Molecular Research Center for Children's Mental Dev., United Graduate School of Child Dev. Osaka Univ. Kanazawa Univ.and Hamamatsu Univ.School of Med. Osaka, Japan.
Neuropsychopharmacology. 2011 Aug;36(9):1921-31. doi: 10.1038/npp.2011.78. Epub 2011 May 18.
The pathogenesis of schizophrenia is thought to involve aberrant immune and inflammatory responses. Nuclear factor kappa B (NF-κB) has important roles in the immune and inflammatory responses. The v-rel avian reticuloendotheliosis viral oncogene homolog A (RELA) gene encodes the major component of the NF-κB complex. We genotyped four single-nucleotide polymorphisms (SNPs) in the RELA gene and performed a gene-based association analysis using 1224 patients with schizophrenia and 1663 controls. We found significant associations of three SNPs (rs11820062: p=0.00011, rs2306365: p=0.0031, and rs7119750: p=0.0080) with schizophrenia and stronger evidence for association in a multi-marker sliding window haplotype analysis (the lowest p=0.00006). The association between this gene and schizophrenia was evident in male subjects but not in female subjects, when separately analyzed by gender. In silico genotype-gene expression analysis using web database and the WGAViewer software revealed that these three schizophrenia-associated SNPs might be related to RELA mRNA expression in immortalized B-lymphocytes. In silico analysis also suggested the putative promoter SNP, rs11820062, might disrupt the consensus transcription factor binding sequence of the androgen receptor. The impact of four RELA polymorphisms on pre-pulse inhibition (PPI) was investigated in 53 patients with schizophrenia. We provided evidence that at risk genotypes of three SNPs were associated with deficits in PPI; however, there was no effect of the one non-risk SNP on PPI. These findings suggest that variants of the RELA gene are associated with risk for schizophrenia and PPI deficits in a Japanese population.
精神分裂症的发病机制被认为涉及异常的免疫和炎症反应。核因子-κB（NF-κB）在免疫和炎症反应中具有重要作用。v-rel 禽网状内皮组织增生病毒癌基因同源物 A（RELA）基因编码 NF-κB 复合物的主要成分。我们对 RELA 基因中的四个单核苷酸多态性（SNP）进行了基因分型，并对 1224 名精神分裂症患者和 1663 名对照进行了基于基因的关联分析。我们发现三个 SNP（rs11820062：p=0.00011，rs2306365：p=0.0031，和 rs7119750：p=0.0080）与精神分裂症显著相关，并且在多标记滑动窗口单体型分析中具有更强的关联证据（最低 p=0.00006）。当按性别分别分析时，该基因与精神分裂症的关联在男性受试者中更为明显，但在女性受试者中则不明显。使用网络数据库和 WGAViewer 软件进行的基因表达分析表明，这三个与精神分裂症相关的 SNP 可能与永生化 B 淋巴细胞中 RELA mRNA 表达有关。计算机分析还表明，假定的启动子 SNP rs11820062 可能破坏了雄激素受体的共识转录因子结合序列。在 53 名精神分裂症患者中，我们研究了四个 RELA 多态性对预脉冲抑制（PPI）的影响。我们提供的证据表明，三个 SNP 的风险基因型与 PPI 缺陷有关；然而，一个非风险 SNP 对 PPI 没有影响。这些发现表明，RELA 基因的变体与日本人群中精神分裂症和 PPI 缺陷的风险相关。
