Identification of susceptibility genes for psychiatric diseases on chromosome 18

18号染色体上精神疾病易感基因的鉴定

• 批准号: 14570955
• 负责人: YAMADA Kazuo
• 金额: $ 2.24万
• 依托单位: RIKEN (The Institute of Physical and Chemical Research)
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2002
• 资助国家: 日本
• 起止时间: 2002 至 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14570955/
• 关键词: Endogenous psychosis; Chromosome 18; Mood disorder; Schizophrenia; Linkage disequilibrium mapping; Transmission disequilibrium test; IMPA2 gene; C18orf gene; C18orfl遺伝子; 関連研究

The pericentromeric region of chromosome 18,especially 18p11.2,is described as a schizophrenia susceptibility locus. We had previously cloned two novel brain-derived transcripts from this region : the gene for a second human myo-inosititol monophosphatase (IMPA2) and a gene of unknown function, C18orf1.We performed a family-based LD study as the first step towards identifying relevant genetic loci around 18p11.2,and then followed up using a case-control approach. These markers covered 18p11.2 at an average density of 1/280 kb. A follow-up study of independent schizophrenics (n=214) and controls (n=313), revealed a significant association between the haplotype constructed by the D18S852 and 6409T>C and schizophrenia (P=0.00001).In addition, we have performed a genome-wide LD survey of susceptibility loci for schizophrenia. We first typed 119 schizophrenic pedigrees (357 individuals) using 444 microsatellite markers. This analysis revealed 14 markers demonstrating significant transmissio … More n distortion. We scrutinized the most significant genomic locus on 11q11-13 by adding 26 new markers for analysis. Three-marker haplotype analysis in the region showed evidence of association with schizophrenia (most significant haplotype P=0.00005,global P=0.022). However, further support for chromosome 18 was not obtained by transmission distortion analysis.Besides, we have genotyped 496 Japanese bipolar patients and 543 control subjects, using 17 SNPs on and around the IMPA2 gene. The distributions of haplotypes defined by -1051G>T,-708G>A,-461C>T and IVS1+1801C>T were different between control and schizophrenia groups (P=0.007). These findings suggest that the IMPA2 gene or a gene nearby may contribute to the overall genetic risk for bipolar disorder. Recently, we set out an in-vitro assay of the gene to reveal an influence of the SNPs on transcriptional activity. The present study should be expanded upon at increased marker resolution, followed by replication and confirmation tests in different sets of larger samples. Less

18号染色体着丝粒周围区域，尤其是18p11.2，被认为是精神分裂症的易感基因。我们在此之前克隆了两个新的脑源性转录本：第二个人肌肌醇单磷酸酶（IMPA 2）基因和一个功能未知的基因C18 orf 1。这些标记以1/280 kb的平均密度覆盖18p11.2。对214例精神分裂症患者和313例正常对照的随访研究表明，D18 S852和6409 T>C构成的单倍型与精神分裂症有显著相关性（P=0.00001）。我们首先使用444个微卫星标记对119个精神分裂症家系（357人）进行分型。该分析揭示了14个标志物显示出显著的传递性。 ...更多信息 n失真。我们通过添加26个新标记进行分析，仔细检查了11 q11 -13上最重要的基因组位点。在该区域的三标记单倍型分析显示与精神分裂症相关的证据（最显著单倍型P= 0.00005，全局P=0.022）。然而，进一步的支持，18号染色体没有获得的传输失真analysis.Besides，我们有496日本双相情感障碍患者和543名对照组，使用17个单核苷酸多态性的IMPA 2基因上和周围。单倍型-1051G>T、-708G>A、-461C>T和IVS 1 + 1801 C>T在对照组和精神分裂症组中的分布差异有统计学意义（P=0.007）。这些发现表明，IMPA 2基因或附近的基因可能有助于双相情感障碍的整体遗传风险。最近，我们提出了一个基因的体外试验，以揭示单核苷酸多态性对转录活性的影响。本研究应扩大后，在增加标记的分辨率，然后在不同的大样本集的复制和确认测试。少

项目成果

Yoshikawa T. et al.: "Progress in genetic studies on functional psychosis. (The present understanding and problems on brain research (Nou kagaku kenkyu no genjou to kadai))"Gihou. 324 (2003)

Yoshikawa T.等人：“功能性精神病遗传学研究的进展。（大脑研究的当前理解和问题（Nou kagaku kenkyu no genjou to kadai））”Gihou。

M Kikuchi, K Yamada, et al.: "Two-step association analyses of the chromosome 18p11.2 region in schizophrenia detect a locus encompassing C18orf1"Molecular Psychiatry. 8(5). 467-469 (2003)

M Kikuchi、K Yamada 等人：“精神分裂症染色体 18p11.2 区域的两步关联分析检测到包含 C18orf1 的基因座”分子精神病学。

Iwayama-Shigeno Y., Yamada K, et al.: "Distribution of haplotypes derived from three common variants of the NR4A2 gene in Japanese patients with schizophrenia"American Journal of Medical Genetics. (in press). (2003)

Iwayama-Shigeno Y.、Yamada K 等人：“来自日本精神分裂症患者 NR4A2 基因三种常见变体的单倍型分布”美国医学遗传学杂志。

Horiuchi Y. et al.: "Possible association between a haplotype of the GABA-A receptor alpha 1 subunit gene (GABRA1) and mood disorders."Biological Psychiatry. 55(1). 40-45 (2004)

Horiuchi Y. 等人：“GABA-A 受体 α 1 亚基基因 (GABRA1) 的单倍型与情绪障碍之间可能存在关联。”生物精神病学。

Yamada K. et al.: "Evidence of association between gamma-aminobutyric acid type A receptor genes located on 5q34 and female patients with mood disorders."Neuroscience Letters. 349(1). 9-12 (2003)

Yamada K. 等人：“位于 5q34 上的 γ-氨基丁酸 A 型受体基因与女性情绪障碍患者之间存在关联的证据。”《神经科学快报》。