Saito Atsushi, Fujikura-Ouchi Yuta, Kuramasu Atsuo, Shimoda Kazutaka, Akiyama Kazufumi, Matsuoka Hiroo, Ito Chihiro
Department of Psychiatry, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai 980-8574, Japan.
Neurosci Lett. 2007 Jan 16;411(3):168-73. doi: 10.1016/j.neulet.2006.08.042. Epub 2006 Nov 22.
A previous study revealed a number of methamphetamine (METH) and phencyclidine (PCP)-reactive tags in a rat brain through serial analysis of gene expression. The present study extends this previous study by investigating whether two genes, which deduced from METH/PCP-reactive tags, were identified as those encoding human transmembrane proteins of the immunoglobulin (Ig) superfamily, neuroplastin (NPTN) and basigin (BSG), confer genetic susceptibility to schizophrenia by analyzing single nucleotide polymorphisms (SNPs). There were nominally significant differences between the two groups in their allelic frequencies (T Ins/Del, chi2=4.910, d.f.=1, P=0.040) and genotypic distributions (T/T or T/Del, chi2=5.116, d.f.=1, P=0.036) of rs3840846 in the 5'-upstream of NPTN. The two groups differed significantly also in their allelic frequencies (G/T, chi2=4.229, d.f.=1, P=0.044), but not genotypic distributions of rs3743500 in the 5'-upstream of NPTN. The haplotypes constructed from the three SNPs (rs3840846, rs3826047 and rs3743500, in order) in the 5'-upstream of NPTN showed a significant association with schizophrenia (permutation P=0.036), in that T-G-T (permutation P=0.028) and del-G-G (permutation P=0.040) were under-represented and over-represented, respectively, in schizophrenia. A reporter construct driven by the 5'-upstream region containing any haplotype consisting of the three SNPs had substantial transcriptional activity. Notably, a reporter construct containing a haplotype T-G-T had significantly lower transcriptional activity as compared with one having a haplotype T-G-G or T-A-G. There was no significant difference between the two groups regarding allelic frequencies, genotypic distribution or the adopted SNP-combinatory haplotype for BSG. These results suggest that NPTN may be involved in genetic susceptibility to schizophrenia.
一项先前的研究通过基因表达序列分析在大鼠大脑中发现了许多对甲基苯丙胺（METH）和苯环己哌啶（PCP）有反应的标签。本研究通过调查从METH/PCP反应性标签推导出来的两个基因，即被鉴定为编码免疫球蛋白（Ig）超家族人类跨膜蛋白的神经塑蛋白（NPTN）和基底细胞黏附分子（BSG），是否通过分析单核苷酸多态性（SNP）赋予精神分裂症遗传易感性，扩展了先前的这项研究。在NPTN 5'上游区域的rs3840846的等位基因频率（T Ins/Del，χ2 = 4.910，自由度 = 1，P = 0.040）和基因型分布（T/T或T/Del，χ2 = 5.116，自由度 = 1，P = 0.036）在两组之间存在名义上的显著差异。两组在NPTN 5'上游区域的rs3743500的等位基因频率（G/T，χ2 = 4.229，自由度 = 1，P = 0.044）上也存在显著差异，但在基因型分布上没有差异。由NPTN 5'上游区域的三个SNP（按顺序为rs3840846、rs3826047和rs3743500）构建的单倍型与精神分裂症存在显著关联（置换P = 0.036），即T-G-T（置换P = 0.028）在精神分裂症中出现频率过低，而del-G-G（置换P = 0.040）出现频率过高。由包含这三个SNP组成的任何单倍型的5'上游区域驱动的报告基因构建体具有大量的转录活性。值得注意的是，与具有单倍型T-G-G或T-A-G的报告基因构建体相比，包含单倍型T-G-T的报告基因构建体的转录活性显著较低。在BSG的等位基因频率、基因型分布或采用的SNP组合单倍型方面，两组之间没有显著差异。这些结果表明，NPTN可能参与了精神分裂症的遗传易感性。
