Roig B, Virgos C, Franco N, Martorell L, Valero J, Costas J, Carracedo A, Labad A, Vilella E
Ctra. de l'Institut Pere Mata s/n, University Psychiatric Hospital, Pere Mata Institute, Reus, Tarragona, Spain.
Mol Psychiatry. 2007 Sep;12(9):833-41. doi: 10.1038/sj.mp.4001995. Epub 2007 Apr 17.
Evidence suggests that myelin alterations could predispose to schizophrenia. Reduced expression of several myelin genes has been observed in schizophrenia patients. Recently, we identified the discoidin domain receptor 1 (DDR1; located at human chromosome 6p21.3) as a myelin gene in the mouse model and in a human oligodendroglial cell line. In the present study we screened for single nucleotide polymorphisms (SNPs) in the DNA from 100 schizophrenia patients. We identified a novel mutation within exon 10 that produces the amino-acid substitution N502S in the a-d isoforms, and M475V in the e isoform. However the frequency of the mutation (2%) was similar in schizophrenia patients and in control subjects. In a case-control assessment with 389 schizophrenic patients and 615 controls, we identified one SNP (SNP9, rs1049623) associated with schizophrenia (odds ratio=1.44, 95% confidence interval: 1.15-1.79, adjusted P=0.0016). This association was confirmed in haplotype analysis; the SNPs 9-10-11 (rs1049623, rs2267641 and rs2239518) haplotype remaining significant even after adjustment for multiple testing (adjusted P=0.0136). Of note was a strong gender dependence in the association, that is, statistical significance restricted to men (adjusted P-value=0.0002). Regression analysis of DDR1 mRNA expression in peripheral blood lymphocytes from schizophrenia patients showed that the presence of the G allele significantly decreased the relative number of mRNA copies in a dose-dependent manner (P=0.003). These data suggest that the risk haplotype tags a cis-acting variant involved in the transcription regulation system of the gene. In conclusion, we propose the DDR1 as a new susceptibility gene for schizophrenia.
有证据表明，髓鞘改变可能易患精神分裂症。在精神分裂症患者中观察到几种髓鞘基因的表达降低。最近，我们在小鼠模型和人类少突胶质细胞系中确定盘状结构域受体1（DDR1；位于人类染色体6p21.3）为一种髓鞘基因。在本研究中，我们对100名精神分裂症患者的DNA进行了单核苷酸多态性（SNP）筛查。我们在第10外显子中发现了一个新突变，该突变在α-d异构体中产生氨基酸替代N502S，在ε异构体中产生M475V。然而，该突变的频率（2%）在精神分裂症患者和对照受试者中相似。在一项对389名精神分裂症患者和615名对照的病例对照评估中，我们确定了一个与精神分裂症相关的SNP（SNP9，rs1049623）（优势比=1.44，95%置信区间：1.15-1.79，校正P=0.0016）。这种关联在单倍型分析中得到证实；即使在进行多重检验校正后，SNP 9-10-11（rs1049623、rs2267641和rs2239518）单倍型仍具有显著性（校正P=0.0136）。值得注意的是，这种关联存在强烈的性别依赖性，即统计学显著性仅限于男性（校正P值=0.0002）。对精神分裂症患者外周血淋巴细胞中DDR1 mRNA表达的回归分析表明，G等位基因的存在以剂量依赖的方式显著降低了mRNA拷贝的相对数量（P=0.003）。这些数据表明，风险单倍型标记了一个参与该基因转录调控系统的顺式作用变体。总之，我们提出DDR1作为精神分裂症的一个新的易感基因。
