Differential gene expression profiles in neurons generated from lymphoblastoid B-cell line-derived iPS cells from monozygotic twin cases with treatment-resistant schizophrenia and discordant responses to clozapine

Takanobu Nakazawa, Masataka Kikuchi, Mitsuru Ishikawa, Hidenaga Yamamori, Kazuki Nagayasu, Takuya Matsumoto, Michiko Fujimoto, Yuka Yasuda, Mikiya Fujiwara, Shota Okada, Kensuke Matsumura, Atsushi Kasai, Atsuko Hayata-Takano, Norihito Shintani, Shusuke Numata, Kazuhiro Takuma, Wado Akamatsu, Hideyuki Okano, Akihiro Nakaya, Hitoshi HashimotoRyota Hashimoto

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

Schizophrenia is a chronic psychiatric disorder with complex genetic and environmental origins. While many antipsychotics have been demonstrated as effective in the treatment of schizophrenia, a substantial number of schizophrenia patients are partially or fully unresponsive to the treatment. Clozapine is the most effective antipsychotic drug for treatment-resistant schizophrenia; however, clozapine has rare but serious side-effects. Furthermore, there is inter-individual variability in the drug response to clozapine treatment. Therefore, the identification of the molecular mechanisms underlying the action of clozapine and drug response predictors is imperative. In the present study, we focused on a pair of monozygotic twin cases with treatment-resistant schizophrenia, in which one twin responded well to clozapine treatment and the other twin did not. Using induced pluripotent stem (iPS) cell-based technology, we generated neurons from iPS cells derived from these patients and subsequently performed RNA-sequencing to compare the transcriptome profiles of the mock or clozapine-treated neurons. Although, these iPS cells similarly differentiated into neurons, several genes encoding homophilic cell adhesion molecules, such as protocadherin genes, showed differential expression patterns between these two patients. These results, which contribute to the current understanding of the molecular mechanisms of clozapine action, establish a new strategy for the use of monozygotic twin studies in schizophrenia research.

Original languageEnglish
Pages (from-to)75-82
Number of pages8
JournalSchizophrenia Research
Volume181
DOIs
Publication statusPublished - 2017 Mar 1

Fingerprint

Induced Pluripotent Stem Cells
Monozygotic Twins
Clozapine
Transcriptome
Schizophrenia
B-Lymphocytes
Neurons
Cell Line
Therapeutics
Antipsychotic Agents
RNA Sequence Analysis
Twin Studies
Cell Adhesion Molecules
Pharmaceutical Preparations
Genes
Psychiatry
Technology
Research

Keywords

  • Clozapine
  • Drug response
  • iPS cell
  • Monozygotic twins
  • Treatment-resistant schizophrenia

ASJC Scopus subject areas

  • Psychiatry and Mental health
  • Biological Psychiatry

Cite this

Differential gene expression profiles in neurons generated from lymphoblastoid B-cell line-derived iPS cells from monozygotic twin cases with treatment-resistant schizophrenia and discordant responses to clozapine. / Nakazawa, Takanobu; Kikuchi, Masataka; Ishikawa, Mitsuru; Yamamori, Hidenaga; Nagayasu, Kazuki; Matsumoto, Takuya; Fujimoto, Michiko; Yasuda, Yuka; Fujiwara, Mikiya; Okada, Shota; Matsumura, Kensuke; Kasai, Atsushi; Hayata-Takano, Atsuko; Shintani, Norihito; Numata, Shusuke; Takuma, Kazuhiro; Akamatsu, Wado; Okano, Hideyuki; Nakaya, Akihiro; Hashimoto, Hitoshi; Hashimoto, Ryota.

In: Schizophrenia Research, Vol. 181, 01.03.2017, p. 75-82.

Research output: Contribution to journalArticle

Nakazawa, T, Kikuchi, M, Ishikawa, M, Yamamori, H, Nagayasu, K, Matsumoto, T, Fujimoto, M, Yasuda, Y, Fujiwara, M, Okada, S, Matsumura, K, Kasai, A, Hayata-Takano, A, Shintani, N, Numata, S, Takuma, K, Akamatsu, W, Okano, H, Nakaya, A, Hashimoto, H & Hashimoto, R 2017, 'Differential gene expression profiles in neurons generated from lymphoblastoid B-cell line-derived iPS cells from monozygotic twin cases with treatment-resistant schizophrenia and discordant responses to clozapine', Schizophrenia Research, vol. 181, pp. 75-82. https://doi.org/10.1016/j.schres.2016.10.012
Nakazawa, Takanobu ; Kikuchi, Masataka ; Ishikawa, Mitsuru ; Yamamori, Hidenaga ; Nagayasu, Kazuki ; Matsumoto, Takuya ; Fujimoto, Michiko ; Yasuda, Yuka ; Fujiwara, Mikiya ; Okada, Shota ; Matsumura, Kensuke ; Kasai, Atsushi ; Hayata-Takano, Atsuko ; Shintani, Norihito ; Numata, Shusuke ; Takuma, Kazuhiro ; Akamatsu, Wado ; Okano, Hideyuki ; Nakaya, Akihiro ; Hashimoto, Hitoshi ; Hashimoto, Ryota. / Differential gene expression profiles in neurons generated from lymphoblastoid B-cell line-derived iPS cells from monozygotic twin cases with treatment-resistant schizophrenia and discordant responses to clozapine. In: Schizophrenia Research. 2017 ; Vol. 181. pp. 75-82.
@article{f3ef62bb01b844c7876052ed46e70747,
title = "Differential gene expression profiles in neurons generated from lymphoblastoid B-cell line-derived iPS cells from monozygotic twin cases with treatment-resistant schizophrenia and discordant responses to clozapine",
abstract = "Schizophrenia is a chronic psychiatric disorder with complex genetic and environmental origins. While many antipsychotics have been demonstrated as effective in the treatment of schizophrenia, a substantial number of schizophrenia patients are partially or fully unresponsive to the treatment. Clozapine is the most effective antipsychotic drug for treatment-resistant schizophrenia; however, clozapine has rare but serious side-effects. Furthermore, there is inter-individual variability in the drug response to clozapine treatment. Therefore, the identification of the molecular mechanisms underlying the action of clozapine and drug response predictors is imperative. In the present study, we focused on a pair of monozygotic twin cases with treatment-resistant schizophrenia, in which one twin responded well to clozapine treatment and the other twin did not. Using induced pluripotent stem (iPS) cell-based technology, we generated neurons from iPS cells derived from these patients and subsequently performed RNA-sequencing to compare the transcriptome profiles of the mock or clozapine-treated neurons. Although, these iPS cells similarly differentiated into neurons, several genes encoding homophilic cell adhesion molecules, such as protocadherin genes, showed differential expression patterns between these two patients. These results, which contribute to the current understanding of the molecular mechanisms of clozapine action, establish a new strategy for the use of monozygotic twin studies in schizophrenia research.",
keywords = "Clozapine, Drug response, iPS cell, Monozygotic twins, Treatment-resistant schizophrenia",
author = "Takanobu Nakazawa and Masataka Kikuchi and Mitsuru Ishikawa and Hidenaga Yamamori and Kazuki Nagayasu and Takuya Matsumoto and Michiko Fujimoto and Yuka Yasuda and Mikiya Fujiwara and Shota Okada and Kensuke Matsumura and Atsushi Kasai and Atsuko Hayata-Takano and Norihito Shintani and Shusuke Numata and Kazuhiro Takuma and Wado Akamatsu and Hideyuki Okano and Akihiro Nakaya and Hitoshi Hashimoto and Ryota Hashimoto",
year = "2017",
month = "3",
day = "1",
doi = "10.1016/j.schres.2016.10.012",
language = "English",
volume = "181",
pages = "75--82",
journal = "Schizophrenia Research",
issn = "0920-9964",
publisher = "Elsevier",

}

TY - JOUR

T1 - Differential gene expression profiles in neurons generated from lymphoblastoid B-cell line-derived iPS cells from monozygotic twin cases with treatment-resistant schizophrenia and discordant responses to clozapine

AU - Nakazawa, Takanobu

AU - Kikuchi, Masataka

AU - Ishikawa, Mitsuru

AU - Yamamori, Hidenaga

AU - Nagayasu, Kazuki

AU - Matsumoto, Takuya

AU - Fujimoto, Michiko

AU - Yasuda, Yuka

AU - Fujiwara, Mikiya

AU - Okada, Shota

AU - Matsumura, Kensuke

AU - Kasai, Atsushi

AU - Hayata-Takano, Atsuko

AU - Shintani, Norihito

AU - Numata, Shusuke

AU - Takuma, Kazuhiro

AU - Akamatsu, Wado

AU - Okano, Hideyuki

AU - Nakaya, Akihiro

AU - Hashimoto, Hitoshi

AU - Hashimoto, Ryota

PY - 2017/3/1

Y1 - 2017/3/1

N2 - Schizophrenia is a chronic psychiatric disorder with complex genetic and environmental origins. While many antipsychotics have been demonstrated as effective in the treatment of schizophrenia, a substantial number of schizophrenia patients are partially or fully unresponsive to the treatment. Clozapine is the most effective antipsychotic drug for treatment-resistant schizophrenia; however, clozapine has rare but serious side-effects. Furthermore, there is inter-individual variability in the drug response to clozapine treatment. Therefore, the identification of the molecular mechanisms underlying the action of clozapine and drug response predictors is imperative. In the present study, we focused on a pair of monozygotic twin cases with treatment-resistant schizophrenia, in which one twin responded well to clozapine treatment and the other twin did not. Using induced pluripotent stem (iPS) cell-based technology, we generated neurons from iPS cells derived from these patients and subsequently performed RNA-sequencing to compare the transcriptome profiles of the mock or clozapine-treated neurons. Although, these iPS cells similarly differentiated into neurons, several genes encoding homophilic cell adhesion molecules, such as protocadherin genes, showed differential expression patterns between these two patients. These results, which contribute to the current understanding of the molecular mechanisms of clozapine action, establish a new strategy for the use of monozygotic twin studies in schizophrenia research.

AB - Schizophrenia is a chronic psychiatric disorder with complex genetic and environmental origins. While many antipsychotics have been demonstrated as effective in the treatment of schizophrenia, a substantial number of schizophrenia patients are partially or fully unresponsive to the treatment. Clozapine is the most effective antipsychotic drug for treatment-resistant schizophrenia; however, clozapine has rare but serious side-effects. Furthermore, there is inter-individual variability in the drug response to clozapine treatment. Therefore, the identification of the molecular mechanisms underlying the action of clozapine and drug response predictors is imperative. In the present study, we focused on a pair of monozygotic twin cases with treatment-resistant schizophrenia, in which one twin responded well to clozapine treatment and the other twin did not. Using induced pluripotent stem (iPS) cell-based technology, we generated neurons from iPS cells derived from these patients and subsequently performed RNA-sequencing to compare the transcriptome profiles of the mock or clozapine-treated neurons. Although, these iPS cells similarly differentiated into neurons, several genes encoding homophilic cell adhesion molecules, such as protocadherin genes, showed differential expression patterns between these two patients. These results, which contribute to the current understanding of the molecular mechanisms of clozapine action, establish a new strategy for the use of monozygotic twin studies in schizophrenia research.

KW - Clozapine

KW - Drug response

KW - iPS cell

KW - Monozygotic twins

KW - Treatment-resistant schizophrenia

UR - http://www.scopus.com/inward/record.url?scp=85006025218&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85006025218&partnerID=8YFLogxK

U2 - 10.1016/j.schres.2016.10.012

DO - 10.1016/j.schres.2016.10.012

M3 - Article

C2 - 28277309

AN - SCOPUS:85006025218

VL - 181

SP - 75

EP - 82

JO - Schizophrenia Research

JF - Schizophrenia Research

SN - 0920-9964

ER -