An investigation of the involvement of methylation in the parhogenesis of mental diseases by differential genomic analyses of monozygotic twins discordant for the diseases.

(1)甲基化与精神分裂症用高效液相色谱法测定白细胞总甲基化胞嘧啶体积，比较精神分裂症患者与年龄、性别匹配的正常对照的差异。男性精神分裂症患者外周血白细胞甲基化胞嘧啶含量明显低于正常对照组。这一差异在年轻患者(35岁)中尤为明显。女性患者无明显差异。人类内源性逆转录病毒(HERV)位于染色体1q21-q22和22q12上，具有被甲基化抑制的转录活性，这是在精神分裂症连锁研究中反复观察到的易感基因。这些结果提示甲基化参与了精神分裂症的发病机制。(2)不一致同卵双胞胎的差异基因组扫描荧光代表性基因组图谱(FRGP)被应用于精神分裂症、双相情感障碍、自闭症和发作性睡病的同卵双胞胎的DNA。来自自闭症、精神分裂症和双相情感障碍的同卵双胞胎中的患病双胞胎和非患病双胞胎之间包含不一致DNA片段的不一致斑点。两个候选基因(4p14、12q24.11)、1gnee(6q13)和1个基因(7q31)被直接克隆。发现双相情感障碍易感基因XBP1DNA微阵列分析显示，与内质网应激相关的XBP1和GRP78基因表达降低。XBP1基因启动子区域的-116G/C多态是导致该基因表达降低的原因。甲基化参与XBP1的表达是下一个关注的焦点

(1) Methylation and schizophreniaTotal me ethylated cytosine volumes in leucocytes were measured using HPLC and compared between patients with schizophrenia and age and sex matched normal controls. Leucocytes from male patients with schizophrenia contained significantly less total me ethylated cytosine than those from normal controls. The difference was observed especially in the young patients (<35 years old). There was no significant difference for female patients. Two Human endogenous retrovirus (HERV) that retain the transcriptional activity which is inhibited by methylation were located on chromosome 1q21-q22 and 22q12 which were susceptible loci repeatedly observed in the linkage study of schizophrenia. These suggest the involvement of methylation in the pathogenesis of schizophrenia(2) Differential genomic scans of discordant monozygotic twinsFluorescent representational genomic profiling (FRGP) was applied to DNAs from monozygotic twins discordant for schizophrenia, bipolar disorder, autism and narcolepsy. Discordant spots containing discordant DNA fragments between affected and non-affected twins from the monozygotic twins from autism, schizophrenia and bipolar disorder. Two candidate genes (4p14, 12q24.11) for autism, 1gnee (6q13) and 1 gene (7q31) were implicated by the direct cloning of the spots. Furthermore, the difference of an autism gene was revealed due to its different methylation status in the promoter region.(3) The discovery of bipolar disorder susceptibility gene, XBP1DNA Microarray analysis of lymphoblasted cells from two monozygotic twins discordant for bipolar disorder revealed lower expression of XBP1 and GRP78 genes that involved in the lowered endoplasmic reticulum (ER) stress. A polymorphism (-116 G/C) in the promoter region of XBP1 was responsible for lowered expression. The involvement of methylation in the expression of XBP1 is a next focus