Division of Human Molecular Genetics, Research Center for Genetic Information, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan.
Am J Med Genet B Neuropsychiatr Genet. 2011 Dec;156B(7):850-8. doi: 10.1002/ajmg.b.31233. Epub 2011 Aug 23.
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 4 hr 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.
由于精神分裂症样症状是由苯环利定(PCP)引起的,苯环利定是 N-甲基-D-天冬氨酸(NMDA)受体的非竞争性拮抗剂,因此 PCP 反应性基因可能参与精神分裂症的病理生理学。我们给 Wistar 大鼠注射 PCP,并在注射后 1 小时和 4 小时分别从大鼠大脑的 5 个不同部位分离组织。我们使用安捷伦大鼠 cDNA 微阵列系统分析这些组织中由 PCP 处理诱导的基因表达。我们观察到在治疗后有 90 个基因和 21 个 EST 的表达水平发生了变化。在通过 qRT-PCR 评估的 10 个表达水平变化超过 2 倍的基因中,我们选择了 7 个基因作为全基因座关联研究的对象,以鉴定日本人群中精神分裂症的易感基因。在单倍型分析中,在 BTG2(P=1.4×10(-6))、PDE4A(P=1.4×10(-6))和 PLAT(P=1×10(-3))的两个 SNP 组合中检测到显著的关联,在错误发现率(FDR)校正后。此外,我们不仅成功地在 PDE4A(P=6.8×10(-12))和 PLAT(P=0.015)中复制了单倍型关联,还在另一个由 2224 例病例和 2250 例对照组成的更大的样本集中检测到 PDE4A 中一个 SNP(P=0.0068)和 PLAT 中两个 SNP(P=0.0260 和 0.0104)的单点关联。这些结果表明 PDE4A 和 PLAT 可能是日本人群中精神分裂症的易感基因。