gene and schizophrenia in the Okinawan population , 1997, Psychiatry and clinical neurosciences.

[22]  Teresa Tallerico,et al.  Dopamine D2 receptor promoter polymorphism: no association with schizophrenia , 1999, Psychiatry Research.

[23]  P. Gorwood,et al.  Association and excess of transmission of a DRD2 haplotype in a sample of French schizophrenic patients. , 2001, Schizophrenia Research.

[24]  M. Itokawa,et al.  A structural polymorphism of human dopamine D2 receptor, D2(Ser311-->Cys). , 1993, Biochemical and biophysical research communications.

[25]  P. Gahlinger,et al.  Computer Programs for Epidemiologists: Pepi Version 4.0 , 2001 .

[26]  M. O’Donovan,et al.  Multicenter linkage study of schizophrenia loci on chromosome 22q , 2004, Molecular Psychiatry.

[27]  M C O'Donovan,et al.  The molecular genetics of schizophrenia: new findings promise new insights , 2004, Molecular Psychiatry.

[28]  S. Kapur,et al.  Schizophrenia: more dopamine, more D2 receptors. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[29]  Douglas W. Jones,et al.  P300 and genetic risk for schizophrenia. , 2003, Archives of general psychiatry.

[30]  Markus M Nöthen,et al.  Association between a promoter polymorphism in the dopamine D2 receptor gene and schizophrenia , 1999, Schizophrenia Research.

[31]  C. Carter,et al.  A specific deficit in context processing in the unaffected siblings of patients with schizophrenia. , 2003, Archives of general psychiatry.

[32]  R. Murray,et al.  Pathways to schizophrenia: the impact of environmental factors. , 2004, The international journal of neuropsychopharmacology.

[33]  Eduardo L. Franco,et al.  Computer Programs for Epidemiologists–PEPI Version 4.0 , 2003 .

[34]  M. Egan,et al.  Abnormal fMRI response of the dorsolateral prefrontal cortex in cognitively intact siblings of patients with schizophrenia. , 2003, The American journal of psychiatry.

[35]  K. Någren,et al.  C957T polymorphism of the dopamine D2 receptor (DRD2) gene affects striatal DRD2 availability in vivo , 2004, Molecular Psychiatry.

[36]  Jeffrey A Lieberman,et al.  Recent advances in the neurobiology of schizophrenia. , 2003, Molecular interventions.

[37]  Tyrone D. Cannon,et al.  A prospective study of childhood neurocognitive functioning in schizophrenic patients and their siblings. , 2003, The American journal of psychiatry.

[38]  M. Laruelle,et al.  Glutamate, Dopamine, and Schizophrenia , 2003 .

[39]  R. Fukuda,et al.  Mismatch PCR RFLP detection of DRD2 Ser311Cys polymorphism and schizophrenia. , 1994, Biochemical and biophysical research communications.

[40]  T. d'Amato,et al.  No major role for the dopamine D2 receptor Ser → Cys311 mutation in schizophrenia , 1994, Psychiatric genetics.

[41]  Kevin T. Hansen,et al.  Dopamine D2 densities and the schizophrenic brain , 1998, Schizophrenia Research.