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Norio Ozaki MD, PhDProfessor, Department of Psychiatry, Nagoya University Graduate School of Medicine


Specialized field

Psychiatry

Career Summary

March 1982:
Graduated from Nagoya University School of Medicine.
March 1990:
Got the Degree of Medical Science at Nagoya University School of Medicine.
July 1990:
Visiting Fellow, Clinical Psychobiology Branch, National Institute of Mental Health.
September 1995:
Assistant Professor, at department of Psychiatry, Fujita Health University School of Medicine.
March 1998:
Professor and Chairman, at department of Psychiatry, Fujita Health University School of Medicine.
October 2003:
Professor and Chairman, at department of Psychiatry, Nagoya University Graduate School of Medicine

Research Theme

Elucidation of Pathophysiology of Mental Disorders

Research Summary

Title

1. DISC1 related genes and schizophrenia

2. Whole genome analysis of antipsychotic response

Backgroung and Aim

1. Schizophrenia is a complex mental disorder with a fairly high degree of heritability. Although the causes of schizophrenia remain unclear, it is now widely accepted that it is a neurodevelopmental and neurodegenerative disorder involving disconnectivity and disorder of the synapses. Disrupted-in-schizophrenia 1 (DISC1) is a promising candidate susceptibility gene involved in neurodevelopment, including maturation of the cerebral cortex. To identify other susceptibility genes for schizophrenia, we screened for DISC1-interacting molecules [NudE-like (NUDEL), Lissencephaly-1 (LIS1), 14-3-3epsilon (YWHAE), growth factor receptor bound protein 2 (GRB2) and Kinesin family 5A of Kinesen1 (KIF5A)], assessing a total of 25 tagging single-nucleotide polymorphisms (SNPs) in a Japanese population.

2. Pharmacogenomic approaches based on genomewide sets of single nucleotide polymorphisms (SNPs) are now feasible and offer the potential to uncover variants that influence drug response. To detect potential predictor gene variants for risperidone response in schizophrenic subjects, we performed a convergent analysis based on 1) a genomewide (100K SNP) SNP pharmacogenetic study of risperidone response and 2) a global transcriptome study of genes with mRNA levels influenced by risperidone exposure in mouse prefrontal cortex.

Results

1. We identified a YWHAE SNP (rs28365859) that showed a highly significant difference between case and control samples, with higher minor allele frequencies in controls (P(allele) = 1.01 x 10(-5) and P(genotype) = 4.08 x 10(-5) in 1429 cases and 1728 controls). Both messenger RNA transcription and protein expression of 14-3-3epsilon were also increased in the lymphocytes of healthy control subjects harboring heterozygous and homozygous minor alleles compared with homozygous major allele subjects. To further investigate a potential role for YWHAE in schizophrenia, we studied Ywhae(+/-) mice in which the level of 14-3-3epsilon protein is reduced to 50% of that in wild-type littermates. These mice displayed weak defects in working memory in the eight-arm radial maze and moderately enhanced anxiety-like behavior in the elevated plus-maze. Our results suggest that YWHAE is a possible susceptibility gene that functions protectively in schizophrenia.

2. Fourteen genes were highlighted as of potential relevance to risperidone activity in both studies: ATP2B2, HS3ST2, UNC5C, BAG3, PDE7B, PAICS, PTGFRN, NR3C2, ZBTB20, ST6GAL2, PIP5K1B, EPHA6, KCNH5, and AJAP1. The SNPs related to these genes that were associated in the pharmacogenetic study were further assessed for evidence for association with schizophrenia in up to three case-control series comprising 1564 cases and 3862 controls in total (Japanese [JPN] 1st and 2nd samples and UK sample). Of 14 SNPs tested, one (rs9389370) in PDE7B showed significant evidence for association with schizophrenia in a discovery sample (p(allele) = .026 in JPN_1st, two-tailed). This finding replicated in a joint analysis of two independent case-control samples (p(JPN_2nd+UK) = .008, one-tailed, uncorrected) and in all combined data sets (p(all) = .0014, two-tailed, uncorrected and p(all) = .018, two-tailed, Bonferroni correction). We identified novel candidate genes for treatment response to risperidone and provide evidence that one of these additionally may confer susceptibility to schizophrenia. Specifically, PDE7B is an attractive candidate gene, although evidence from integrated methodology, including pharmacogenomics, pharmacotranscriptomic, and case-control association approaches.

Principal Research Achievement

  1. Furumura K, Koide T, Okada T, Murase S, Aleksic B, Hayakawa N, Shiino T, Nakamura Y, Tamaji A, Ishikawa N, Ohoka H, Usui H, Banno N, Morita T, Goto S, Kanai A, Masuda T, Ozaki N: Prospective Study on the Association between Harm Avoidance and Postpartum Depressive State in a Maternal Cohort of Japanese Women. PLoS One, in press (2012)
  2. Aleksic B, Kushima I, Hashimoto R, Ohi K, Ikeda M, Yoshimi A, Nakamura Y, Ito Y, Okochi T, Fukuo Y, Yasuda Y, Fukumoto M, Yamamori H, Ujike H, Suzuki M, Inada T, Takeda M, Kaibuchi K, Iwata N, Ozaki N: Analysis of the VAV3 as Candidate Gene for Schizophrenia: Evidences From Voxel-Based Morphometry and Mutation Screening. Schizophr Bull, in press (2012)
  3. Tamaji A, Iwamoto K, Kawamura Y, Takahashi M, Ebe K, Kawano N, Kunimoto S, Aleksic B, Noda Y, Ozaki N: Differential effects of diazepam, tandospirone, and paroxetine on plasma brain-derived neurotrophic factor level under mental stress. Hum Psychopharmacol, in press (2012)
  4. Kushima I, Okada T, Ozaki N: Developmental disorders. Brain Nerve, 64, 139-147 (2012)
  5. Torii Y, Iritani S, Sekiguchi H, Habuchi C, Hagikura M, Arai T, Ikeda K, Akiyama H, Ozaki N: Effects of aging on the morphologies of Heschl's gyrus and the superior temporal gyrus in schizophrenia: a postmortem study. Schizophr Res, 134, 137-142 (2012)
  6. Banno M, Koide T, Aleksic B, Yamada K, Kikuchi T, Kohmura K, Adachi Y, Kawano N, Kushima I, Ikeda M, Inada T, Yoshikawa T, Iwata N, Ozaki N: A case control association study and cognitive function analysis of neuropilin and tolloid-like 1 gene and schizophrenia in the Japanese population. PLoS One, 6, e28929 (2011)
  7. Fuchikami M, Morinobu S, Segawa M, Okamoto Y, Yamawaki S, Ozaki N, Inoue T, Kusumi I, Koyama T, Tsuchiyama K, Terao T: DNA methylation profiles of the brain-derived neurotrophic factor (BDNF) gene as a potent diagnostic biomarker in major depression. PLoS One, 6, e23881 (2011)
  8. Ikeda M, Aleksic B, Kinoshita Y, Okochi T, Kawashima K, Kushima I, Ito Y, Nakamura Y, Kishi T, Okumura T, Fukuo Y, Williams HJ, Hamshere ML, Ivanov D, Inada T, Suzuki M, Hashimoto R, Ujike H, Takeda M, Craddock N, Kaibuchi K, Owen MJ, Ozaki N, O'Donovan MC, Iwata N: Genome-wide association study of schizophrenia in a Japanese population. Biol Psychiatry, 69, 472-478 (2011)
  9. Ishikawa N, Goto S, Murase S, Kanai A, Masuda T, Aleksic B, Usui H, Ozaki N: Prospective study of maternal depressive symptomatology among Japanese women. J Psychosom Res, 71, 264-269 (2011)
  10. Kishi T, Yoshimura R, Fukuo Y, Kitajima T, Okochi T, Matsunaga S, Inada T, Kunugi H, Kato T, Yoshikawa T, Ujike H, Umene-Nakano W, Nakamura J, Ozaki N, Serretti A, Correll CU, Iwata N: The CLOCK gene and mood disorders: a case-control study and meta-analysis. Chronobiol Int, 28, 825-833 (2011)
  11. Niwa M, Matsumoto Y, Mouri A, Ozaki N, Nabeshima T: Vulnerability in early life to changes in the rearing environment plays a crucial role in the aetiopathology of psychiatric disorders. Int J Neuropsychopharmacol, 14, 459-477 (2011)
  12. Sekiguchi H, Iritani S, Habuchi C, Torii Y, Kuroda K, Kaibuchi K, Ozaki N: Impairment of the tyrosine hydroxylase neuronal network in the orbitofrontal cortex of a genetically modified mouse model of schizophrenia. Brain Res, 1392, 47-53 (2011)
  13. Takahashi N, Nielsen KS, Aleksic B, Petersen S, Ikeda M, Kushima I, Vacaresse N, Ujike H, Iwata N, Dubreuil V, Mirza N, Sakurai T, Ozaki N, Buxbaum JD, Sap J: Loss of function studies in mice and genetic association link receptor protein tyrosine phosphatase alpha to schizophrenia. Biol Psychiatry, 70, 626-635 (2011)
  14. Takata A, Kim SH, Ozaki N, Iwata N, Kunugi H, Inada T, Ujike H, Nakamura K, Mori N, Ahn YM, Joo EJ, Song JY, Kanba S, Yoshikawa T, Kim YS, Kato T: Association of ANK3 with bipolar disorder confirmed in East Asia. Am J Med Genet B Neuropsychiatr Genet, 156B, 312-315 (2011)
  15. Yoshimura T, Usui H, Takahashi N, Yoshimi A, Saito S, Aleksic B, Ujike H, Inada T, Yamada M, Uchimura N, Iwata N, Sora I, Iyo M, Ozaki N: Association analysis of the GDNF gene with methamphetamine use disorder in a Japanese population. Prog Neuropsychopharmacol Biol Psychiatry, 35, 1268-1272 (2011)
  16. Kushima I, Nakamura Y, Aleksic B, Ikeda M, Ito Y, Shiino T, Okochi T, Fukuo Y, Ujike H, Suzuki M, Inada T, Hashimoto R, Takeda M, Kaibuchi K, Iwata N, Ozaki N: Resequencing and Association Analysis of the KALRN and EPHB1 Genes And Their Contribution to Schizophrenia Susceptibility. Schizophr Bull, in press (2011)
  17. Ikeda M, Aleksic B, Kinoshita Y, Okochi T, Kawashima K, Kushima I, Ito Y, Nakamura Y, Kishi T, Okumura T, Fukuo Y, Williams HJ, Hamshere ML, Ivanov D, Inada T, Suzuki M, Hashimoto R, Ujike H, Takeda M, Craddock N, Kaibuchi K, Owen MJ, Ozaki N, O'Donovan MC, Iwata N: Genome-Wide Association Study of Schizophrenia in a Japanese Population. Biol Psychiatry, 69, 472-478 (2011)
  18. Syu A, Ishiguro H, Inada T, Horiuchi Y, Tanaka S, Ishikawa M, Arai M, Itokawa M, Niizato K, Iritani S, Ozaki N, Takahashi M, Kakita A, Takahashi H, Nawa H, Keino-Masu K, Arikawa-Hirasawa E, Arinami T: Association of the HSPG2 Gene with Neuroleptic-Induced Tardive Dyskinesia. Neuropsychopharmacology, 35, 1155-1164 (2010)
  19. Hashimoto R, Noguchi H, Hori H, Nakabayashi T, Suzuki T, Iwata N, Ozaki N, Kosuga A, Tatsumi M, Kamijima K, Harada S, Takeda M, Saitoh O, Kunugi H: A genetic variation in the dysbindin gene (DTNBP1) is associated with memory performance in healthy controls. World J Biol Psychiatry, 11, 431-438 (2010)
  20. Ishiguro H, Koga M, Horiuchi Y, Noguchi E, Morikawa M, Suzuki Y, Arai M, Niizato K, Iritani S, Itokawa M, Inada T, Iwata N, Ozaki N, Ujike H, Kunugi H, Sasaki T, Takahashi M, Watanabe Y, Someya T, Kakita A, Takahashi H, Nawa H, Arinami T: Supportive evidence for reduced expression of GNB1L in schizophrenia, Schizophr Bull, in press (2011)
  21. Takahashi M, Hayashi H, Watanabe Y, Sawamura K, Fukui N, Watanabe J, Kitajima T, Yamanouchi Y, Iwata N, Mizukami K, Hori T, Shimoda K, Ujike H, Ozaki N, Iijima K, Takemura K, Aoshima H, Someya T: Diagnostic classification of schizophrenia by neural network analysis of blood-based gene expression signatures. Schizophr Res, 119, 210-218 (2010)
  22. Ohnuma T, Shibata N, Baba H, Ohi K, Yasuda Y, Nakamura Y, Okochi T, Naitoh H, Hashimoto R, Iwata N, Ozaki N, Takeda M, Arai H: No association between DAO and schizophrenia in a Japanese patient population: a multicenter replication study. Schizophr Res, 118, 300-302 (2010)
  23. Ohi K, Hashimoto R, Yasuda Y, Yoshida T, Takahashi H, Iike N, Iwase M, Kamino K, Ishii R, Kazui H, Fukumoto M, Takamura H, Yamamori H, Azechi M, Ikezawa K, Tanimukai H, Tagami S, Morihara T, Okochi M, Yamada K, Numata S, Ikeda M, Tanaka T, Kudo T, Ueno S, Yoshikawa T, Ohmori T, Iwata N, Ozaki N, Takeda M: The chitinase 3-like 1 gene and schizophrenia: Evidence from a multi-center case-control study and meta-analysis. Schizophr Res, 116, 126-132 (2010)
  24. Kushima I, Aleksic B, Ito Y, Nakamura Y, Nakamura K, Mori N, Kikuchi M, Inada T, Kunugi H, Nanko S, Kato T, Yoshikawa T, Ujike H, Suzuki M, Iwata N, Ozaki N: Association study of ubiquitin-specific peptidase 46 (USP46) with bipolar disorder and schizophrenia in a Japanese population. J Hum Genet, 55, 133-136 (2010)
  25. Kushima I, Aleksic B, Ikeda M, Yamanouchi Y, Kinoshita Y, Ito Y, Nakamura Y, Inada T, Iwata N, Ozaki N: Association study of bromodomain-containing 1 gene with schizophrenia in Japanese population. Am J Med Genet B Neuropsychiatr Genet, 153B, 786-791 (2010)
  26. Ishiguro H, Horiuchi Y, Ishikawa M, Koga M, Imai K, Suzuki Y, Morikawa M, Inada T, Watanabe Y, Takahashi M, Someya T, Ujike H, Iwata N, Ozaki N, Onaivi ES, Kunugi H, Sasaki T, Itokawa M, Arai M, Niizato K, Iritani S, Naka I, Ohashi J, Kakita A, Takahashi H, Nawa H, Arinami T: Brain Cannabinoid CB2 Receptor in Schizophrenia. Biol Psychiatry, 67, 974-982 (2010)
  27. Ikeda M, Tomita Y, Mouri A, Koga M, Okochi T, Yoshimura R, Yamanouchi Y, Kinoshita Y, Hashimoto R, Williams H.J, Takeda M, Nakamura J, Nabeshima T, Owen M.J, O'Donovan M.C, H. Honda, Arinami T, Ozaki N, Iwata N: Identification of Novel Candidate Genes for Treatment Response to Risperidone and Susceptibility for Schizophrenia: Integrated Analysis Among Pharmacogenomics, Mouse Expression, and Genetic Case-Control Association Approaches. Biol Psychiatry, 1, 67, 263-269 (2010)
  28. Ikeda M, Aleksic B, Kirov G, Kinoshita Y, Yamanouchi Y, Kitajima T, Kawashima K, Okochi T, Kishi T, Zaharieva I, Owen MJ, O'Donovan MC, Ozaki N, Iwata N: Copy number variation in schizophrenia in the Japanese population. Biol Psychiatry, 67, 283-286 (2010)
  29. Iidaka T, Saito DN, Komeda H, Mano Y, Kanayama N, Osumi T, Ozaki N, Sadato N: Transient Neural Activation in Human Amygdala Involved in Aversive Conditioning of Face and Voice. J Cogn Neurosci, 22, 2074-2085 (2010)
  30. Aleksic B, Kushima I, Ito Y, Nakamura Y, Ujike H, Suzuki M, Inada T, Hashimoto R, Takeda M, Iwata N, and Ozaki N: Genetic association study of KREMEN1 and DKK1 and schizophrenia in a Japanese population. Schizophr Res, 118, 113-117 (2010)
  31. Koga M, Ishiguro H, Yazaki S, Horiuchi Y, Arai M, Niizato K, Iritani S, Itokawa M, Inada T, Iwata N, Ozaki N, Ujike H, Kunugi H, Sasaki T, Takahashi M, Watanabe Y, Someya T, Kakita A, Takahashi H, Nawa H, Muchardt C, Yaniv M, Arinami T. Involvement of SMARCA2/BRM in the SWI/SNF chromatin-remodeling complex in schizophrenia. Hum Mol Genet, 18, 2483-2494 (2009)
  32. Yoshimi A, Takahashi N, Saito S, Ito Y, Aleksic B, Usui H, Kawamura Y, Waki Y, Yoshikawa T, Kato T, Iwata N, Inada T, Noda Y, Ozaki N. Genetic analysis of the gene coding for DARPP-32 (PPP1R1B) in Japanese patients with schizophrenia or bipolar disorder. Schizophr Res, 100, 334-341 (2008)
  33. Yamasaki N, Maekawa M, Kobayashi K, Kajii Y, Maeda J, Soma M, Takao K, Tanda K, Ohira K, Toyama K, Kanzaki K, Fukunaga K, Sudo Y, Ichinose H, Ikeda M, Iwata N, Ozaki N, Suzuki H, Higuchi M, Suhara T, Yuasa S, Miyakawa T. Alpha-CaMKII deficiency causes immature dentate gyrus, a novel candidate endophenotype of psychiatric disorders. Mol Brain, 1, 6 (2008)
  34. Uhl GR, Drgon T, Liu QR, Johnson C, Walther D, Komiyama T, Harano M, Sekine Y, Inada T, Ozaki N, Iyo M, Iwata N, Yamada M, Sora I, Chen CK, Liu HC, Ujike H, Lin SK. Genome-wide association for methamphetamine dependence: convergent results from 2 samples. Arch Gen Psychiatry, 65, 345-355 (2008)
  35. Kuratomi G, Iwamoto K, Bundo M, Kusumi I, Kato N, Iwata N, Ozaki N, Kato T. Aberrant DNA methylation associated with bipolar disorder identified from discordant monozygotic twins. Mol Psychiatry, 13, 429-441 (2008)
  36. Kishimoto M, Ujike H, Motohashi Y, Tanaka Y, Okahisa Y, Kotaka T, Harano M, Inada T, Yamada M, Komiyama T, Hori T, Sekine Y, Iwata N, Sora I, Iyo M, Ozaki N, Kuroda S. The Dysbindin Gene (DTNBP1) Is Associated with Methamphetamine Psychosis. Biol Psychiatry, 63, 191-196 (2008)
  37. Inada T, Koga M, Ishiguro H, Horiuchi Y, Syu A, Yoshio T, Takahashi N, Ozaki N, Arinami T. Pathway-based association analysis of genome-wide screening data suggest that genes associated with the gamma-aminobutyric acid receptor signaling pathway are involved in neuroleptic-induced, treatment-resistant tardive dyskinesia. Pharmacogenet Genomics, 18, 317-323 (2008)
  38. Ikeda M, Yamanouchi Y, Kinoshita Y, Kitajima T, Yoshimura R, Hashimoto S, O'Donovan MC, Nakamura J, Ozaki N, Iwata N. Variants of dopamine and serotonin candidate genes as predictors of response to risperidone treatment in first-episode schizophrenia. Pharmacogenomics, 9, 1437-1443 (2008)
  39. Ikeda M, Takahashi N, Saito S, Aleksic B, Watanabe Y, Nunokawa A, Yamanouchi Y, Kitajima T, Kinoshita Y, Kishi T, Kawashima K, Hashimoto R, Ujike H, Inada T, Someya T, Takeda M, Ozaki N, Iwata N. Failure to replicate the association between NRG1 and schizophrenia using Japanese large sample. Schizophr Res, 101, 1-8 (2008)
  40. Ikeda M, Hikita T, Taya S, Uraguchi-Asaki J, Toyo-oka K, Wynshaw-Boris A, Ujike H, Inada T, Takao K, Miyakawa T, Ozaki N, Kaibuchi K, Iwata N. Identification of YWHAE, a gene encoding 14-3-3epsilon, as a possible susceptibility gene for schizophrenia. Hum Mol Genet, 17, 3212-3222 (2008)
  41. Ohnishi T et al. A Promoter Haplotype of the Inositol Monophosphatase 2 Gene (IMPA2) at 18p11.2 Confers a Possible Risk for Bipolar Disorder by Enhancing Transcription. Neuropsychopharmacology 32: 1727-1737 (2007)
  42. Matsuzawa D et al. Identification of Functional Polymorphisms in the Promoter Region of the Human PICK1 Gene and Their Association With Methamphetamine Psychosis. Am. J. Psychiatry 164: 1105-1114 (2007)
  43. Horiuchi Y et al. Support for association of the PPP3CC gene with schizophrenia. Mol. Psychiatry 12: 891-893 (2007)
  44. Hashimoto R et al. Pituitary adenylate cyclase-activating polypeptide is associated with schizophrenia. Mol. Psychiatry 12: 1026-1032 (2007)
  45. Ikeda M et al. Positive association of the serotonin 5-HT7 receptor gene with schizophrenia in a Japanese population. Neuropsychopharmacology 31: 866-871 (2006)
  46. Hashimoto R et al. Impact of the DISC1 Ser704Cys polymorphism on risk for major depression, brain morphology and ERK signaling. Hum. Mol. Genet. 15: 3024-3033 (2006)
  47. Ikeda M et al. Association Analysis of Chromosome 5 GABA(A) Receptor Cluster in Japanese Schizophrenia Patients. Biol. Psychiatry 58: 440-445 (2005)
  48. Arinami T et al. Genomewide high-density SNP linkage analysis of 236 Japanese families supports the existence of schizophrenia susceptibility Loci on chromosomes 1p, 14q, and 20p. Am. J. Hum. Genet. 77: 937-944 (2005)
  49. Iidaka T et al. A variant C178T in the regulatory region of the serotonin receptor gene HTR3A modulates neural activation in the human amygdala. J. Neurosci. 25: 6460-6466 (2005)
  50. Okada M et al. Modification of Human 5-HT2C Receptor Function by Cys23Ser, an Abundant, Naturally Occurring Amino Acid Substitution. Mol. Psychiatry 9: 55-64 (2004)
  51. Numakawa T et al. Evidence of novel neuronal functions of dysbindin, a susceptibility gene for schizophrenia. Hum. Mol. Genet. 13: 2699-2708 (2004)
  52. Iwata N et al. No Association With the Neuregulin 1 Haplotype to Japanese Schizophrenia. Mol. Psychiatry 9: 126-127 (2004)
  53. Ikeda M et al. Association of AKT1 with schizophrenia confirmed in a Japanese population. Biol. Psychiatry 56: 698-700 (2004)
  54. Ozaki N et al. Serotonin transporter missense mutation associated with a complex neuropsychiatric phenotype. Mol. Psychiatry 8: 933-936 (2003)
  55. Iwata N et al. Association of a 5-HT(5A) receptor polymorphism, Pro15Ser, to schizophrenia. Mol. Psychiatry 6: 217-219 (2001)
  56. Lappalainen J et al. Linkage of antisocial alcoholism to the serotonin 5-HT1B receptor gene in 2 populations. Arch. Gen. Psychiatry 55: 989-994 (1998)
  57. Schwartz PJ et al. Effects of meta-chlorophenylpiperazine infusions in patients with seasonal affective disorder and healthy control subjects. Diurnal responses and nocturnal regulatory mechanisms. Arch. Gen. Psychiatry 54: 375-385 (1997)
  58. Ozaki N. et al. Two naturally occurring amino acid substitutions of the 5-HT2A receptor, similar prevalence in patients with seasonal affective disorder and controls. Biol. Psychiatry 40: 1267-1272 (1996)
  59. Malhotra AK et al. Lack of association between polymorphisms in the 5-HT2A receptor gene and the antipsychotic response to clozapine. Am. J. Psychiatry 153: 1092-1094 (1996)
  60. Ozaki N et al. Prevalence of seasonal difficulties in mood and behavior among Japanese civil servants. Am. J. Psychiatry 152: 1225-1227 (1995)

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