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遺伝子グループ詳細

精神疾患の遺伝子研究

1) 末梢血発現研究

精神疾患は脳の病気であるが、HPA系、免疫系、自律神経系を介して全身に影響が及ぶ。 その中でも我々は、精神疾患、とりわけ、うつ病の候補遺伝子における白血球遺伝子発現 への影響を治療前後のサンプルを用いて詳細に検討してきました(serotonin transporter, HDAC5, CREB, VEGFなど)。最近では、DNAマイクロアレイを用いて、網羅的にうつ病 に関連する新たな遺伝子の同定、診断キットの開発、抗うつ薬やリチウムの作用機序解明 に取り組んでいます。

2) SNP解析研究

機能的に、病態的にうつ病や統合失調症で関与が推定される遺伝子を中心に関連研究を行 っている。これまでにDISC1遺伝子に注目し、DISC1関連遺伝子を中心に関連研究を行い、 PDE4B遺伝子が統合失調症と、PCNT遺伝子がうつ病と関連がすることを報告しました。 また、他大学と共同で大規模な関連研究も行っています。

3) DNAメチル化修飾解析研究

精神疾患の病態に関与する要因として、遺伝子多型や環境因子だけでなくエピジェネティックスの重要性が指摘されています。 DNAのメチル化修飾とは、シトシン塩基(C)とグアニン塩基(G)が連続している配列の部分(CpG)でシトシンがメチル化されることを言います。 この修飾は、塩基配列の変化を伴わず、クロマチンの構造変化、ゲノムインプリンティング、X染色体の不活化、遺伝子発現に関与することが知られています。 これまでに癌の病態や治療反応性への関連が多く報告されており、近年、精神科領域でも注目されている分野の1つです。 我々は、メチル化修飾解析研究チップを用いた網羅的な解析を行い、統合失調症、気分障害、発達障害に関連する新たな遺伝子の同定、診断キットの開発、 抗精病薬の作用機序解明に取り組んでいます。

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2012年以降の各研究の業績(2018年7月更新)

1)白血球遺伝子発現解析
  1. Watanabe SY, Numata S, Iga JI, Kinoshita M, Umehara H, et al. Gene expression-based biological test for major depressive disorder: an advanced study. Neuropsychiatr Dis Treat. 2017 Feb 21;13:535-541.
  2. Yoshino Y, Kawabe K, Yamazaki K, Watanabe S, Numata S, et al. Elevated TREM2 mRNA expression in leukocytes in schizophrenia but not major depressive disorder. J Neural Transm (Vienna). 2016 Jun;123(6):637-41.
  3. Iga JI, Watanabe SY, Numata S, Umehara H, Nishi A, et al. Association study of polymorphism in the serotonin transporter gene promoter, methylation profiles, and expression in patients with major depressive disorder. Hum Psychopharmacol. 2016 May;31(3):193-9.
  4. Mori Y, Yoshino Y, Ochi S, Yamazaki K, Kawabe K, et al. TREM2 mRNA Expression in Leukocytes Is Increased in Alzheimer's Disease and Schizophrenia. PLoS One. 2015 Sep 2;10(9):e0136835.
  5. Watanabe SY, Iga JI, Ishii K, Numata S, Shimodera S, et al. Biological tests for major depressive disorder that involve leukocyte gene expression assays. J Psychiatr Res. 2015 Jul-Aug;66-67C:1-6.
  6. Watanabe S, Iga J, Nishi A, Numata S, Kinoshita M, et al. Microarray analysis of global gene expression in leukocytes following lithium treatment. Hum Psychopharmacol. 2014 Mar;29(2):190-8.
2)遺伝子塩基配列解析
  1. Zhang Y, Hishimoto A, Otsuka I, Watanabe Y, Numata S, et al. Longer telomeres in elderly schizophrenia are associated with long-term hospitalization in the Japanese population. J Psychiatr Res. 2018 Aug;103:161-166.
  2. Nishi A, Numata S, Tajima A, Zhu X, Ito K, et al.. De novo non-synonymous TBL1XR1 mutation alters Wnt signaling activity. Sci Rep. 2017 Jun 6;7(1):2887.
  3. Saito T, Ikeda M, Hashimoto R, Iwata N; Members of the Clozapine Pharmacogenomics Consortium of Japan are the following, Yamamori H, et al. Yasuda Y, Fujimoto M, Kondo K, Shimasaki A, Kawase K, Miyata M, Mushiroda T, Transethnic Replication Study to Assess the Association Between Clozapine-Induced Agranulocytosis/Granulocytopenia and Genes at 12p12.2 in a Japanese Population. Biol Psychiatry. 2017 Jul 1;82(1):e9-e10.
  4. Kinoshita M, Numata S, Tajima A, Nishi A, Muraki S, et al. Cumulative effect of the plasma total homocysteine-related genetic variants on schizophrenia risk. Psychiatry Res. 2016 Dec 30;246:833-837.
  5. Umehara H, Numata S, Tajima A, Nishi A, Nakataki M, et al. Calcium Signaling Pathway Is Associated with the Long-Term Clinical Response to Selective Serotonin Reuptake Inhibitors (SSRI) and SSRI with Antipsychotics in Patients with Obsessive-Compulsive Disorder. PLoS One. 2016 Jun 9;11(6):e0157232.
  6. Kushima I, Aleksic B, Nakatochi M, Shimamura T, Shiino T, et al. High-resolution copy number variation analysis of schizophrenia in Japan. Mol Psychiatry. 2017 Mar;22(3):430-440.
  7. Saito T, Ikeda M, Mushiroda T, Ozeki T, Kondo K, et al. Pharmacogenomic Study of Clozapine-Induced Agranulocytosis/Granulocytopenia in a Japanese Population. Biol Psychiatry. 2016 Feb 11. [Epub ahead of print]
  8. Nakazawa T, Hashimoto R, Sakoori K, Sugaya Y, Tanimura A, et al. Emerging roles of ARHGAP33 in intracellular trafficking of TrkB and pathophysiology of neuropsychiatric disorders. Nat Commun. 2016 Feb 3;7:10594.
  9. Umehara H, Numata S, Kinoshita M, Watanabe S, Nakaaki S,et al. No association between BDNF Val66Met polymorphism and treatment response in obsessive-compulsive disorder in the Japanese population. Neuropsychiatric Disease and Treatment. 2016 Mar 11;12:611-5.
  10. Umehara H, Numata S, Tajima A, Kinoshita M, Nakaaki S, et al. No association between the COMT Val158Met polymorphism and the long-term clinical response in obsessive-compulsive disorder in the Japanese population. Hum Psychopharmacol. 2015 Sep;30(5):372-6.
  11. Watanabe SY, Iga JI, Numata S, Umehara H, Nishi A, et al. Polymorphism in the promoter of the gene for the serotonin transporter affects the age of onset of major depressive disorder in the Japanese population. J Affect Disord. 2015 May 15;183:156-158.
  12. Yoshino Y, Mori Y, Ochi S, Numata S, Ishimaru T, et al. No abnormal hexanucleotide repeat expansion of C9ORF72 in Japanese schizophrenia patients. J Neural Transm (Vienna). 2015 May;122(5):731-2.
  13. Yoshino Y, Abe M, Numata S, Ochi S, Mori Y, et al. Missense variants of the alanine:glyoxylate aminotransferase 2 gene are not associated with Japanese schizophrenia patients. Prog Neuropsychopharmacol Biol Psychiatry. 2014 Aug 4;53:137-41.
  14. Liu J, Numata S, Ikeda M, Watanabe Y, Zheng XB, et al. An evaluation of association between a novel hippocampal biology related SNP (rs7294919) and schizophrenia. PLoS One. 2013 Nov 22;8(11):e80696.
  15. Watanabe SY, Iga J, Numata S, Nakataki M, Tanahashi T, et al. Association Study of Fat-mass and Obesity-associated Gene and Body Mass Index in Japanese Patients with Schizophrenia and Healthy Subjects. Clin Psychopharmacol Neurosci. 2012 Dec;10(3):185-9.
  16. Kinoshita M, Numata S, Tajima A, Ohi K, Hashimoto R, et al. Meta-analysis of association studies between DISC1 missense variants and schizophrenia in the Japanese population. Schizophr Res. 2012 Nov;141(2-3):271-3.
  17. Ikeda M, Aleksic B, Yamada K, Iwayama-Shigeno Y, Matsuo K, et al. Genetic evidence for association between NOTCH4 and schizophrenia supported by a GWAS follow-up study in a Japanese population. Mol Psychiatry. 2013 Jun;18(6):636-8.
  18. Ohi K, Hashimoto R, Yasuda Y, Fukumoto M, Yamamori H, et al. Functional genetic variation at the NRGN gene and schizophrenia: Evidence from a gene-based case-control study and gene expression analysis. Am J Med Genet B Neuropsychiatr Genet. 2012 Jun;159B(4):405-13.
3)エピジェネティクス研究
  1. Kinoshita M, Numata S, Tajima A, Yamamori H, Yasuda Y, et al. Effect of Clozapine on DNA Methylation in Peripheral Leukocytes from Patients with Treatment-Resistant Schizophrenia. Int J Mol Sci. 2017 Mar 14;18(3). pii: E632
  2. Yoshino Y, Kawabe K, Mori T, Mori Y, Yamazaki K et al. Low methylation rates of dopamine receptor D2 gene promoter sites in Japanese schizophrenia subjects. World J Biol Psychiatry. 2016 Sep;17(6):449-56.
  3. Inoshita M, Numata S, Tajima A, Kinoshita M, Umehara H, et al. Sex differences of leukocytes DNA methylation adjusted for estimated cellular proportions. Biol Sex Differ. 2015 Jun 25;6:11.
  4. Numata S, Ishii K, Tajima A, Iga JI, Kinoshita M, et al. Blood Diagnostic Biomarkers for Major Depressive Disorder using Multiplex DNA Methylation Profiles: Discovery and Validation. Epigenetics. 2015 Feb;10(2):135-41.
  5. Numata S, Ye T, Herman M, Lipska BK. DNA methylation changes in the postmortem dorsolateral prefrontal cortex of patients with schizophrenia. Front Genet. 2014 Aug 26;5:280
  6. Kinoshita M, Numata S, Tajima A, Ohi K, Hashimoto R, et al. Aberrant DNA methylation of blood in schizophrenia by adjusting for estimated cellular proportions. Neuromolecular Med. 2014 Dec;16(4):697-703.
  7. Kinoshita M, Numata S, Tajima A, Shimodera S, Imoto I, et al. Plasma total homocysteine is associated with DNA methylation in patients with schizophrenia. Epigenetics. 2013 Jun 1;8(6):584-90.
  8. Kinoshita M, Numata S, Tajima A, Shimodera S, Ono S, et al. DNA Methylation Signatures of Peripheral Leukocytes in Schizophrenia. Neuromolecular Med. 2013 Mar;15(1):95-101
  9. Numata S, Ye T, Hyde TM, Guitart-Navarro X, Tao R, et al. DNA methylation signatures in development and aging of the human prefrontal cortex. Am J Hum Genet. 2012 Feb 10;90(2):260-72.
4)血漿研究
  1. Tomioka Y, Numata S, Kinoshita M, Umehara H, Watanabe SY, et al.. Decreased serum pyridoxal levels in schizophrenia: meta-analysis and Mendelian randomization analysis. J Psychiatry Neurosci. 2018 May;43(3):194-200.
  2. Inoshita M, Umehara H, Watanabe SY, Nakataki M, Kinoshita M, et al. Elevated peripheral blood glutamate levels in major depressive disorder. Neuropsychiatr Dis Treat. 2018 Apr 6;14:945-953.
  3. Kudo N, Yamamori H, Ishima T, Nemoto K, Yasuda Y, et al.. Plasma Levels of Soluble Tumor Necrosis Factor Receptor 2 (sTNFR2) Are Associated with Hippocampal Volume and Cognitive Performance in Patients with Schizophrenia. Int J Neuropsychopharmacol. 2018 Jul 1;21(7):631-639.
  4. Okazaki S, Hishimoto A, Otsuka I, Watanabe Y, Numata S, et al. Increased serum levels and promoter polymorphisms of macrophage migration inhibitory factor in schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry. 2018 Apr 20;83:33-41.
  5. Umehara H, Numata S, Watanabe SY, Hatakeyama Y, Kinoshita M, et al. Altered KYN/TRP, Gln/Glu, and Met/methionine sulfoxide ratios in the blood plasma of medication-free patients with major depressive disorder. Sci Rep. 2017 Jul 7;7(1):4855.
  6. Numata S, Kinoshita M, Tajima A, Nishi A, Imoto I, et al. Evaluation of an association between plasma total homocysteine and schizophrenia by a Mendelian randomization analysis. BMC Med Genet. 2015 Jul 26;16:54
  7. Yamamori H, Hashimoto R, Fujita Y, Numata S, Yasuda Y, et al. Changes in plasma D-serine, L-serine, and glycine levels in treatment-resistant schizophrenia before and after clozapine treatment. Neurosci Lett. 2014 Oct 17;582:93-8.
  8. Nishi A, Numata S, Tajima A, Kinoshita M, Kikuchi K, et al. Meta-analyses of Blood Homocysteine Levels for Gender and Genetic Association Studies of the MTHFR C677T Polymorphism in Schizophrenia. Schizophr Bull. 2014 Sep;40(5):1154-63.
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