Identification of rare genetic variants associated with bipolar disorder and comprehensive analysis to elucidate its pathophysiology

• Project/Area Number: 25253072
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Psychiatric science
• Research Institution: Nagoya University
• Principal Investigator: OZAKI Norio 名古屋大学, 医学(系)研究科(研究院), 教授 (40281480)
• Co-Investigator(Renkei-kenkyūsha): IRITANI Syuji 名古屋大学, 大学院医学系研究科, 寄附講座教授 (60191904) ; IIDAKA Tetsuya 名古屋大学, 大学院医学系研究科, 准教授 (70324366) ; ALEKSIC Branko 名古屋大学, 大学院医学系研究科(国際), 特任准教授 (60547511) ; KUNIMOTO Shohko 名古屋大学, 大学院医学系研究科, 特任助教 (30350135) ; KANBA Shigenobu (NODA Yukihiro / OKANO Hideyuki / IWATA Nakao) 九州大学, 医学部, 教授 (60312112)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥45,500,000 (Direct Cost: ¥35,000,000、Indirect Cost: ¥10,500,000); Fiscal Year 2015: ¥13,000,000 (Direct Cost: ¥10,000,000、Indirect Cost: ¥3,000,000); Fiscal Year 2014: ¥9,100,000 (Direct Cost: ¥7,000,000、Indirect Cost: ¥2,100,000); Fiscal Year 2013: ¥23,400,000 (Direct Cost: ¥18,000,000、Indirect Cost: ¥5,400,000)
• Keywords: 双極性障害 / ゲノムコピー数変異 / ゲノムコピー数多型 / CNV

Outline of Final Research Achievements

We performed a high-resolution genome-wide copy number variation (CNV) analysis on Japanese patients with bipolar disorder (BP). We identified clinically significant CNVs in around 6% of BP patients. Among others, PCDH15 (protocadherin 15) was identified as a promising candidate gene because exonic deletions were observed in three patients. From two BP patients with PCDH15 deletions, we established induced pluripotent stem (iPS) cell lines. We applied genome-modifying technology of CRISPR/Cas9 method and generated the Pcdh15-deficient mice, carrying the NHEJ mutant allele.

Research Products

• [Journal Article] Catecholaminergic neuronal network dysfunction in the frontal lobe of a genetic mouse model of schizophrenia (2016)
  • Author(s): Shuji Iritani, Hirotaka Sekiguchi, Chikako Habuchi, Youta Torii, Keisuke Kuroda, Kozo Kaibuchi and Norio Ozaki
  • Journal Title: Acta Neuropsychiatrica Volume: 28 Issue: 2 Pages: 117-123
  • DOI: 10.1017/neu.2015.51
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] White matter microstructure between the pre-SMA and the cingulum bundle is related to response conflict in healthy subjects. (2015)
  • Author(s): Yamamoto M, Kushima I, Kimura H, Hayashi A, Kawano N, Aleksic B, Iidaka T, Ozaki N
  • Journal Title: Brain Behav Volume: 5 Issue: 10
  • DOI: 10.1002/brb3.375
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Glia-related genes and their contribution to schizophrenia. (2015)
  • Author(s): Wang C, Aleksic B, Ozaki N
  • Journal Title: Psychiatry Clin Neurosci Volume: in press Issue: 8 Pages: 448-461
  • DOI: 10.1111/pcn.12290
  • Peer Reviewed / Open Access
• [Journal Article] The Disrupted-in-Schizophrenia-1 Ser704Cys polymorphism and brain neurodevelopmental markers in schizophrenia and healthy subjects. (2015)
  • Author(s): Takahashi T, Nakamura M, Nakamura Y, Aleksic B, Kido M, Sasabayashi D, Takayanagi Y, Furuichi A, Nishikawa Y, Noguchi K, Ozaki N, Suzuki M
  • Journal Title: Prog Neuropsychopharmacol Biol Psychiatry Volume: 56 Pages: 11-17
  • DOI: 10.1016/j.pnpbp.2014.07.005
  • Peer Reviewed / Open Access
• [Journal Article] Identification of rare, single-nucleotide mutations in NDE1 and their contributions to schizophrenia susceptibility (2015)
  • Author(s): Kimura H, Tsuboi D, Wang C, Kushima I, Koide T, Ikeda M, Iwayama Y, Toyota T, Yamamoto N, Kunimoto S, Nakamura Y, Yoshimi A, Banno M, Xing J, Takasaki Y, Yoshida M, Aleksic B, Uno Y, Okada T, Iidaka T, Inada T, Suzuki M, Ujike H, Kunugi H, Kato T, Yoshikawa T, Iwata N, Kaibuchi K
  • Journal Title: Schizophrenia Bulltein Volume: 41 Issue: 3 Pages: 744
  • DOI: 10.1093/schbul/sbu147
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Association study of BCL9 gene polymorphism rs583583 with schizophrenia and negative symptoms in Japanese population. (2015)
  • Author(s): Kimura H, Tanaka S, Kushima I, Koide T, Banno M, Kikuchi T, Nakamura Y, Shiino T, Yoshimi A, Oya-Ito T, Xing J, Wang C, Takasaki Y, Aleksic B, Okada T, Ikeda M, Inada T, Iidaka T, Iwata N, Ozaki N.
  • Journal Title: Scientific reports Volume: 5 Issue: 1 Pages: 15705-15705
  • DOI: 10.1038/srep15705
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Blonanserin ameliorates phencyclidine-induced visual-recognition memory deficits: the complex mechanism of blonanserin action involving D3-5-HT2A and D1-NMDA receptors in the mPFC (2015)
  • Author(s): Hida H, Mouri A, Mori K, Matsumoto Y, Seki T, Taniguchi M, Yamada K, Iwamoto K, Ozaki N, Nabeshima T, Noda Y
  • Journal Title: Neuropsychopharmacology Volume: 40 Issue: 3 Pages: 601-613
  • DOI: 10.1038/npp.2014.207
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] No support for replication of the genetic variants identified by a recent mega-analysis of the treatment response to antidepressants (2015)
  • Author(s): Hatano M, Ikeda M, Kondo K, Saito T, Shimasaki A, Esaki K, Umene-Nakano W, Yoshimura R, Nakamura J, Ozaki N, Iwata N
  • Journal Title: J Hum Genet Volume: in press Issue: 6 Pages: 343-344
  • DOI: 10.1038/jhg.2015.21
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Replication and cross-phenotype study based upon schizophrenia GWASs data in the Japanese population: Support for association of MHC region with psychosis (2014)
  • Author(s): Saito T, Kondo K, Iwayama Y, Shimasaki A, Aleksic B, Yamada K, Toyota T, Hattori E, Esaki K, Ujike H, Inada T, Kunugi H, Kato T, Yoshikawa T, Ozaki N, Ikeda M, Iwata N.
  • Journal Title: Am J Med Genet B Neuropsychiatr Genet Volume: 165 Issue: 5 Pages: 421
  • DOI: 10.1002/ajmg.b.32246
  • Peer Reviewed / Open Access
• [Journal Article] Genetic association study between the detected risk variants based upon type II diabetes GWAS and psychotic disorders in the Japanese population (2014)
  • Author(s): Kajio Y, Kondo K, Saito T, Iwayama Y, Aleksic B, Yamada K, Toyota T, Hattori E, Ujike H, Inada T, Kunugi H, Kato T, Yoshikawa T, Ozaki N, Ikeda M, Iwata N.
  • Journal Title: J Hum Genet Volume: 59 Issue: 1 Pages: 54
  • DOI: 10.1038/jhg.2013.116
  • Peer Reviewed
• [Journal Article] Effects of maternal depressive symptomatology during pregnancy and the postpartum period on infant-mother attachment. (2014)
  • Author(s): Ohoka H, Koide T, Goto S, Murase S, Kanai A, Masuda T, Aleksic B, Ishikawa N, Furumura K, Ozaki N
  • Journal Title: Psychiatry Clin Neurosci Volume: 68 Issue: 8 Pages: 631-639
  • DOI: 10.1111/pcn.12171
  • Peer Reviewed
• [Journal Article] Genome-wide association study identifies a potent locus associated with human opioid sensitivity. (2014)
  • Author(s): Nishizawa D, Fukuda K, Kasai S, Hasegawa J, Aoki Y, Nishi A, Saita N, Koukita Y, Nagashima M, Katoh R, Satoh Y, Tagami M, Higuchi S, Ujike H, Ozaki N, Inada T, Iwata N, Sora I, Iyo M, Kondo N, Won MJ, Naruse N, Uehara-Aoyama K, Itokawa M, Koga M, Arinami T, Kaneko Y, Hayashida M, Ikeda K.
  • Journal Title: Mol Psychiatry Volume: 19(1) Issue: 1 Pages: 55-62
  • DOI: 10.1038/mp.2012.164
  • Peer Reviewed
• [Journal Article] Plasma dehydroepiandrosterone sulfate levels in patients with major depressive disorder correlate with remission during treatment with antidepressants (2014)
  • Author(s): Tokiko Morita, Koji Senzaki, Ryoko Ishihara, Kazunori Umeda, Nakao Iwata, Taku Nagai, Hirotake Hida, Toshitaka Nabeshima, Kazunori Yukawa, Norio Ozaki, Yukihiro Noda
  • Journal Title: Hum. Psychopharmacol.: Clin. Exp. Volume: 29 Issue: 3 Pages: 280-286
  • DOI: 10.1002/hup.2400
  • Peer Reviewed / Open Access
• [Journal Article] Factor structure of the Japanese version of the edinburgh postnatal depression scale in the postpartum period. (2014)
  • Author(s): Kubota C, Okada T, Aleksic B, Nakamura Y, Kunimoto S, Morikawa M, Shiino T, Tamaji A, Ohoka H, Banno N, Morita T, Murase S, Goto S, Kanai A, Masuda T, Ando M, Ozaki N
  • Journal Title: PLoS One Volume: 9 Issue: 8 Pages: e103941-e103941
  • DOI: 10.1371/journal.pone.0103941
  • Peer Reviewed
• [Journal Article] A population-specific uncommon variant in GRIN3A associated with schizophrenia (2013)
  • Author(s): Takata A, Iwayama Y, Fukuo Y, Ikeda M, Okochi T, Maekawa M, Toyota T, YamadaK, Hattori E, Ohnishi T, Toyoshima M, Ujike H, Inada T, Kunugi H, Ozaki N, Nanko S, Nakamura K, Mori N, Kanba S, Iwata N, Kato T, Yoshikawa T.
  • Journal Title: Biol Psychiatry. Volume: 73 Issue: 6 Pages: 532
  • DOI: 10.1016/j.biopsych.2012.10.024
  • Peer Reviewed
• [Journal Article] Common variants in bcl9 gene and schizophrenia in a japanese population: Association study, meta-analysis and cognitive function analysis. (2013)
  • Author(s): Shiino T, Koide T, Kushima I, Ikeda M, Kunimoto S, Nakamura Y, Yoshimi A, Aleksic B, Banno M, Kikuchi T, Kohmura K, Adachi Y, Kawano N, Okada T, Inada T, Ujike H, Iidaka T, Suzuki M, Iwata N, Ozaki N
  • Journal Title: J Med Biochem Volume: 32 (4) Pages: 351-357
  • Peer Reviewed
• [Journal Article] Functional analysis of deep intronic SNP rs13438494 in intron 24 of PCLO gene (2013)
  • Author(s): Seo S, Takayama K, Uno K, Ohi K, Hashimoto R, Nishizawa D, Ikeda K, Ozaki N, Nabeshima T, Miyamoto Y, Nitta A
  • Journal Title: PLoS ONE Volume: 8(10) Issue: 10 Pages: e76960-e76960
  • DOI: 10.1371/journal.pone.0076960
  • Peer Reviewed
• [Journal Article] Assessment of Response to Lithium Maintenance Treatment in Bipolar Disorder: A Consortium on Lithium Genetics (ConLiGen) Report. (2013)
  • Author(s): Manchia M, Adli M, Akula N, Ozaki N,他96名
  • Journal Title: PLoS One Volume: 8 (6)
  • Peer Reviewed
• [Journal Article] Genetic Variants on 3q21 and in the Sp8 Transcription Factor Gene (SP8) as Susceptibility Loci for Psychotic Disorders: A Genetic Association Study (2013)
  • Author(s): Kondo K, Ikeda M, Kajio Y, Saito T, Iwayama Y, Aleksic B, Yamada K, Toyota T, Hattori E, Ujike H, Inada T, Kunugi H, Kato T, Yoshikawa T, Ozaki N, Iwata N
  • Journal Title: PLoS One Volume: 8 Issue: 8 Pages: e70964-e70964
  • DOI: 10.1371/journal.pone.0070964
  • Peer Reviewed
• [Journal Article] Lack of association of EGR2 variants with bipolar disorder in Japanese population (2013)
  • Author(s): Balan S, Yamada K, Iwayama Y, Toyota T, Ohnishi T, Maekawa M, Toyoshima M, Iwata Y, Suzuki K, Kikuchi M, Ujike H, Inada T, Kunugi H, Ozaki N, Iwata N, Nanko S, Kato T, Yoshikawa T
  • Journal Title: Gene Volume: 526 Issue: 2 Pages: 246
  • DOI: 10.1016/j.gene.2013.05.055
  • Peer Reviewed
• [Journal Article] Definition and refinement of the 7q36.3 duplication region associated with schizophrenia (2013)
  • Author(s): Aleksic B, Kushima I, Ohye T, Ikeda M, Kunimoto S, Nakamura Y, Yoshimi A, Koide T, Iritani S, Kurahashi H, Iwata N, Ozaki N
  • Journal Title: Sci Rep Volume: 3 Issue: 1 Pages: 2587-2587
  • DOI: 10.1038/srep02587
  • Peer Reviewed
• [Journal Article] Further evidence of an association between a genetic variant in BMP7 and treatment response to SSRIs in major depressive disorder (2013)
  • Author(s): Esaki K, Kondo K, Hatano M, Saito T, Kishi T, Umene-Nakano W, Yoshimura R, Nakamura J, Ozaki N, Ikeda M and Iwata N
  • Journal Title: Journal of human genetics Volume: 58(8) Issue: 8 Pages: 568-9
  • DOI: 10.1038/jhg.2013.52
  • NAID: 10031195290
  • Peer Reviewed
• [Journal Article] Analysis of the VAV3 as candidate gene for schizophrenia : evidences from voxel based morphometry and mutation screening. (2012)
  • Author(s): 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
  • Journal Title: Schizophrenia Bulletin Volume: 39 Issue: 3 Pages: 39-39
  • DOI: 10.1093/schbul/sbs038
  • Peer Reviewed