Positive association of Phencyclidine-responsive genes, PDE4A and PLAT, with schizophrenia

Xiangdong Deng, Hiromi Takaki, Lixiang Wang, Tosihide Kuroki, Tatsuo Nakahara, Kijiro Hashimoto, Hideaki Ninomiya, Tadao Arinami, Toshiya Inada, Hiroshi Ujike, Masanari Itokawa, Mamoru Tochigi, Yuichiro Watanabe, Toshiyuki Someya, Hiroshi Kunugi, Nakao Iwata, Norio Ozaki, Hiroki Shibata, Yasuyuki Fukumaki

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Abstract

As schizophrenia-like symptoms are produced by administration of phencyclidine (PCP), a noncompetitive antagonist of N-methyl-D-aspartate (NMDA) receptors, PCP-responsive genes could be involved in the pathophysiology of schizophrenia. We injected PCP to Wistar rats and isolated five different parts of the brain in 1 and 4hr after the injection. We analyzed the gene expression induced by the PCP treatment of these tissues using the AGILENT rat cDNA microarray system. We observed changes in expression level in 90 genes and 21 ESTs after the treatment. Out of the 10 genes showing >2-fold expressional change evaluated by qRT-PCR, we selected 7 genes as subjects for the locus-wide association study to identify susceptibility genes for schizophrenia in the Japanese population. In haplotype analysis, significant associations were detected in combinations of two SNPs of BTG2 (P=1.4×10 -6 ), PDE4A (P=1.4×10 -6 ), and PLAT (P=1×10 -3 ), after false discovery rate (FDR) correction. Additionally, we not only successfully replicated the haplotype associations in PDE4A (P=6.8×10 -12 ) and PLAT (P=0.015), but also detected single-point associations of one SNP in PDE4A (P=0.0068) and two SNPs in PLAT (P=0.0260 and 0.0104) in another larger sample set consisting of 2,224 cases and 2,250 controls. These results indicate that PDE4A and PLAT may be susceptibility genes for schizophrenia in the Japanese population.

Original languageEnglish
Pages (from-to)850-858
Number of pages9
JournalAmerican Journal of Medical Genetics, Part B: Neuropsychiatric Genetics
Volume156
Issue number7
DOIs
Publication statusPublished - 01-12-2011

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Phencyclidine
Schizophrenia
Genes
Single Nucleotide Polymorphism
Haplotypes
Expressed Sequence Tags
Oligonucleotide Array Sequence Analysis
N-Methyl-D-Aspartate Receptors
Population
Wistar Rats
Gene Expression
Polymerase Chain Reaction
Injections
Brain
Therapeutics

All Science Journal Classification (ASJC) codes

  • Genetics(clinical)
  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience

Cite this

Deng, Xiangdong ; Takaki, Hiromi ; Wang, Lixiang ; Kuroki, Tosihide ; Nakahara, Tatsuo ; Hashimoto, Kijiro ; Ninomiya, Hideaki ; Arinami, Tadao ; Inada, Toshiya ; Ujike, Hiroshi ; Itokawa, Masanari ; Tochigi, Mamoru ; Watanabe, Yuichiro ; Someya, Toshiyuki ; Kunugi, Hiroshi ; Iwata, Nakao ; Ozaki, Norio ; Shibata, Hiroki ; Fukumaki, Yasuyuki. / Positive association of Phencyclidine-responsive genes, PDE4A and PLAT, with schizophrenia. In: American Journal of Medical Genetics, Part B: Neuropsychiatric Genetics. 2011 ; Vol. 156, No. 7. pp. 850-858.
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abstract = "As schizophrenia-like symptoms are produced by administration of phencyclidine (PCP), a noncompetitive antagonist of N-methyl-D-aspartate (NMDA) receptors, PCP-responsive genes could be involved in the pathophysiology of schizophrenia. We injected PCP to Wistar rats and isolated five different parts of the brain in 1 and 4hr after the injection. We analyzed the gene expression induced by the PCP treatment of these tissues using the AGILENT rat cDNA microarray system. We observed changes in expression level in 90 genes and 21 ESTs after the treatment. Out of the 10 genes showing >2-fold expressional change evaluated by qRT-PCR, we selected 7 genes as subjects for the locus-wide association study to identify susceptibility genes for schizophrenia in the Japanese population. In haplotype analysis, significant associations were detected in combinations of two SNPs of BTG2 (P=1.4×10 -6 ), PDE4A (P=1.4×10 -6 ), and PLAT (P=1×10 -3 ), after false discovery rate (FDR) correction. Additionally, we not only successfully replicated the haplotype associations in PDE4A (P=6.8×10 -12 ) and PLAT (P=0.015), but also detected single-point associations of one SNP in PDE4A (P=0.0068) and two SNPs in PLAT (P=0.0260 and 0.0104) in another larger sample set consisting of 2,224 cases and 2,250 controls. These results indicate that PDE4A and PLAT may be susceptibility genes for schizophrenia in the Japanese population.",
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Deng, X, Takaki, H, Wang, L, Kuroki, T, Nakahara, T, Hashimoto, K, Ninomiya, H, Arinami, T, Inada, T, Ujike, H, Itokawa, M, Tochigi, M, Watanabe, Y, Someya, T, Kunugi, H, Iwata, N, Ozaki, N, Shibata, H & Fukumaki, Y 2011, 'Positive association of Phencyclidine-responsive genes, PDE4A and PLAT, with schizophrenia', American Journal of Medical Genetics, Part B: Neuropsychiatric Genetics, vol. 156, no. 7, pp. 850-858. https://doi.org/10.1002/ajmg.b.31233

Positive association of Phencyclidine-responsive genes, PDE4A and PLAT, with schizophrenia. / Deng, Xiangdong; Takaki, Hiromi; Wang, Lixiang; Kuroki, Tosihide; Nakahara, Tatsuo; Hashimoto, Kijiro; Ninomiya, Hideaki; Arinami, Tadao; Inada, Toshiya; Ujike, Hiroshi; Itokawa, Masanari; Tochigi, Mamoru; Watanabe, Yuichiro; Someya, Toshiyuki; Kunugi, Hiroshi; Iwata, Nakao; Ozaki, Norio; Shibata, Hiroki; Fukumaki, Yasuyuki.

In: American Journal of Medical Genetics, Part B: Neuropsychiatric Genetics, Vol. 156, No. 7, 01.12.2011, p. 850-858.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Positive association of Phencyclidine-responsive genes, PDE4A and PLAT, with schizophrenia

AU - Deng, Xiangdong

AU - Takaki, Hiromi

AU - Wang, Lixiang

AU - Kuroki, Tosihide

AU - Nakahara, Tatsuo

AU - Hashimoto, Kijiro

AU - Ninomiya, Hideaki

AU - Arinami, Tadao

AU - Inada, Toshiya

AU - Ujike, Hiroshi

AU - Itokawa, Masanari

AU - Tochigi, Mamoru

AU - Watanabe, Yuichiro

AU - Someya, Toshiyuki

AU - Kunugi, Hiroshi

AU - Iwata, Nakao

AU - Ozaki, Norio

AU - Shibata, Hiroki

AU - Fukumaki, Yasuyuki

PY - 2011/12/1

Y1 - 2011/12/1

N2 - As schizophrenia-like symptoms are produced by administration of phencyclidine (PCP), a noncompetitive antagonist of N-methyl-D-aspartate (NMDA) receptors, PCP-responsive genes could be involved in the pathophysiology of schizophrenia. We injected PCP to Wistar rats and isolated five different parts of the brain in 1 and 4hr after the injection. We analyzed the gene expression induced by the PCP treatment of these tissues using the AGILENT rat cDNA microarray system. We observed changes in expression level in 90 genes and 21 ESTs after the treatment. Out of the 10 genes showing >2-fold expressional change evaluated by qRT-PCR, we selected 7 genes as subjects for the locus-wide association study to identify susceptibility genes for schizophrenia in the Japanese population. In haplotype analysis, significant associations were detected in combinations of two SNPs of BTG2 (P=1.4×10 -6 ), PDE4A (P=1.4×10 -6 ), and PLAT (P=1×10 -3 ), after false discovery rate (FDR) correction. Additionally, we not only successfully replicated the haplotype associations in PDE4A (P=6.8×10 -12 ) and PLAT (P=0.015), but also detected single-point associations of one SNP in PDE4A (P=0.0068) and two SNPs in PLAT (P=0.0260 and 0.0104) in another larger sample set consisting of 2,224 cases and 2,250 controls. These results indicate that PDE4A and PLAT may be susceptibility genes for schizophrenia in the Japanese population.

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