2002 Fiscal Year Annual Research Report

全ゲノムスキャンによる内因性精神病の感受性遺伝子群の同定

Research Project

Project/Area Number	12307020
Research Institution	RIKEN
Principal Investigator	吉川武男理化学研究所, 分子精神科学研究チーム, チームリーダー (30249958)
Co-Investigator(Kenkyū-buntansha)	有波忠雄筑波大学, 基礎医学系, 助教授 (10212648) 山田和男理化学研究所, 分子精神科学研究チーム, 研究員 (10322695) 海老原充理化学研究所, 分子精神科学研究チーム, 研究員 (80232974)
Keywords	統合失調症 / 染色体18番 / ETDT / ハプロタイプ / C18orf1 / SNP / マイクロサテライトマーカー
Research Abstract	我々は現在までに130家系、総勢420人の統合失調症サンプルを収集し、全ゲノムを5cM(染色体6番、11番、18番、22番)ないし10cM密度(それ以外の染色体)のマイクロサテライトマーカーを用いてfamily-based association testで解析した結果、染色体9番、11番、15番、16番、18番に有意なP値を認めた。本年度は、染色体18番短腕の18p11領域(14Mb)に絞ってさらに16個のマーカーを使って調べた。その結果、C18orf1という遺伝子由来のマーカーD18S852と6409T>C、およびその遺伝子から約20kb動原体よりのマーカーD18S40で有意な結果を得た。次に、別途収集したunrelated統合失調症患者約200名、unrelated対照者200名のサンプルを用いてtow-locusハプロタイプ解析を行ったところ、D18S852-6409T>CでP=0.00001を得た。これらの結果は、C18orf1上あるいはごく近傍に統合失調症の感受性変異があることを示唆する。C18orf1は我々が以前クローニングした脳に発現する遺伝子で、タイプIb膜タンパクである。また、alternative splicing, alternative promoter usageで4種類の遺伝子産物が生成されることが予想されている。そこで、C18orf1のエクソン領域のmutation screeningを行った。その結果、5'非翻訳領域に-96A>Gという新たな多型を見いだした。この多型を用いて、統合失調症サンプルでケースコントロール解析を行ったところ、対立遺伝子分布でP=0.005、遺伝子型分布でP=0.048という有意な結果を得た。以上の結果から、C18orf1遺伝子は染色体18番短腕上の重要な統合失調症の候補遺伝子と考えられ、今後さらに検討が必要である。

Research Products
(12 results)

All Other

All Publications (12 results)

[Publications] Toyota, T., et al.: "Molecular analysis, mutation screening, and association study of adenylate cyclase type 9 gene_(ADCY9) in mood disorders"American Journal of Medical Genetics, Neuropsychiatric Genetics. 114. 84-92 (2002)
[Publications] Yoshikawa, T. et al.: "Identification of multiple genetic loci linked to the propensity for "behavioral despair" in mice"Genome Research. 12. 357-366 (2002)
[Publications] Akanuma, N., et al.: "Interictal schizophrenia-like psychosis in a patient with double cortex syndrome"The Journal of Neuropsychiatry and Clinical Neurosciences. 14. 210-213 (2002)
[Publications] Reyes, G.D., et al.: "Map of candidate genes and STSs on 18p11.2, a bipolar disorder and schizophrenia susceptibility region"Molecular Psychiatry. 7. 337-339 (2002)
[Publications] Hattori, E., et al.: "An association study of the short tandem repeat in the 5' upstream region of the cholecystokinin gene with mood disorders in the Japanese population"American Journal of Medical Genetics, Neuropsychiatric Genetics. 114. 523-526 (2002)
[Publications] Toyota, T., et al.: "Association analysis of adenylate cyclase type 9 gene using pedigree disequilibrium test in bipolar disorder"Molecular Psychiatry. 7. 450-452 (2002)
[Publications] Ebihara, M., et al.: "Genomic organization and promoter analysis of the human nicotinic acetylcholine receptor α6 subunit (CHNRA6) gene : Alu and other elements direct transcriptional repression"Gene. 298. 101-108 (2002)
[Publications] Ohtsuki, T., et al.: "Association between serotonin 4 receptor gene polymorphisms and bipolar disorder in Japanese case-control samples and the NIMH Genetics Initiative Bipolar Pedigrees"Mol. Psychiatry. 7. 954-961 (2002)
[Publications] Yoshitsugu, K., et al.: "Fine mapping of an isodicentric Y chromosomal breakpoint from a schizophrenic patient"American Journal of Medical Genetics, Neuropsychiatric Genetics. 116B. 27-31 (2003)
[Publications] Iwayama-Shigeno, Y., et al.: "Distribution of haplotypes derived from three common variants of the NR4A2 gene in Japanese schizophrenic patients"American Journal of Medical Genetics, Neuropsychiatric Genetics. (in press). (2003)
[Publications] Ebihara, M., et al.: "Thanscriptional activities of cholecystokinin promoter haplotypes and their relevance to panic disorder susceptibility"American Journal of Medical Genetics, Neuropsychiatric Genetics. (in press). (2003)
[Publications] Kikuchi, M., et al.: "Two-step association analyses of the chromosome 18p 11.2 region in schizophrenia detect a locus encompassing C18orf1"Molecular Psychiatry. (in press). (2003)

2002 Fiscal Year Annual Research Report

全ゲノムスキャンによる内因性精神病の感受性遺伝子群の同定

Principal Investigator

吉川 武男 理化学研究所, 分子精神科学研究チーム, チームリーダー (30249958)

Research Products

[Publications] Toyota, T., et al.: "Molecular analysis, mutation screening, and association study of adenylate cyclase type 9 gene_(ADCY9) in mood disorders"American Journal of Medical Genetics, Neuropsychiatric Genetics. 114. 84-92 (2002)

[Publications] Yoshikawa, T. et al.: "Identification of multiple genetic loci linked to the propensity for "behavioral despair" in mice"Genome Research. 12. 357-366 (2002)

[Publications] Akanuma, N., et al.: "Interictal schizophrenia-like psychosis in a patient with double cortex syndrome"The Journal of Neuropsychiatry and Clinical Neurosciences. 14. 210-213 (2002)

[Publications] Reyes, G.D., et al.: "Map of candidate genes and STSs on 18p11.2, a bipolar disorder and schizophrenia susceptibility region"Molecular Psychiatry. 7. 337-339 (2002)

[Publications] Hattori, E., et al.: "An association study of the short tandem repeat in the 5' upstream region of the cholecystokinin gene with mood disorders in the Japanese population"American Journal of Medical Genetics, Neuropsychiatric Genetics. 114. 523-526 (2002)

[Publications] Toyota, T., et al.: "Association analysis of adenylate cyclase type 9 gene using pedigree disequilibrium test in bipolar disorder"Molecular Psychiatry. 7. 450-452 (2002)

[Publications] Ebihara, M., et al.: "Genomic organization and promoter analysis of the human nicotinic acetylcholine receptor α6 subunit (CHNRA6) gene : Alu and other elements direct transcriptional repression"Gene. 298. 101-108 (2002)

[Publications] Ohtsuki, T., et al.: "Association between serotonin 4 receptor gene polymorphisms and bipolar disorder in Japanese case-control samples and the NIMH Genetics Initiative Bipolar Pedigrees"Mol. Psychiatry. 7. 954-961 (2002)

[Publications] Yoshitsugu, K., et al.: "Fine mapping of an isodicentric Y chromosomal breakpoint from a schizophrenic patient"American Journal of Medical Genetics, Neuropsychiatric Genetics. 116B. 27-31 (2003)

[Publications] Iwayama-Shigeno, Y., et al.: "Distribution of haplotypes derived from three common variants of the NR4A2 gene in Japanese schizophrenic patients"American Journal of Medical Genetics, Neuropsychiatric Genetics. (in press). (2003)

[Publications] Ebihara, M., et al.: "Thanscriptional activities of cholecystokinin promoter haplotypes and their relevance to panic disorder susceptibility"American Journal of Medical Genetics, Neuropsychiatric Genetics. (in press). (2003)

[Publications] Kikuchi, M., et al.: "Two-step association analyses of the chromosome 18p 11.2 region in schizophrenia detect a locus encompassing C18orf1"Molecular Psychiatry. (in press). (2003)

吉川武男理化学研究所, 分子精神科学研究チーム, チームリーダー (30249958)