Variants of the RELA gene are associated with schizophrenia and their startle responses.
Variants of the RELA gene are associated with schizophrenia and their startle responses.
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DOI：
10.1038/npp.2011.78
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发表时间：
2011-08
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--
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中科院分区：
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精神分裂症的发病机制被认为与异常的免疫和炎症反应有关。核因子κB （NF-κB）在免疫和炎症反应中起重要作用。v-rel禽流感网状内皮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基因的4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名对照组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, rs7119750: p=0.0080）与精神分裂症有显著的关联，并且在多标记滑动窗口单倍型分析中有更强的关联证据（最低p=0.00006）。当按性别分开分析时，该基因与精神分裂症之间的关联在男性受试者中很明显，而在女性受试者中则不明显。利用web数据库和WGAViewer软件进行基因型基因表达分析，发现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的表达有关。计算机分析还表明，假定的启动子SNP rs11820062可能会破坏公认的雄激素受体转录因子结合序列。研究了53例精神分裂症患者的四种RELA多态性对脉冲前抑制（PPI）的影响。我们提供的证据表明，三个snp的高危基因型与PPI缺陷相关；然而，一个非风险SNP对PPI没有影响。这些发现表明，RELA基因的变异与日本人群中精神分裂症和PPI缺陷的风险相关。
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.
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