Abstract
Recent association studies suggest that polymorphisms in the promoter and exon 1 upstream region of the dopamine D4 receptor (DRD4) gene play a functional role in the development of common psychiatric illnesses, although there are also conflicting results. In this study, we re-sequenced this region to identify all genomic variants, and tested them for association with schizophrenia. A total of 570 Japanese schizophrenic cases with matched controls were studied by genotyping all identified/validated common polymorphisms (−1106T>C, −906T>C, −809G>A, −616G>C, −521T>C, −376C>T, −291C>T and 12-bp repeat) and a known microsatellite (120-bp tandem duplication) in the upstream region. A single nucleotide polymorphism (SNP) −809G>A in the promoter region was found to be significantly associated with disease (P=0.018 and 0.032 for allelic and genotypic comparisons, respectively), although not surviving after Bonferroni correction. Logistic regression analysis showed that a combination of the four polymorphisms, −809G>A, −616G>C, −291C>T and the 12-bp repeat, conferred a susceptibility to schizophrenia. These results suggest that the upstream variants have a primary functional effect in the etiology of schizophrenia in the Japanese population.
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References
Ambrosio AM, Kennedy JL, Macciardi F, Barr C, Soares MJ, Oliveira CR, Pato CN (2004) No evidence of association or linkage disequilibrium between polymorphisms in the 5′ upstream and coding regions of the dopamine D4 receptor gene and schizophrenia in a Portuguese population. Am J Med Genet B Neuropsychiatr Genet 125:20–24
Barrett JC, Fry B, Maller J, Daly MJ (2005) Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21:263–265
Benjamin J, Li L, Patterson C, Greenberg BD, Murphy DL, Hamer DH (1996) Population and familial association between the D4 dopamine receptor gene and measures of Novelty Seeking. Nat Genet 12:81–84
Cordell HJ, Clayton DG (2002) A unified stepwise regression procedure for evaluating the relative effects of polymorphisms within a gene using case/control or family data: application to HLA in type 1 diabetes. Am J Hum Genet 70:124–141
D’Souza UM, Russ C, Tahir E, Mill J, McGuffin P, Asherson PJ, Craig IW (2004) Functional effects of a tandem duplication polymorphism in the 5′ flanking region of the DRD4 gene. Biol Psychiatry 56:691–697
Dudbridge F (2003) Pedigree disequilibrium tests for multilocus haplotypes. Genet Epidemiol 25:115–121
Ebstein RP, Novick O, Umansky R, Priel B, Osher Y, Blaine D, Bennett ER, Nemanov L, Katz M, Belmaker RH (1996) Dopamine D4 receptor (D4DR) exon III polymorphism associated with the human personality trait of Novelty Seeking. Nat Genet 12:78–80
Faraone SV, Doyle AE, Mick E, Biederman J (2001) 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 158:1052–1057
Gelernter J, Kennedy JL, van Tol HH, Civelli O, Kidd KK (1992) The D4 dopamine receptor (DRD4) maps to distal 11p close to HRAS. Genomics 13:208–210
Hong CJ, Chiu HJ, Chang YS, Sim CB (1998) Twelve-nucleotide repeat polymorphism of D4 dopamine receptor gene in Chinese familial schizophrenic patients. Biol Psychiatry 43:432–435
Hwu HG, Hong CJ, Lee YL, Lee PC, Lee SF (1998) Dopamine D4 receptor gene polymorphisms and neuroleptic response in schizophrenia. Biol Psychiatry 44:483–487
Jonsson E, Brene S, Geijer T, Terenius L, Tylec A, Persson ML, Sedvall G (1996) A search for association between schizophrenia and dopamine-related alleles. Eur Arch Psychiatry Clin Neurosci 246:297–304
Jonsson EG, Ivo R, Forslund K, Mattila-Evenden M, Rylander G, Cichon S, Propping P, Nothen MM, Asberg M, Sedvall GC (2001) No association between a promoter dopamine D(4) receptor gene variant and schizophrenia. Am J Med Genet 105:525–528
Kaiser R, Konneker M, Henneken M, Dettling M, Muller-Oerlinghausen B, Roots I, Brockmoller J (2000) Dopamine D4 receptor 48-bp repeat polymorphism: no association with response to antipsychotic treatment, but association with catatonic schizophrenia. Mol Psychiatry 5:418–424
Kohn Y, Ebstein RP, Heresco-Levy U, Shapira B, Nemanov L, Gritsenko I, Avnon M, Lerer B (1997) Dopamine D4 receptor gene polymorphisms: relation to ethnicity, no association with schizophrenia and response to clozapine in Israeli subjects. Eur Neuropsychopharmacol 7:39–43
LaHoste GJ, Swanson JM, Wigal SB, Glabe C, Wigal T, King N, Kennedy JL (1996) Dopamine D4 receptor gene polymorphism is associated with attention deficit hyperactivity disorder. Mol Psychiatry 1:121–124
Lung FW, Chen N, Shu BC (2006) Dopamine D4 receptor gene and the −521C>T polymorphism of the upstream region of the dopamine D4 receptor gene in schizophrenia. Psychiatr Genet 16:139–143
Mitsuyasu H, Hirata N, Sakai Y, Shibata H, Takeda Y, Ninomiya H, Kawasaki H, Tashiro N, Fukumaki Y (2001) Association analysis of polymorphisms in the upstream region of the human dopamine D4 receptor gene (DRD4) with schizophrenia and personality traits. J Hum Genet 46:26–31
Murray AM, Hyde TM, Knable MB, Herman MM, Bigelow LB, Carter JM, Weinberger DR, Kleinman JE (1995) Distribution of putative D4 dopamine receptors in postmortem striatum from patients with schizophrenia. J Neurosci 15:2186–2191
Okuyama Y, Ishiguro H, Toru M, Arinami T (1999) A genetic polymorphism in the promoter region of DRD4 associated with expression and schizophrenia. Biochem Biophys Res Commun 258:292–295
Petronis A, Van Tol HH, Lichter JB, Livak KJ, Kennedy JL (1993) The D4 dopamine receptor gene maps on 11p proximal to HRAS. Genomics 18:161–163
Petronis A, Macciardi F, Athanassiades A, Paterson AD, Verga M, Meltzer HY, Cola P, Buchanan JA, Van Tol HH, Kennedy JL (1995) Association study between the dopamine D4 receptor gene and schizophrenia. Am J Med Genet 60:452–455
Prasad S, Semwal P, Deshpande S, Bhatia T, Nimgaonkar VL, Thelma BK (2002) Molecular genetics of schizophrenia: past, present and future. J Biosci 27:35–52
Pritchard JK, Stephens M, Donnelly P (2000) Inference of population structure using multilocus genotype data. Genetics 155:945–959
Purcell S, Cherny SS, Sham PC (2003) Genetic power calculator: design of linkage and association genetic mapping studies of complex traits. Bioinformatics 19:149–150
Sanak M, Zelek-Molik A, Nalepa I, Wegrzyn J, Wciorka J (2005) The dopamine D4 receptor VNTR in Polish schizophrenia patients. Schizophr Res 73:129–131
Sanyal S, Van Tol HH (1997) Review the role of dopamine D4 receptors in schizophrenia and antipsychotic action. J Psychiatr Res 31:219–232
Seeman P, Guan HC, Van Tol HH (1993) Dopamine D4 receptors elevated in schizophrenia. Nature 365:441–445
Segman RH, Goltser T, Heresco-Levy U, Finkel B, Shalem R, Schlafman M, Yakir A, Greenberg D, Strous R, Lerner A, Shelevoy A, Lerer B (2003) Association of dopaminergic and serotonergic genes with tardive dyskinesia in patients with chronic schizophrenia. Pharmacogenomics J 3:277–283
Serretti A, Lilli R, Lorenzi C, Lattuada E, Smeraldi E (2001) DRD4 exon 3 variants associated with delusional symptomatology in major psychoses: a study on 2,011 affected subjects. Am J Med Genet 105:283–290
Shimizu H, Iwayama Y, Yamada K, Toyota T, Minabe Y, Nakamura K, Nakajima M, Hattori E, Mori N, Osumi N, Yoshikawa T (2006) Genetic and expression analyses of the STOP (MAP6) gene in schizophrenia. Schizophr Res 84:244–252
Stefanis NC, Bresnick JN, Kerwin RW, Schofield WN, McAllister G (1998) Elevation of D4 dopamine receptor mRNA in postmortem schizophrenic brain. Brain Res Mol Brain Res 53:112–119
Sumiyoshi T, Stockmeier CA, Overholser JC, Thompson PA, Meltzer HY (1995) Dopamine D4 receptors and effects of guanine nucleotides on [3H]raclopride binding in postmortem caudate nucleus of subjects with schizophrenia or major depression. Brain Res 681:109–116
Van Tol HH, Bunzow JR, Guan HC, Sunahara RK, Seeman P, Niznik HB, Civelli O (1991) Cloning of the gene for a human dopamine D4 receptor with high affinity for the antipsychotic clozapine. Nature 350:610–614
Van Tol HH, Wu CM, Guan HC, Ohara K, Bunzow JR, Civelli O, Kennedy J, Seeman P, Niznik HB, Jovanovic V (1992) Multiple dopamine D4 receptor variants in the human population. Nature 358:149–152
Xing QH, Wu SN, Lin ZG, Li HF, Yang JD, Feng GY, Wang MT, Yang WW, He L (2003) Association analysis of polymorphisms in the upstream region of the human dopamine D4 receptor gene in schizophrenia. Schizophr Res 65:9–14
Acknowledgments
We thank the members of the Research Resource Center at the RIKEN Brain Science Institute for the sequencing and GeneScan typing service. This work was supported by RIKEN BSI Funds, Research on Brain Science Funds from the Ministry of Health Labor and Welfare, Grant-in Aid from the MEXT and CREST funds from the Japan Science and Technology Agency, Japan.
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The nucleotide polymorphism data reported is available in the DDBJ/EMBL/GenBank databases under the accession number ss61570833.
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Nakajima, M., Hattori, E., Yamada, K. et al. Association and synergistic interaction between promoter variants of the DRD4 gene in Japanese schizophrenics. J Hum Genet 52, 86–91 (2007). https://doi.org/10.1007/s10038-006-0084-3
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DOI: https://doi.org/10.1007/s10038-006-0084-3
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