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.
authors.affiliation: Department of Pharmacology, Graduate School of Dentistry, Osaka University, 1-8 Yamadaoka, Suita, Osaka 565-0871, Japan; Laboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan; iPS Cell-Based Research Project on Brain Neuropharmacology and Toxicology, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan.
authors.forename: Takanobu
authors.initials: T
authors.lastname: Nakazawa
authors.affiliation: Department of Genome Informatics, Graduate School of Medicine, Osaka University, 2-2, Yamadaoka, Suita, Osaka 565-0871, Japan.
authors.forename: Masataka
authors.initials: M
authors.lastname: Kikuchi
authors.affiliation: Department of Physiology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Ishikawa
authors.affiliation: Department of Psychiatry, Osaka University Graduate School of Medicine, D3, 2-2, Yamadaoka, Suita, Osaka 565-0871, Japan.
authors.forename: Hidenaga
authors.initials: H
authors.lastname: Yamamori
authors.affiliation: Laboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan; iPS Cell-Based Research Project on Brain Neuropharmacology and Toxicology, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan.
authors.forename: Kazuki
authors.initials: K
authors.lastname: Nagayasu
authors.affiliation: Department of Physiology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan; Institute for Innovation, Ajinomoto Co., Inc., 1-1 Suzukicho, Kawasaki-ku, Kawasaki, Kanagawa 210-8681, Japan.
authors.forename: Takuya
authors.initials: T
authors.lastname: Matsumoto
authors.affiliation: Department of Psychiatry, Osaka University Graduate School of Medicine, D3, 2-2, Yamadaoka, Suita, Osaka 565-0871, Japan.
authors.forename: Michiko
authors.initials: M
authors.lastname: Fujimoto
authors.affiliation: Department of Psychiatry, Osaka University Graduate School of Medicine, D3, 2-2, Yamadaoka, Suita, Osaka 565-0871, Japan; Oncology Center, Osaka University Hospital, 2-15, Yamadaoka, Suita, Osaka 565-0871, Japan.
authors.forename: Yuka
authors.initials: Y
authors.lastname: Yasuda
authors.affiliation: Laboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan.
authors.forename: Mikiya
authors.initials: M
authors.lastname: Fujiwara
authors.affiliation: Laboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan.
authors.forename: Shota
authors.initials: S
authors.lastname: Okada
authors.affiliation: Laboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan.
authors.forename: Kensuke
authors.initials: K
authors.lastname: Matsumura
authors.affiliation: Laboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kasai
authors.affiliation: Laboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan.
authors.forename: Atsuko
authors.initials: A
authors.lastname: Hayata-Takano
authors.affiliation: Laboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan.
authors.forename: Norihito
authors.initials: N
authors.lastname: Shintani
authors.affiliation: Department of Psychiatry, Course of Integrated Brain Sciences, School of Medicine, University of Tokushima, 2-50-1 Kuramotocho, Tokushima, Tokushima 770-8503, Japan.
authors.forename: Shusuke
authors.initials: S
authors.lastname: Numata
authors.affiliation: Department of Pharmacology, Graduate School of Dentistry, Osaka University, 1-8 Yamadaoka, Suita, Osaka 565-0871, Japan; Molecular Research Center for Children's Mental Development, United Graduate School of Child Development, Osaka University, D3, 2-2, Yamadaoka, Suita, Osaka, 565-0871, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Takuma
authors.affiliation: Department of Physiology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan; Center for Genomic and Regenerative Medicine, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan.
authors.forename: Wado
authors.initials: W
authors.lastname: Akamatsu
authors.affiliation: Department of Physiology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Okano
authors.affiliation: Department of Genome Informatics, Graduate School of Medicine, Osaka University, 2-2, Yamadaoka, Suita, Osaka 565-0871, Japan.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Nakaya
authors.affiliation: Laboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan; iPS Cell-Based Research Project on Brain Neuropharmacology and Toxicology, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan; Molecular Research Center for Children's Mental Development, United Graduate School of Child Development, Osaka University, D3, 2-2, Yamadaoka, Suita, Osaka, 565-0871, Japan; Division of Bioscience, Institute for Datability Science, Osaka University, 1-1 Yamadaoka, Suita, Osaka 565-0871, Japan.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Hashimoto
authors.affiliation: Department of Psychiatry, Osaka University Graduate School of Medicine, D3, 2-2, Yamadaoka, Suita, Osaka 565-0871, Japan; Molecular Research Center for Children's Mental Development, United Graduate School of Child Development, Osaka University, D3, 2-2, Yamadaoka, Suita, Osaka, 565-0871, Japan. Electronic address: hashimor@psy.med.osaka-u.ac.jp.
authors.forename: Ryota
authors.initials: R
authors.lastname: Hashimoto
mesh_terms: D014150:Antipsychotic Agents / Q000627:therapeutic use*; D001402:B-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D000073537:Biological Variation, Population; D003024:Clozapine / Q000627:therapeutic use*; D004200:Diseases in Twins / Q000188:drug therapy / Q000378:metabolism; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000187:drug effects / Q000378:metabolism; D008875:Middle Aged; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism*; D012559:Schizophrenia / Q000188:drug therapy* / Q000378:metabolism*; D059467:Transcriptome / Q000187:drug effects; D014430:Twins, Monozygotic
chemical_list: D014150:Antipsychotic Agents; D003024:Clozapine
keywords: Clozapine; Drug response; Monozygotic twins; Treatment-resistant schizophrenia; iPS cell