Candidate Gene Analysis of Mood Disorder, including the IMPA2 Gene

情绪障碍候选基因分析，包括 IMPA2 基因

• 批准号: 10670891
• 负责人: YOSHIKAWA Takeo
• 金额: $ 1.92万
• 依托单位: RIKEN (The Institute of Physical and Chemical Research) (1999)Tokyo Medical and Dental University (1998)
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1998
• 资助国家: 日本
• 起止时间: 1998 至 1999
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-10670891/
• 关键词: mood disorder; schizophrenia; chromosome 18; IMPA2; polymorphism; association study; 気分障害; 連鎖解析; ケースコントロールスタディ

In our search for candidate genes for affective disorder on the short arm of chromosome 18, we cloned IMPA2, a previously unreported myo-inositol monophosphatase, that mapped to 18p11.2. Recently, a marker GOLF was shown to be linked to schizophrenia by both linkage analysis and family-based association study. Interestingly the location of the IMPA2 is very close to the GOLF(100kb). For the screening of mutations in the IMPA2 gene, we have determined the genomic structure and identified 10 different polymorphisms: (1)-466G>A (promoter), (2)-219C>T (promoter), (3)58G>A (exon 1), (4)IVS1-15G>A, (5)401T>C (Leu53Leu) (exon 2), (6)468C>T (His76tyr) (exon 2), (7)IVS5+13-14insA (intron 5), (8)776T>C (Arg178Arg), (9)800C>T (Phe186Phe) (exon6), (10)1079C>G (Thr279Thr) (exon 8). In the present study, we performed association tests on Japanese cohorts that included 302 schizophrenics, 212 patients with affective disorder and 308 matched controls. The missense mutation (His76Tyr) was not detected in these samples. We genotyped the three different polymorphisms, (3), (4) and (9). None of these were found to be associated with mood disorders. In contrast, in the schizophrenia sample there were significant genotypic and/or allelic associations regarding all the polymorphisms. These results suggest that the IMPA2 gene may be involved in a pathogenesis of schizophrenia in Japanese population. Since possible functional polymorphisms are only those which exist in the promoter region, it will be important to examine transcriptional consequences induced by those variants, in addition to refine the critical region by further genetic analysis.

在寻找位于18号染色体短臂上的情感障碍候选基因的过程中，我们克隆了一种此前未见报道的肌醇单磷酸酶IMPA2，该基因定位于18p11.2。最近，通过连锁分析和基于家庭的关联研究，高尔夫球被证明与精神分裂症有关。有趣的是，IMPA2的位置离高尔夫球场非常近(100kb)。为了筛选IMPA2基因的突变，我们确定了10种不同的多态性：(1)-466G&gt；A(启动子)，(2)-219C&gt；T(启动子)，(3)58G&gt；A(外显子1)，(4)IVS1-15G&gt；A，(5)401T&gt；C(Leu53Leu)(外显子2)，(6)468C&gt；T(His76tyr)(外显子2)，(7)IVS5+13-14A(内含子5)，(8)776T&gt；C(Arg178Arg)，(9)800C&gt；T(Phe186Phe)(外显子6)，(10)1079C&gt；G(Thr279Thr)(外显子8)。在本研究中，我们对包括302名精神分裂症患者、212名情感障碍患者和308名匹配对照的日本队列进行了关联性测试。在这些样本中未检测到错义突变(His76Tyr)。我们对(3)、(4)和(9)这三个不同的多态进行了基因分型。所有这些都没有发现与情绪障碍有关。相比之下，在精神分裂症样本中，所有的多态都存在显著的基因和/或等位基因关联。这些结果提示IMPA2基因可能参与了日本人群精神分裂症的发病机制。由于可能的功能多态只存在于启动子区域，因此除了通过进一步的遗传分析来提炼关键区域外，检查这些变异引起的转录后果将是重要的。

项目成果

Kurumaji A.,Nomoto H.,Yoshikawa T.et al.: "An association study between two missense variations of the benzodiazepine receptor (peripheral) gene and schizophrenia in a Japanese sample"J Neural Trans.. (in press).

Kurumaji A.、Nomoto H.、Yoshikawa T.等人：“日本样本中苯二氮卓受体（外周）基因的两种错义变异与精神分裂症之间的关联研究”J Neural Trans..（出版中）。

吉川武男、山田和: "精神疾患(内因性精神病)の遺伝子解析(わかる脳と神経)"羊土社(東京). 8 (1999)

Takeo Yoshikawa、Kazu Yamada：“精神疾病（内源性精神病）的遗传分析（了解大脑和神经）”Yodosha（东京）8（1999）。

Kurumaji, A., Nomoto, H., Yoshikawa, T., Okubo, Y. and Toru, M.: "An association study between two missense variations of the benzodiazepine receptor (peripheral) gene and schizophrenia in a Japanese sample"J Neural Trans.. (in press).

Kurumaji, A.、Nomoto, H.、Yoshikawa, T.、Okubo, Y. 和 Toru, M.：“日本样本中苯二氮卓受体（外周）基因的两种错义变异与精神分裂症之间的关联研究”J Neural

Yoshikawa, T. et al.: "Evidence for association of the myo-insitol monophoshatase2(IMPA2) genewith schizophrenia and unipolar disorder in Lapanese samples"Mol. Psychiatry. (in press).

Yoshikawa, T. 等人：“拉帕样本中肌醇单磷酸酶 2 (IMPA2) 基因与精神分裂症和单相情感障碍相关的证据”Mol。

吉川武男、豊田倫子: "精神疾患感受性遺伝子地図"中山書店(東京)(印刷中).

Takeo Yoshikawa、Rinko Toyota：“精神障碍易感性基因图”中山书店（东京）（出版中）。