Association and synergistic interaction between promoter variants of the DRD4 gene in Japanese schizophrenics.
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.
Nakajima
Mizuho
M
Laboratory for Molecular Psychiatry, RIKEN Brain Science Institute, 2-1 Hirosawa, Wako-city, Saitama, 351-0198, Japan.|Department of Paediatrics, Tokyo Medical University, Shinjuku, Tokyo, 160-0023, Japan.
Hattori
Eiji
E
Laboratory for Molecular Psychiatry, RIKEN Brain Science Institute, 2-1 Hirosawa, Wako-city, Saitama, 351-0198, Japan.
Yamada
Kazuo
K
Laboratory for Molecular Psychiatry, RIKEN Brain Science Institute, 2-1 Hirosawa, Wako-city, Saitama, 351-0198, Japan.
Iwayama
Yoshimi
Y
Laboratory for Molecular Psychiatry, RIKEN Brain Science Institute, 2-1 Hirosawa, Wako-city, Saitama, 351-0198, Japan.
Toyota
Tomoko
T
Laboratory for Molecular Psychiatry, RIKEN Brain Science Institute, 2-1 Hirosawa, Wako-city, Saitama, 351-0198, Japan.
Iwata
Yasuhide
Y
Department of Psychiatry and Neurology, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, 431-3192, Japan.
Tsuchiya
Kenji J
KJ
Department of Psychiatry and Neurology, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, 431-3192, Japan.
Sugihara
Genichi
G
Department of Psychiatry and Neurology, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, 431-3192, Japan.
Hashimoto
Kenji
K
Division of Clinical Neuroscience, Chiba University, Center for Forensic Mental Health, Chiba, 260-8670, Japan.
Watanabe
Hiroyuki
H
Department of Psychiatry, Chiba University, Graduate School of Medicine, Chiba, Japan.
Iyo
Masaomi
M
Department of Psychiatry, Chiba University, Graduate School of Medicine, Chiba, Japan.
Hoshika
Akinori
A
Department of Paediatrics, Tokyo Medical University, Shinjuku, Tokyo, 160-0023, Japan.
Yoshikawa
Takeo
T
Laboratory for Molecular Psychiatry, RIKEN Brain Science Institute, 2-1 Hirosawa, Wako-city, Saitama, 351-0198, Japan. takeo@brain.riken.jp.|CREST, Japan Science and Technology Agency, Saitama, Japan. takeo@brain.riken.jp.
D005091:Exons; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D007564:Japan; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D050638:Receptors, Dopamine D4 / Q000235:genetics*; D012559:Schizophrenia / Q000175:diagnosis / Q000235:genetics*
C493599:DRD4 protein, human; D050638:Receptors, Dopamine D4