Mamoru Tochigi
| Health Care Center | Professor |
Researcher Information
Career
- Apr. 2022 - Present
The University of Electro-Communications, Health Service Center, Professor, Japan - 01 Nov. 2017 - 31 Mar. 2022
Teikyo University School of Medicine, Department of Neuropsychiatry, Professor - 01 Apr. 2013 - 31 Oct. 2017
Teikyo University School of Medicine, Department of Neuropsychiatry, Associate Professor - 01 Apr. 2010 - 31 Mar. 2013
The University of Tokyo, Faculty of Medicine, Lecturer - 01 Apr. 2008 - 31 Mar. 2010
Centre for Addiction and Mental Health, Psychiatric Neurogenetics Section, Post-doctoral fellow - 01 Apr. 2007 - 31 Mar. 2010
University of Tokyo Hospital, Department of Neuropsychiatry, Assistant Professor
Research Activity Information
Paper
- Cross-Disorder Analysis of Genic and Regulatory Copy Number Variations in Bipolar Disorder, Schizophrenia, and Autism Spectrum Disorder.
Itaru Kushima; Masahiro Nakatochi; Branko Aleksic; Takashi Okada; Hiroki Kimura; Hidekazu Kato; Mako Morikawa; Toshiya Inada; Kanako Ishizuka; Youta Torii; Yukako Nakamura; Satoshi Tanaka; Miho Imaeda; Nagahide Takahashi; Maeri Yamamoto; Kunihiro Iwamoto; Yoshihiro Nawa; Nanayo Ogawa; Shuji Iritani; Yu Hayashi; Tzuyao Lo; Gantsooj Otgonbayar; Sho Furuta; Nakao Iwata; Masashi Ikeda; Takeo Saito; Kohei Ninomiya; Tomo Okochi; Ryota Hashimoto; Hidenaga Yamamori; Yuka Yasuda; Michiko Fujimoto; Kenichiro Miura; Masanari Itokawa; Makoto Arai; Mitsuhiro Miyashita; Kazuya Toriumi; Kazutaka Ohi; Toshiki Shioiri; Kiyoyuki Kitaichi; Toshiyuki Someya; Yuichiro Watanabe; Jun Egawa; Tsutomu Takahashi; Michio Suzuki; Tsukasa Sasaki; Mamoru Tochigi; Fumichika Nishimura; Hidenori Yamasue; Hitoshi Kuwabara; Tomoyasu Wakuda; Takahiro A Kato; Shigenobu Kanba; Hideki Horikawa; Masahide Usami; Masaki Kodaira; Kyota Watanabe; Takeo Yoshikawa; Tomoko Toyota; Shigeru Yokoyama; Toshio Munesue; Ryo Kimura; Yasuko Funabiki; Hirotaka Kosaka; Minyoung Jung; Kiyoto Kasai; Tempei Ikegame; Seiichiro Jinde; Shusuke Numata; Makoto Kinoshita; Tadafumi Kato; Chihiro Kakiuchi; Kazuhiro Yamakawa; Toshimitsu Suzuki; Naoki Hashimoto; Shuhei Ishikawa; Bun Yamagata; Shintaro Nio; Toshiya Murai; Shuraku Son; Yasuto Kunii; Hirooki Yabe; Masumi Inagaki; Yu-Ichi Goto; Yuto Okumura; Tomoya Ito; Yuko Arioka; Daisuke Mori; Norio Ozaki
Biological psychiatry, 92, 5, 362-374, 01 Sep. 2022, Peer-reviwed, True, BACKGROUND: We aimed to determine the similarities and differences in the roles of genic and regulatory copy number variations (CNVs) in bipolar disorder (BD), schizophrenia (SCZ), and autism spectrum disorder (ASD). METHODS: Based on high-resolution CNV data from 8708 Japanese samples, we performed to our knowledge the largest cross-disorder analysis of genic and regulatory CNVs in BD, SCZ, and ASD. RESULTS: In genic CNVs, we found an increased burden of smaller (<100 kb) exonic deletions in BD, which contrasted with the highest burden of larger (>500 kb) exonic CNVs in SCZ/ASD. Pathogenic CNVs linked to neurodevelopmental disorders were significantly associated with the risk for each disorder, but BD and SCZ/ASD differed in terms of the effect size (smaller in BD) and subtype distribution of CNVs linked to neurodevelopmental disorders. We identified 3 synaptic genes (DLG2, PCDH15, and ASTN2) as risk factors for BD. Whereas gene set analysis showed that BD-associated pathways were restricted to chromatin biology, SCZ and ASD involved more extensive and similar pathways. Nevertheless, a correlation analysis of gene set results indicated weak but significant pathway similarities between BD and SCZ or ASD (r = 0.25-0.31). In SCZ and ASD, but not BD, CNVs were significantly enriched in enhancers and promoters in brain tissue. CONCLUSIONS: BD and SCZ/ASD differ in terms of CNV burden, characteristics of CNVs linked to neurodevelopmental disorders, and regulatory CNVs. On the other hand, they have shared molecular mechanisms, including chromatin biology. The BD risk genes identified here could provide insight into the pathogenesis of BD.
Scientific journal, English - A preliminary study on predictors of treatment response to repetitive transcranial magnetic stimulation in patients with treatment‐resistant depression in Japan
Haruki Ikawa; Mamoru Tochigi; Yoshihiro Noda; Hiroshi Oba; Tatsuro Kaminaga; Keita Sakurai; Emi Ikebuchi; Naoki Hayashi; Hiroshi Kunugi
Neuropsychopharmacology Reports, Wiley, 30 Aug. 2022, Peer-reviwed
Scientific journal - 排泄障害への牛車腎気丸服用後にADLと認知機能が改善したウェルニッケ・コルサコフ症候群(WKS)の1例
野村 芳子; 秀瀬 真輔; 金井 理恵; 押久保 岳; 渡邊 由香子; 赤羽 晃寿; 栃木 衛; 功刀 浩
精神神経学雑誌, (公社)日本精神神経学会, 124, 4付録, S-388, Apr. 2022
Japanese - A loss-of-function variant in SUV39H2 identified in autism-spectrum disorder causes altered H3K9 trimethylation and dysregulation of protocadherin β-cluster genes in the developing brain.
Shabeesh Balan; Yoshimi Iwayama; Tetsuo Ohnishi; Mikiko Fukuda; Atsuko Shirai; Ayumi Yamada; Sara Weirich; Maren Kirstin Schuhmacher; Kalarickal Vijayan Dileep; Toshihiro Endo; Yasuko Hisano; Kaoru Kotoshiba; Tomoko Toyota; Takeshi Otowa; Hitoshi Kuwabara; Mamoru Tochigi; Akiko Watanabe; Hisako Ohba; Motoko Maekawa; Manabu Toyoshima; Tsukasa Sasaki; Kazuhiko Nakamura; Masatsugu Tsujii; Hideo Matsuzaki; Kam Y J Zhang; Albert Jeltsch; Yoichi Shinkai; Takeo Yoshikawa
Molecular psychiatry, 26, 12, 7550-7559, 15 Jul. 2021, Peer-reviwed, True, Recent evidence has documented the potential roles of histone-modifying enzymes in autism-spectrum disorder (ASD). Aberrant histone H3 lysine 9 (H3K9) dimethylation resulting from genetic variants in histone methyltransferases is known for neurodevelopmental and behavioral anomalies. However, a systematic examination of H3K9 methylation dynamics in ASD is lacking. Here we resequenced nine genes for histone methyltransferases and demethylases involved in H3K9 methylation in individuals with ASD and healthy controls using targeted next-generation sequencing. We identified a novel rare variant (A211S) in the SUV39H2, which was predicted to be deleterious. The variant showed strongly reduced histone methyltransferase activity in vitro. In silico analysis showed that the variant destabilizes the hydrophobic core and allosterically affects the enzyme activity. The Suv39h2-KO mice displayed hyperactivity and reduced behavioral flexibility in learning the tasks that required complex behavioral adaptation, which is relevant for ASD. The Suv39h2 deficit evoked an elevated expression of a subset of protocadherin β (Pcdhb) cluster genes in the embryonic brain, which is attributable to the loss of H3K9 trimethylation (me3) at the gene promoters. Reduced H3K9me3 persisted in the cerebellum of Suv39h2-deficient mice to an adult stage. Congruently, reduced expression of SUV39H1 and SUV39H2 in the postmortem brain samples of ASD individuals was observed, underscoring the role of H3K9me3 deficiency in ASD etiology. The present study provides direct evidence for the role of SUV39H2 in ASD and suggests a molecular cascade of SUV39H2 dysfunction leading to H3K9me3 deficiency followed by an untimely, elevated expression of Pcdhb cluster genes during early neurodevelopment.
Scientific journal, English - 成人発達障害の入院治療について 帝京大学医学部附属病院メンタルヘルス科の現状
森岡 久雄; 金田 渉; 渡邊 由香子; 赤羽 晃寿; 伊東 ゆたか; 栃木 衛; 林 直樹
板橋区医師会医学会誌, (公社)板橋区医師会, 24, 132-132, Jan. 2021
Japanese - Association of Serotonin Transporter Gene (5-HTTLPR/rs25531) Polymorphism with Comorbidities of Panic Disorder.
Shunsuke Tanahashi; Hisashi Tanii; Yoshiaki Konishi; Takeshi Otowa; Tsukasa Sasaki; Mamoru Tochigi; Yuji Okazaki; Hisanobu Kaiya; Motohiro Okada
Neuropsychobiology, 80, 4, 1-9, 17 Dec. 2020, Peer-reviwed, True, INTRODUCTION: Panic disorder (PD) has many comorbidities such as depression, bipolar disorder (BPD), and agoraphobia (AG). PD is a moderately heritable anxiety disorder whose pathogenesis is not well understood. Recently, a tri-allelic serotonin transporter (5-HTTLPR/rs25531) polymorphism was reported to be more sensitive to personality traits compared to the bi-allelic 5-HTTLPR polymorphism. We hypothesized that the 5-HTTLPR/rs25531 polymorphism may lead to a pathological anxious state depending on the presence or absence of a comorbidity in PD. METHODS: In this study, we investigated the relationship between comorbidities in PD and tri-allelic 5-HTTLPR polymorphisms. A total of 515 patients with PD (148 males, 367 females) were genotyped, and the Revised NEO Personality Inventory as well as anxiety-related psychological tests were administered. Depression, BPD, and AG were diagnosed as comorbidities. RESULTS: For the tri-allele 5-HTTLPR genotype, a significant interaction effect was found between openness to experience and comorbid depression. Examination of the interaction between AG and the tri-allelic 5-HTTLPR genotype revealed that L' allele carriers are associated with higher trait anxiety than the S'S' genotype group in PD without AG. CONCLUSION: Some anxiety and personality traits can be characterized by the tri-allelic gene effect of 5-HTTLPR. These results suggest that tri-allelic 5-HTTLPR genotypes have genetic effects on the presence of comorbidities of PD.
Scientific journal, English - 自殺報道と帝京大学附属病院救命救急センターでの自殺行動患者の受け入れと関連についての検討(第二報)
江村 康; 金田 渉; 松村 謙一; 赤羽 晃寿; 栃木 衛; 林 直樹
精神神経学雑誌, (公社)日本精神神経学会, 2020特別号, S571-S571, Sep. 2020, Peer-reviwed
Japanese - 経頭蓋磁気刺激による治療抵抗性うつ病の治療と局所脳血流量変化の検討
井川 春樹; 栃木 衛; 櫻井 圭太; 神長 達郎; 赤羽 晃寿; 池淵 恵美; 大場 洋; 功刀 浩; 林 直樹
日本神経精神薬理学会年会・日本生物学的精神医学会年会・日本精神薬学会総会・学術集会合同年会プログラム・抄録集, 日本神経精神薬理学会・日本生物学的精神医学会・日本精神薬学会, 50回・42回・4回, 181-181, Aug. 2020
Japanese - Utility of VSRAD for diagnosing Alzheimer's disease in patients screened for dementia.
Gaku Oshikubo; Akihisa Akahane; Aki Unno; Yukako Watanabe; Emi Ikebuchi; Mamoru Tochigi; Naoki Hayashi
The Journal of international medical research, 48, 4, 300060520917270-300060520917270, Apr. 2020, Peer-reviwed, True, OBJECTIVE: To investigate the utility of the voxel-based specific regional analysis system for Alzheimer’s disease (VSRAD). METHODS: Clinical data from patients who underwent screening for dementia using VSRAD and the Japanese version of COGNISTAT, the Neurobehavioral Cognitive Status Examination, were retrospectively investigated to specify the domains of cognitive function that correlate with the statistical mean value of positive Z-scores in the target volume-of-interest (VOI). A receiver operating characteristic (ROC) curve was constructed to assess the mean value of positive Z-scores in discriminating patients with AD. RESULTS: A total of 72 patients were included (18 male and 54 female; 15 patients with AD). The mean value of positive Z-scores in the target VOI was significantly correlated with standardized COGNISTAT scores for Orientation and Memory in all patients (r = –0.35 and –0.38, respectively). ROC curve analysis revealed that a cut-off of 1.57 for mean value of positive Z-scores in the target VOI provided 69.4% accuracy in discriminating patients with AD, with a sensitivity of 0.80 and specificity of 0.67. CONCLUSIONS: The results evinced the value of VSRAD in diagnosing AD. The degree of atrophy represented by the target VOI may reflect impairments in Orientation and Memory, which are early stage symptoms observed in AD.
Scientific journal, English - Sensitivity to gene dosage and gene expression affects genes with copy number variants observed among neuropsychiatric diseases.
Maria Yamasaki; Takashi Makino; Seik-Soon Khor; Hiromi Toyoda; Taku Miyagawa; Xiaoxi Liu; Hitoshi Kuwabara; Yukiko Kano; Takafumi Shimada; Toshiro Sugiyama; Hisami Nishida; Nagisa Sugaya; Mamoru Tochigi; Takeshi Otowa; Yuji Okazaki; Hisanobu Kaiya; Yoshiya Kawamura; Akinori Miyashita; Ryozo Kuwano; Kiyoto Kasai; Hisashi Tanii; Tsukasa Sasaki; Makoto Honda; Katsushi Tokunaga
BMC medical genomics, 13, 1, 55-55, 29 Mar. 2020, Peer-reviwed, True, BACKGROUND: Copy number variants (CNVs) have been reported to be associated with diseases, traits, and evolution. However, it is hard to determine which gene should have priority as a target for further functional experiments if a CNV is rare or a singleton. In this study, we attempted to overcome this issue by using two approaches: by assessing the influences of gene dosage sensitivity and gene expression sensitivity. Dosage sensitive genes derived from two-round whole-genome duplication in previous studies. In addition, we proposed a cross-sectional omics approach that utilizes open data from GTEx to assess the effect of whole-genome CNVs on gene expression. METHODS: Affymetrix Genome-Wide SNP Array 6.0 was used to detect CNVs by PennCNV and CNV Workshop. After quality controls for population stratification, family relationship and CNV detection, 287 patients with narcolepsy, 133 patients with essential hypersomnia, 380 patients with panic disorders, 164 patients with autism, 784 patients with Alzheimer disease and 1280 healthy individuals remained for the enrichment analysis. RESULTS: Overall, significant enrichment of dosage sensitive genes was found across patients with narcolepsy, panic disorders and autism. Particularly, significant enrichment of dosage-sensitive genes in duplications was observed across all diseases except for Alzheimer disease. For deletions, less or no enrichment of dosage-sensitive genes with deletions was seen in the patients when compared to the healthy individuals. Interestingly, significant enrichments of genes with expression sensitivity in brain were observed in patients with panic disorder and autism. While duplications presented a higher burden, deletions did not cause significant differences when compared to the healthy individuals. When we assess the effect of sensitivity to genome dosage and gene expression at the same time, the highest ratio of enrichment was observed in the group including dosage-sensitive genes and genes with expression sensitivity only in brain. In addition, shared CNV regions among the five neuropsychiatric diseases were also investigated. CONCLUSIONS: This study contributed the evidence that dosage-sensitive genes are associated with CNVs among neuropsychiatric diseases. In addition, we utilized open data from GTEx to assess the effect of whole-genome CNVs on gene expression. We also investigated shared CNV region among neuropsychiatric diseases.
English - 身体拘束中にヘパリン起因性血小板減少症を発症した1例
杉崎 諒太; 渡邊 由香子; 赤羽 晃寿; 押久保 岳; 三宅 浩司; 江村 康; 狩野 悦生; 栃木 衛; 林 直樹
精神神経学雑誌, (公社)日本精神神経学会, 122, 1, 57-57, Jan. 2020
Japanese - 経過中にパーキンソニズムを呈し治療に難渋したうつ病の1例
永井 誠一; 金田 渉; 赤羽 晃寿; 森岡 久雄; 渡邊 公聡; 金井 理恵; 栃木 衛; 林 直樹
精神神経学雑誌, (公社)日本精神神経学会, 122, 1, 54-55, Jan. 2020
Japanese - 自殺報道と帝京大学附属病院救命救急センターでの自殺行動患者の受け入れとの関連についての検討
江村 康; 金田 渉; 松村 謙一; 赤羽 晃寿; 栃木 衛; 林 直樹; 池淵 恵美
精神神経学雑誌, (公社)日本精神神経学会, 2019特別号, S642-S642, Jun. 2019, Peer-reviwed
Japanese - A case of methamphetamine use disorder presenting a condition of ultra-rapid cycler bipolar disorder.
Ikawa H; Kanata S; Akahane A; Tochigi M; Hayashi N; Ikebuchi E
SAGE open medical case reports, 7, 2050313X19827739, 2019, Peer-reviwed, True, Methamphetamine, a potent psychostimulant, may cause a condition of mood disorder among users. However, arguments concerning methamphetamine-induced mood disorder remain insufficient. This case study describes a male with methamphetamine-induced bipolar disorder not accompanied by psychotic symptoms, who twice in an 11-year treatment period, manifested an ultra-rapid cycler condition alternating between manic and depressive mood states with 3- to 7-day durations for each. The conditions ensued after a bout of high-dose methamphetamine use and shifted to a moderately depressive condition within 1 month after the use under a treatment regimen of aripiprazole and mood stabilizers. The cycler condition may be characteristic of a type of the bipolar disorder and a sign usable for characterization. Further efforts are needed to seek distinctive features and to improve diagnostic assessment of methamphetamine-induced mood disorders.
English - Association between single nucleotide polymorphisms in estrogen receptor 1/2 genes and symptomatic severity of autism spectrum disorder.
Doi H; Fujisawa TX; Iwanaga R; Matsuzaki J; Kawasaki C; Tochigi M; Sasaki T; Kato N; Shinohara K
Research in developmental disabilities, 82, 20-26, Nov. 2018, Peer-reviwed, True, BACKGROUND: Previous studies on etiology of autism spectrum disorders (ASD) have shown strong contribution of hereditary factors. On the basis the heterogeneity in ASD symptoms, it is highly possible that each independent domain of ASD symptom is linked to a different set of genetic risk factors. However, few empirical investigations have been carried out to examine this hypothesis. AIMS: The aim of the present study was to investigate the association between single-nucleotide polymorphisms (SNPs) in estrogen receptor genes, which several previous studies have identified as potential risk factors of ASD, and the severity of each independent aspect of ASD symptom within an Asian clinical sample. METHOD AND PROCEDURES: We investigated the association between severities of four ASD symptoms (Social Communication, Social Interaction, Stereotypies and Sensory Abnormalities, and Emotional Regulation) measured by childhood autism rating scale and SNPs in genes of estrogen receptor 1 and 2, ESR1 rs11155819 and ESR2 rs1152582, in 96 Japanese individuals with ASD. OUTCOMES AND RESULTS: The analysis revealed that severities in the impairment of social interaction and emotional regulation were linked to SNPs in ESR1 rs11155819 and ESR2 rs1152582, respectively. The effect of genotype was not observed for the other aspects of ASD symptoms. CONCLUSIONS AND IMPLICATIONS: These findings support our contention that the severity of each ASD symptom domain is determined by a distinct set of genetic risk factors.
Scientific journal, English - Comparative Analyses of Copy-Number Variation in Autism Spectrum Disorder and Schizophrenia Reveal Etiological Overlap and Biological Insights.
Itaru Kushima; Branko Aleksic; Masahiro Nakatochi; Teppei Shimamura; Takashi Okada; Yota Uno; Mako Morikawa; Kanako Ishizuka; Tomoko Shiino; Hiroki Kimura; Yuko Arioka; Akira Yoshimi; Yuto Takasaki; Yanjie Yu; Yukako Nakamura; Maeri Yamamoto; Tetsuya Iidaka; Shuji Iritani; Toshiya Inada; Nanayo Ogawa; Emiko Shishido; Youta Torii; Naoko Kawano; Yutaka Omura; Toru Yoshikawa; Tokio Uchiyama; Toshimichi Yamamoto; Masashi Ikeda; Ryota Hashimoto; Hidenaga Yamamori; Yuka Yasuda; Toshiyuki Someya; Yuichiro Watanabe; Jun Egawa; Ayako Nunokawa; Masanari Itokawa; Makoto Arai; Mitsuhiro Miyashita; Akiko Kobori; Michio Suzuki; Tsutomu Takahashi; Masahide Usami; Masaki Kodaira; Kyota Watanabe; Tsukasa Sasaki; Hitoshi Kuwabara; Mamoru Tochigi; Fumichika Nishimura; Hidenori Yamasue; Yosuke Eriguchi; Seico Benner; Masaki Kojima; Walid Yassin; Toshio Munesue; Shigeru Yokoyama; Ryo Kimura; Yasuko Funabiki; Hirotaka Kosaka; Makoto Ishitobi; Tetsuro Ohmori; Shusuke Numata; Takeo Yoshikawa; Tomoko Toyota; Kazuhiro Yamakawa; Toshimitsu Suzuki; Yushi Inoue; Kentaro Nakaoka; Yu-Ichi Goto; Masumi Inagaki; Naoki Hashimoto; Ichiro Kusumi; Shuraku Son; Toshiya Murai; Tempei Ikegame; Naohiro Okada; Kiyoto Kasai; Shohko Kunimoto; Daisuke Mori; Nakao Iwata; Norio Ozaki
Cell reports, 24, 11, 2838-2856, 11 Sep. 2018, Peer-reviwed, True, Compelling evidence in Caucasian populations suggests a role for copy-number variations (CNVs) in autism spectrum disorder (ASD) and schizophrenia (SCZ). We analyzed 1,108 ASD cases, 2,458 SCZ cases, and 2,095 controls in a Japanese population and confirmed an increased burden of rare exonic CNVs in both disorders. Clinically significant (or pathogenic) CNVs, including those at 29 loci common to both disorders, were found in about 8% of ASD and SCZ cases, which was significantly higher than in controls. Phenotypic analysis revealed an association between clinically significant CNVs and intellectual disability. Gene set analysis showed significant overlap of biological pathways in both disorders including oxidative stress response, lipid metabolism/modification, and genomic integrity. Finally, based on bioinformatics analysis, we identified multiple disease-relevant genes in eight well-known ASD/SCZ-associated CNV loci (e.g., 22q11.2, 3q29). Our findings suggest an etiological overlap of ASD and SCZ and provide biological insights into these disorders.
Scientific journal, English - Mutations of the glycine cleavage system genes possibly affect the negative symptoms of schizophrenia through metabolomic profile changes.
Akane Yoshikawa; Fumichika Nishimura; Aya Inai; Yosuke Eriguchi; Masaki Nishioka; Atsuhiko Takaya; Mamoru Tochigi; Yoshiya Kawamura; Tadashi Umekage; Kayoko Kato; Tsukasa Sasaki; Yoshiaki Ohashi; Kazuya Iwamoto; Kiyoto Kasai; Chihiro Kakiuchi
Psychiatry and clinical neurosciences, 72, 3, 168-179, Mar. 2018, Peer-reviwed, True, AIM: Hypofunction of N-methyl-D-aspartate receptors (NMDAR) may contribute to the pathophysiology of schizophrenia (SCZ). Recently, the glycine cleavage system (GCS) was shown to affect NMDAR function in the brain. GCS functional defects cause nonketotic hyperglycinemia, the atypical phenotype of which presents psychiatric symptoms similar to SCZ. Here, we examined the involvement of GCS in SCZ. METHODS: First, to identify the rare variants and the exonic deletions, we resequenced all the coding exons and the splice sites of four GCS genes (GLDC, AMT, GCSH, and DLD) in 474 patients with SCZ and 475 controls and performed multiplex ligation-dependent probe amplification analysis in SCZ. Next, we performed metabolome analysis using plasma of patients harboring GCS variants (n = 5) and controls (n = 5) by capillary electrophoresis time-of-flight mass spectrometry. The correlation between plasma metabolites and Positive and Negative Syndrome Scale score was further examined. RESULTS: Possibly damaging variants were observed in SCZ: A203V, S801N in GLDC, near the atypical nonketotic hyperglycinemia causative mutations (A202V, A802V); G825D in GLDC, a potential neural tube defect causative mutation; and R253X in AMT. Marked elevation of plasma 5-oxoproline (pyroglutamic acid), aspartate, and glutamate, which might affect NMDAR function, was observed in patients harboring GCS variants. The aspartate level inversely correlated with negative symptoms (r = -0.942, P = 0.0166). CONCLUSION: These results suggest that GCS rare variants possibly contribute to the pathophysiology of SCZ by affecting the negative symptoms through elevation of aspartate.
Scientific journal, English - An epigenome-wide methylation study of healthy individuals with or without depressive symptoms
Mihoko Shimada; Takeshi Otowa; Taku Miyagawa; Tadashi Umekage; Yoshiya Kawamura; Miki Bundo; Kazuya Iwamoto; Tempei Ikegame; Mamoru Tochigi; Kiyoto Kasai; Hisanobu Kaiya; Hisashi Tanii; Yuji Okazaki; Katsushi Tokunaga; Tsukasa Sasaki
Journal of Human Genetics, Nature Publishing Group, 63, 3, 319-326, 01 Mar. 2018, Peer-reviwed, Major depressive disorder is a common psychiatric disorder that is thought to be triggered by both genetic and environmental factors. Depressive symptoms are an important public health problem and contribute to vulnerability to major depression. Although a substantial number of genetic and epigenetic studies have been performed to date, the detailed etiology of depression remains unclear and there are no validated biomarkers. DNA methylation is one of the major epigenetic modifications that play diverse roles in the etiology of complex diseases. In this study, we performed an epigenome-wide association study (EWAS) of DNA methylation on subjects with (N = 20) or without (N = 27) depressive symptoms in order to examine whether different levels of DNA methylation were associated with depressive tendencies. Employing methylation-array technology, a total of 363,887 methylation sites across the genomes were investigated and several candidate CpG sites associated with depressive symptoms were identified, especially annotated to genes linked to a G-protein coupled receptor protein signaling pathway. These data provide a strong impetus for validation studies using a larger cohort and support the possibility that G-protein coupled receptor protein signaling pathways are involved in the pathogenesis of depression.
Scientific journal, English - Whole-exome sequencing and gene-based rare variant association tests suggest that PLA2G4E might be a risk gene for panic disorder.
Yoshiro Morimoto; Mihoko Shimada-Sugimoto; Takeshi Otowa; Shintaro Yoshida; Akira Kinoshita; Hiroyuki Mishima; Naohiro Yamaguchi; Takatoshi Mori; Akira Imamura; Hiroki Ozawa; Naohiro Kurotaki; Christiane Ziegler; Katharina Domschke; Jürgen Deckert; Tadashi Umekage; Mamoru Tochigi; Hisanobu Kaiya; Yuji Okazaki; Katsushi Tokunaga; Tsukasa Sasaki; Koh-Ichiro Yoshiura; Shinji Ono
Translational psychiatry, 8, 1, 41-41, 02 Feb. 2018, Peer-reviwed, True, Panic disorder (PD) is characterized by recurrent and unexpected panic attacks, subsequent anticipatory anxiety, and phobic avoidance. Recent epidemiological and genetic studies have revealed that genetic factors contribute to the pathogenesis of PD. We performed whole-exome sequencing on one Japanese family, including multiple patients with panic disorder, which identified seven rare protein-altering variants. We then screened these genes in a Japanese PD case-control group (384 sporadic PD patients and 571 controls), resulting in the detection of three novel single nucleotide variants as potential candidates for PD (chr15: 42631993, T>C in GANC; chr15: 42342861, G>T in PLA2G4E; chr20: 3641457, G>C in GFRA4). Statistical analyses of these three genes showed that PLA2G4E yielded the lowest p value in gene-based rare variant association tests by Efficient and Parallelizable Association Container Toolbox algorithms; however, the p value did not reach the significance threshold in the Japanese. Likewise, in a German case-control study (96 sporadic PD patients and 96 controls), PLA2G4E showed the lowest p value but again did not reach the significance threshold. In conclusion, we failed to find any significant variants or genes responsible for the development of PD. Nonetheless, our results still leave open the possibility that rare protein-altering variants in PLA2G4E contribute to the risk of PD, considering the function of this gene.
Scientific journal, English - Novel rare variations in genes that regulate developmental change in N-methyl-d-aspartate receptor in patients with schizophrenia.
Akane Yoshikawa; Fumichika Nishimura; Aya Inai; Yosuke Eriguchi; Masaki Nishioka; Atsuhiko Takaya; Mamoru Tochigi; Yoshiya Kawamura; Tadashi Umekage; Kayoko Kato; Tsukasa Sasaki; Kiyoto Kasai; Chihiro Kakiuchi
Human genome variation, 5, 17056-17056, 2018, Peer-reviwed, True, The mechanism underlying the vulnerability to developing schizophrenia (SCZ) during adolescence remains elusive. Hypofunction of N-methyl-d-aspartate receptors (NMDARs) has been implicated in the pathophysiology of SCZ. During development, the composition of synaptic NMDARs dramatically changes from NR2B-containing NMDARs to NR2A-containing NMDARs through the phosphorylation of NR2B S1480 or Y1472 by CDK5, CSNK2A1, and EphB2, which plays a pivotal role in the maturation of neural circuits. We hypothesized that the dysregulation of developmental change in NMDARs could be involved in the onset of SCZ. Using next-generation sequencing, we re-sequenced all the coding regions and splice sites of CDK5, CSNK2A1, and EphB2 in 474 patients with SCZ and 475 healthy controls. Variants on the database for human control subjects of Japanese origin were removed and all the nonsynonymous and nonsense variants were validated using Sanger sequencing. Four novel variants in CDK5 were observed in patients with SCZ but were not observed in controls. The total number of variants, however, was not significantly different between the SCZ and control groups (P=0.062). In silico analyses predicted P271T to be damaging. Further genetic research using a larger sample is required to examine whether CDK5 is involved in the pathophysiology of SCZ.
Scientific journal, English - Identification of candidate genes involved in the etiology of sporadic Tourette syndrome by exome sequencing
Yosuke Eriguchi; Hitoshi Kuwabara; Aya Inai; Yuki Kawakubo; Fumichika Nishimura; Chihiro Kakiuchi; Mamoru Tochigi; Jun Ohashi; Naoto Aoki; Kayoko Kato; Hiroyuki Ishiura; Jun Mitsui; Shoji Tsuji; Koichiro Doi; Jun Yoshimura; Shinichi Morishita; Takafumi Shimada; Masaomi Furukawa; Tadashi Umekage; Tsukasa Sasaki; Kiyoto Kasai; Yukiko Kano
AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS, WILEY, 174, 7, 712-723, Oct. 2017, Peer-reviwed, Tourette Syndrome (TS) is a neurodevelopmental disorder characterized by chronic motor and vocal tics. Although there is a large genetic contribution, the genetic architecture of TS remains unclear. Exome sequencing has successfully revealed the contribution of de novo mutations in sporadic cases with neuropsychiatric disorders such as autism and schizophrenia. Here, using exome sequencing, we investigated de novo mutations in individuals with sporadic TS to identify novel risk loci and elucidate the genetic background of TS. Exome analysis was conducted for sporadic TS cases: nine trio families and one quartet family with concordant twins were investigated. Missense mutations were evaluated using functional prediction algorithms, and their population frequencies were calculated based on three public databases. Gene expression patterns in the brain were analyzed using the BrainSpan Developmental Transcriptome. Thirty de novo mutations, including four synonymous and four missense mutations, were identified. Among the missense mutations, one in the rapamycin-insensitive companion of mammalian target of rapamycin (RICTOR)-coding gene (rs140964083: G > A, found in one proband) was predicted to be hazardous. In the three public databases analyzed, variants in the same SNP locus were absent, and variants in the same gene were either absent or present at an extremely low frequency (3/5,008), indicating the rarity of hazardous RICTOR mutations in the general population. The de novo variant of RICTOR may be implicated in the development of sporadic TS, and RICTOR is a novel candidate factor for TS etiology.
Scientific journal, English - Epigenome-wide association study of DNA methylation in panic disorder
Mihoko Shimada-Sugimoto; Takeshi Otowa; Taku Miyagawa; Tadashi Umekage; Yoshiya Kawamura; Miki Bundo; Kazuya Iwamoto; Mamoru Tochigi; Kiyoto Kasai; Hisanobu Kaiya; Hisashi Tanii; Yuji Okazaki; Katsushi Tokunaga; Tsukasa Sasaki
Clinical Epigenetics, Springer Verlag, 9, 1, 6, 21 Jan. 2017, Peer-reviwed, Background: Panic disorder (PD) is considered to be a multifactorial disorder emerging from interactions among multiple genetic and environmental factors. To date, although genetic studies reported several susceptibility genes with PD, few of them were replicated and the pathogenesis of PD remains to be clarified. Epigenetics is considered to play an important role in etiology of complex traits and diseases, and DNA methylation is one of the major forms of epigenetic modifications. In this study, we performed an epigenome-wide association study of PD using DNA methylation arrays so as to investigate the possibility that different levels of DNA methylation might be associated with PD. Methods: The DNA methylation levels of CpG sites across the genome were examined with genomic DNA samples (PD, N = 48, control, N = 48) extracted from peripheral blood. Methylation arrays were used for the analysis. β values, which represent the levels of DNA methylation, were normalized via an appropriate pipeline. Then, β values were converted to M values via the logit transformation for epigenome-wide association study. The relationship between each DNA methylation site and PD was assessed by linear regression analysis with adjustments for the effects of leukocyte subsets. Results: Forty CpG sites showed significant association with PD at 5% FDR correction, though the differences of the DNA methylation levels were relatively small. Most of the significant CpG sites (37/40 CpG sites) were located in or around CpG islands. Many of the significant CpG sites (27/40 CpG sites) were located upstream of genes, and all such CpG sites with the exception of two were hypomethylated in PD subjects. A pathway analysis on the genes annotated to the significant CpG sites identified several pathways, including “positive regulation of lymphocyte activation.” Conclusions: Although future studies with larger number of samples are necessary to confirm the small DNA methylation abnormalities associated with PD, there is a possibility that several CpG sites might be associated, together as a group, with PD.
Scientific journal, English - Epigenome-wide association study of DNA methylation in panic disorder
Mihoko Shimada-Sugimoto; Takeshi Otowa; Taku Miyagawa; Tadashi Umekage; Yoshiya Kawamura; Miki Bundo; Kazuya Iwamoto; Mamoru Tochigi; Kiyoto Kasai; Hisanobu Kaiya; Hisashi Tanii; Yuji Okazaki; Katsushi Tokunaga; Tsukasa Sasaki
CLINICAL EPIGENETICS, BIOMED CENTRAL LTD, 9, 6, Jan. 2017, Peer-reviwed, Background: Panic disorder (PD) is considered to be a multifactorial disorder emerging from interactions among multiple genetic and environmental factors. To date, although genetic studies reported several susceptibility genes with PD, few of them were replicated and the pathogenesis of PD remains to be clarified. Epigenetics is considered to play an important role in etiology of complex traits and diseases, and DNA methylation is one of the major forms of epigenetic modifications. In this study, we performed an epigenome-wide association study of PD using DNA methylation arrays so as to investigate the possibility that different levels of DNA methylation might be associated with PD.
Methods: The DNA methylation levels of CpG sites across the genome were examined with genomic DNA samples (PD, N = 48, control, N = 48) extracted from peripheral blood. Methylation arrays were used for the analysis. (beta) values, which represent the levels of DNA methylation, were normalized via an appropriate pipeline. Then, beta values were converted to M values via the logit transformation for epigenome-wide association study. The relationship between each DNA methylation site and PD was assessed by linear regression analysis with adjustments for the effects of leukocyte subsets.
Results: Forty CpG sites showed significant association with PD at 5% FDR correction, though the differences of the DNA methylation levels were relatively small. Most of the significant CpG sites (37/40 CpG sites) were located in or around CpG islands. Many of the significant CpG sites (27/40 CpG sites) were located upstream of genes, and all such CpG sites with the exception of two were hypomethylated in PD subjects. A pathway analysis on the genes annotated to the significant CpG sites identified several pathways, including "positive regulation of lymphocyte activation."
Conclusions: Although future studies with larger number of samples are necessary to confirm the small DNA methylation abnormalities associated with PD, there is a possibility that several CpG sites might be associated, together as a group, with PD.
Scientific journal, English - Association of Aryl Hydrocarbon Receptor-Related Gene Variants with the Severity of Autism Spectrum Disorders
Takashi X. Fujisawa; Shota Nishitani; Ryoichiro Iwanaga; Junko Matsuzaki; Chisato Kawasaki; Mamoru Tochigi; Tsukasa Sasaki; Nobumasa Kato; Kazuyuki Shinohara
FRONTIERS IN PSYCHIATRY, FRONTIERS MEDIA SA, 7, 184, Nov. 2016, Peer-reviwed, Exposure to environmental chemicals, such as dioxin, is known to have adverse effects on the homeostasis of gonadal steroids, thereby potentially altering the sexual differentiation of the brain to express autistic traits. Dioxin like chemicals act on the aryl hydrocarbon receptor (AhR), polymorphisms, and mutations of AhR-related gene may exert pathological influences on sexual differentiation of the brain, causing autistic traits. To ascertain the relationship between AhR-related gene polymorphisms and autism susceptibility, we identified genotypes of them in patients and controls and determined whether there are different gene and genotype distributions between both groups. In addition, to clarify the relationships between the polymorphisms and the severity of autism, we compared the two genotypes of AhR-related genes (rs2066853, rs2228099) with the severity of autistic symptoms. Although no statistically significant difference was found between autism spectrum disorder (ASD) patients and control individuals for the genotypic distribution of any of the polymorphisms studied herein, a significant difference in the total score of severity was observed in rs2228099 polymorphism, suggesting that the polymorphism modifies the severity of ASD symptoms but not ASD susceptibility. Moreover, we found that a significant difference in the social communication score of severity was observed. These results suggest that the rs2228099 polymorphism is possibly associated with the severity of social communication impairment among the diverse ASD symptoms.
Scientific journal, English - Evaluation of polygenic risks for narcolepsy and essential hypersomnia
Yamasaki M; Miyagawa T; Toyoda H; Khor S; Liu X; Kuwabara H; Kano Y; Shimada T; Sugiyama T; Nishida H; Sugaya N; Tochigi M; Otowa T; Okazaki Y; Kaiya H; Kawamura Y; Miyashita A; Kuwano R; Kasai K; Tanii H; Sasaki T; Honda M; Tokunaga K
Journal of Human Genetics, Springer Nature, 61, 10, 873-878, Oct. 2016, Peer-reviwed
Scientific journal, English - Genome-wide Association Study of Autism Spectrum Disorder in the East Asian Populations
Xiaoxi Liu; Takafumi Shimada; Takeshi Otowa; Yu-Yu Wu; Yoshiya Kawamura; Mamoru Tochigi; Yasuhide Iwata; Tadashi Umekage; Tomoko Toyota; Motoko Maekawa; Yoshimi Iwayama; Katsuaki Suzuki; Chihiro Kakiuchi; Hitoshi Kuwabara; Yukiko Kano; Hisami Nishida; Toshiro Sugiyama; Nobumasa Kato; Chia-Hsiang Chen; Norio Mori; Kazuo Yamada; Takeo Yoshikawa; Kiyoto Kasai; Katsushi Tokunaga; Tsukasa Sasaki; Susan Shur-Fen Gau
AUTISM RESEARCH, WILEY, 9, 3, 340-349, Mar. 2016, Peer-reviwed, Autism spectrum disorder is a heterogeneous neurodevelopmental disorder with strong genetic basis. To identify common genetic variations conferring the risk of ASD, we performed a two-stage genome-wide association study using ASD family and healthy control samples obtained from East Asian populations. A total of 166 ASD families (n=500) and 642 healthy controls from the Japanese population were used as the discovery cohort. Approximately 900,000 single nucleotide polymorphisms (SNPs) were genotyped using Affymetrix Genome-Wide Human SNP array 6.0 chips. In the replication stage, 205 Japanese ASD cases and 184 healthy controls, as well as 418 Chinese Han trios (n=1,254), were genotyped by TaqMan platform. Case-control analysis, family based association test, and transmission/disequilibrium test (TDT) were then conducted to test the association. In the discovery stage, significant associations were suggested for 14 loci, including 5 known ASD candidate genes: GPC6, JARID2, YTHDC2, CNTN4, and CSMD1. In addition, significant associations were identified for several novel genes with intriguing functions, such as JPH3, PTPRD, CUX1, and RIT2. After a meta-analysis combining the Japanese replication samples, the strongest signal was found at rs16976358 (P=6.04 x 10(-7)), which is located near the RIT2 gene. In summary, our results provide independent support to known ASD candidate genes and highlight a number of novel genes warranted to be further investigated in a larger sample set in an effort to improve our understanding of the genetic basis of ASD. Autism Res2016, 9: 340-349. (c) 2015 International Society for Autism Research, Wiley Periodicals, Inc.
Scientific journal, English - Annual longitudinal survey at up to five time points reveals reciprocal effects of bedtime delay and depression/anxiety in adolescents.
Tochigi M; Usami S; Matamura M; Kitagawa Y; Fukushima M; Yonehara H; Togo F; Nishida A; Sasaki T
Sleep medicine, 17, 81-86, Jan. 2016, Peer-reviwed - Analysis of SLITRK1 in Japanese patients with Tourette syndrome using a next-generation sequencer
Aya Inai; Mamoru Tochigi; Hitoshi Kuwabara; Fumichika Nishimura; Kayoko Kato; Yosuke Eriguchi; Takafumi Shimada; Masaomi Furukawa; Yoshiya Kawamura; Tsukasa Sasaki; Chihiro Kakiuchi; Kiyoto Kasai; Yukiko Kano
PSYCHIATRIC GENETICS, LIPPINCOTT WILLIAMS & WILKINS, 25, 6, 256-258, Dec. 2015, Peer-reviwed, The SLITRK1 (Slit and Trk-like 1) gene has been suggested to be a promising candidate for Tourette syndrome (TS) since the first report that identified its two rare variants adjacent to the chromosome inversion in a TS child with inv(13) (q31.1;q33.1). A series of replication studies have been carried out, whereas the role of the gene has not been elucidated. The present study aimed to determine whether the two or novel nonsynonymous variants were identified in Japanese TS patients and carry out an association analysis of the gene in a Japanese population. We did not observe the two or any novel nonsynonymous variants in the gene. In contrast, a significant difference was observed in the distributions of the haplotypes consisting of rs9546538, rs9531520, and rs9593835 between the patients and the controls. This result may partially support the implication of SLITRK1 in the pathogenesis of TS, warranting further studies of the gene. Copyright (C) 2015 Wolters Kluwer Health, Inc. All rights reserved.
Scientific journal, English - Effect of metabotropic glutamate receptor-3 variants on prefrontal brain activity in schizophrenia: An imaging genetics study using multi-channel near-infrared spectroscopy
Akihide Kinoshita; Ryu Takizawa; Shinsuke Koike; Yoshihiro Satomura; Shingo Kawasaki; Yuki Kawakubo; Kohei Marumo; Mamoru Tochigi; Tsukasa Sasaki; Yukika Nishimura; Kiyoto Kasai
PROGRESS IN NEURO-PSYCHOPHARMACOLOGY & BIOLOGICAL PSYCHIATRY, PERGAMON-ELSEVIER SCIENCE LTD, 62, 14-21, Oct. 2015, Peer-reviwed, Background: The glutamatergic system is essential for learning and memory through its crucial role in neural development and synaptic plasticity. Genes associated with the glutamatergic system, including metabotropic glutamate receptor (mGluR or GRM) genes, have been implicated in the pathophysiology of schizophrenia. Few studies, however, have investigated a relationship between polymorphism of glutamate-related genes and cortical function in vivo in patients with schizophrenia. We thus explored an association between genetic variations in GRM3 and brain activation driven by a cognitive task in the prefrontal cortex in patients with schizophrenia.
Materials and Methods: Thirty-one outpatients with schizophrenia and 48 healthy controls participated in this study. We measured four candidate single nucleotide polymorphisms (rs274622, rs2299225, rs1468412, and rs6465084) of GRM3, and activity in the prefrontal and temporal cortices during a category version of a verbal fluency task, using a 52-channel near-infrared spectroscopy instrument.
Results and Discussion: The rs274622 C carriers with schizophrenia were associated with significantly smaller prefrontal activation than patients with TT genotype. This between-genotype difference tended to be confined to the patient group. GRM3 polymorphisms are associated with prefrontal activation during cognitive task in schizophrenia. (C) 2015 Elsevier Inc. All rights reserved.
Scientific journal, English - Graves' hyperthyroidism-induced psychosis in a patient with periventricular nodular heterotopia
Gaku Oshikubo; Mamoru Tochigi; Akihisa Akahane; Naoki Hayashi; Emi Ikebuchi
PSYCHIATRY AND CLINICAL NEUROSCIENCES, WILEY-BLACKWELL, 69, 8, 505-506, Aug. 2015, Peer-reviwed
English - Anger tendency may be associated with duration of illness in panic disorder
Nagisa Sugaya; Eiji Yoshida; Shin Yasuda; Mamoru Tochigi; Kunio Takei; Takeshi Otowa; Tadashi Umekage; Yoshiaki Konishi; Yuji Sakano; Shinobu Nomura; Yuji Okazaki; Hisanobu Kaiya; Hisashi Tanii; Tsukasa Sasaki
BIOPSYCHOSOCIAL MEDICINE, BIOMED CENTRAL LTD, 9, 6, Mar. 2015, Peer-reviwed, Background: Several studies have reported an increased tendency towards anger in patients with panic disorder (PD). If this propensity for anger arises from the pathological process of PD, it may be associated with the duration of the illness. The present study therefore examined the relationship between duration of PD and the personality tendency to experience anger in PD patients.
Methods: Participants were 413 patients (132 men and 281 women; age = 38.7 years) with PD. Diagnoses were confirmed using the Mini-International Neuropsychiatric Interview. Illness duration ranged from less than a year to 51 years. After participants completed the Revised NEO Personality Inventory, we examined the association between illness duration and the Angry Hostility and Impulsiveness subscale scores. In the analysis, participants were divided into two groups by duration of illness (long group, n = 186 and short group, n = 200) using the median value (9 years) as a cut-off because of the skewed distribution of the duration. Patients with an illness duration of 9 years (n = 27) were excluded from the comparison.
Results: The duration of illness was significantly correlated with the Angry Hostility score (p = 0.002) after controlling for age. Scores were significantly higher in the long group than in the short group (p = 0.04). No significant association was observed between Impulsiveness scores and duration of illness.
Conclusion: The present study suggests that longer PD duration is related to a stronger tendency to experience anger.
Scientific journal, English - Genetic Overlap Between Antipsychotic Response and Susceptibility to Schizophrenia
Masashi Ikeda; Reiji Yoshimura; Ryota Hashimoto; Kenji Kondo; Takeo Saito; Ayu Shimasaki; Kazutaka Ohi; Mamoru Tochigi; Yoshiya Kawamura; Nao Nishida; Taku Miyagawa; Tsukasa Sasaki; Katsushi Tokunaga; Kiyoto Kasai; Masatoshi Takeda; Jun Nakamura; Norio Ozaki; Nakao Iwata
JOURNAL OF CLINICAL PSYCHOPHARMACOLOGY, LIPPINCOTT WILLIAMS & WILKINS, 35, 1, 85-88, Feb. 2015, Peer-reviwed
English - DNA Modification Study of Major Depressive Disorder: Beyond Locus-by-Locus Comparisons
Gabriel Oh; Sun-Chong Wang; Mrinal Pal; Zheng Fei Chen; Tarang Khare; Mamoru Tochigi; Catherine Ng; Yeqing A. Yang; Andrew Kwan; Zachary A. Kaminsky; Jonathan Mill; Cerisse Gunasinghe; Jennifer L. Tackett; Irving I. Gottesman; Gonneke Willemsen; Eco J. C. de Geus; Jacqueline M. Vink; P. Eline Slagboom; Naomi R. Wray; Andrew C. Heath; Grant W. Montgomery; Gustavo Turecki; Nicholas G. Martin; Dorret I. Boomsma; Peter McGuffin; Rafal Kustra; Art Petronis
BIOLOGICAL PSYCHIATRY, ELSEVIER SCIENCE INC, 77, 3, 246-255, Feb. 2015, Peer-reviwed, BACKGROUND: Major depressive disorder (MDD) exhibits numerous clinical and molecular features that are consistent with putative epigenetic misregulation. Despite growing interest in epigenetic studies of psychiatric diseases, the methodologies guiding such studies have not been well defined.
METHODS: We performed DNA modification analysis in white blood cells from monozygotic twins discordant for MDD, in brain prefrontal cortex, and germline (sperm) samples from affected individuals and control subjects (total N = 304) using 8.1K CpG island microarrays and fine mapping. In addition to the traditional locus-by-locus comparisons, we explored the potential of new analytical approaches in epigenomic studies.
RESULTS: In the microarray experiment, we detected a number of nominally significant DNA modification differences in MDD and validated selected targets using bisulfite pyrosequencing. Some MDD epigenetic changes, however, overlapped across brain, blood, and sperm more often than expected by chance. We also demonstrated that stratification for disease severity and age may increase the statistical power of epimutation detection. Finally, a series of new analytical approaches, such as DNA modification networks and machine-learning algorithms using binary and quantitative depression phenotypes, provided additional insights on the epigenetic contributions to MDD.
CONCLUSIONS: Mapping epigenetic differences in MDD (and other psychiatric diseases) is a complex task. However, combining traditional and innovative analytical strategies may lead to identification of disease-specific etiopathogenic epimutations.
Scientific journal, English - Neural correlate of autistic-like traits and a common allele in the oxytocin receptor gene
Yuki Saito; Motomu Suga; Mamoru Tochigi; Osamu Abe; Noriaki Yahata; Yuki Kawakubo; Xiaoxi Liu; Yoshiya Kawamura; Tsukasa Sasaki; Kiyoto Kasai; Hidenori Yamasue
SOCIAL COGNITIVE AND AFFECTIVE NEUROSCIENCE, OXFORD UNIV PRESS, 9, 10, 1443-1450, Oct. 2014, Peer-reviwed, Sub-clinical autistic-like traits (ALTs) are continuously distributed in the general population and genetically linked to autism. Although identifying the neurogenetic backgrounds of ALTs might enhance our ability to identify those of autism, they are largely unstudied. Here, we have examined the neuroanatomical basis of ALTs and their association with the oxytocin receptor gene (OXTR) rs2254298A, a known risk allele for autism in Asian populations which has also been implicated in limbic-paralimbic brain structures. First, we extracted a four-factor structure of ALTs, as measured using the Autism-Spectrum Quotient, including 'prosociality', 'communication', 'details/patterns' and 'imagination' in 135 neurotypical adults (79 men, 56 women) to reduce the genetic heterogeneity of ALTs. Then, in the same population, voxel-based morphometry revealed that lower 'prosociality', which indicates strong ALTs, was significantly correlated to smaller regional grey matter volume in the right insula in males. Males with lower 'prosociality' also had less interregional structural coupling between the right insula and the ventral anterior cingulate cortex. Furthermore, males with OXTR rs2254298A had significantly smaller grey matter volume in the right insula. These results show that decreased volume of the insula is a neuroanatomical correlate of ALTs and a potential intermediate phenotype linking ALTs with OXTR in male subjects.
Scientific journal, English - Common variants at 1p36 are associated with superior frontal gyrus volume
Hashimoto R; Ikeda M; Yamashita F; Ohi K; Yamamori H; Yasuda Y; Fujimoto M; Fukunaga M; Nemoto K; Takahashi T; Tochigi M; Onitsuka T; Yamasue H; Matsuo K; Iidaka T; Iwata N; Suzuki M; Takeda M; Kasai K; Ozaki N
TRANSLATIONAL PSYCHIATRY, 4, Oct. 2014, Peer-reviwed
Scientific journal, English - Associations between sleep habits and mental health status and suicidality in a longitudinal survey of monozygotic twin adolescents
Misato Matamura; Mamoru Tochigi; Satoshi Usami; Hiromi Yonehara; Masako Fukushima; Atsushi Nishida; Fumiharu Togo; Tsukasa Sasaki
JOURNAL OF SLEEP RESEARCH, WILEY-BLACKWELL, 23, 3, 290-294, Jun. 2014, Peer-reviwed, Several epidemiological studies have indicated that there is a relationship between sleep habits, such as sleep duration, bedtime and bedtime regularity, and mental health status, including depression and anxiety in adolescents. However, it is still to be clarified whether the relationship is direct cause-and-effect or mediated by the influence of genetic and other traits, i.e. quasi-correlation. To examine this issue, we conducted a twin study using a total of 314 data for monozygotic twins from a longitudinal survey of sleep habits and mental health status conducted in a unified junior and senior high school (grades 7-12), located in Tokyo, Japan. Three-level hierarchical linear model analysis showed that both bedtime and sleep duration had significant associations with the Japanese version of the 12-item General Health Questionnaire (GHQ-12) score, suicidal thoughts and the experience of self-harm behaviours when genetic factors and shared environmental factors, which were completely shared between co-twins, were controlled for. These associations were statistically significant even after controlling for bedtime regularity, which was also associated significantly with the GHQ-12 score. These suggest that the associations between sleep habits and mental health status were still statistically significant after controlling for the influence of genetic and shared environmental factors of twins, and that there may be a direct cause-and-effect in the relationship in adolescents. Thus, late bedtime and short sleep duration could predict subsequent development of depression and anxiety, including suicidal or self-injury risk. This suggests that poor mental health status in adolescents might be improved by health education and intervention concerning sleep and lifestyle habits.
Scientific journal, English - Gene x gene x gender interaction of BDNF and COMT genotypes associated with panic disorder
Yoshiaki Konishi; Hisashi Tanii; Takeshi Otowa; Tsukasa Sasaki; Mamoru Tochigi; Tadashi Umekage; Eishi Motomura; Takashi Shiroyama; Hisanobu Kaiya; Yuji Okazaki; Motohiro Okada
PROGRESS IN NEURO-PSYCHOPHARMACOLOGY & BIOLOGICAL PSYCHIATRY, PERGAMON-ELSEVIER SCIENCE LTD, 51, 119-125, Jun. 2014, Peer-reviwed, Genetic and gender differences are among the factors that have a role in the etiology of panic disorder (PD). It is thought that PD is related to neurotransmitter pathways, such as brain-derived neurotrophic factor (BDNF) and catechol-O-methyltransferase (COMT), both of which are involved in the regulation of the monoamine mechanism. We examined the interactions of BDNF, COMT and gender differences in terms of personality characteristics in PD. The subjects were 470 patients (178 men, 292 women) with a DSM-IV diagnosis of PD, and 458 healthy controls (195 men, 263 women). The subjects were further clinically characterized using the Revised NEO Personality Inventory (NEO-PI-R) and State-Trait Anxiety Inventory (STAI). COMT Val158Met polymorphisms (rs4680) and BDNF Val66Met (rs6265) polymorphisms were genotyped using allelic discrimination by a real-time PCR assay. A multivariate analysis of covariance (MANCOVA) was performed with STAI and NEO-PI-R scores as the dependent factor, gender and genotyping groups (BDNF and COMT) as fixed factors, and the covariate of age in the PD and healthy control groups. Post hoc MANCOVA tests were conducted to evaluate COMT x BDNF interactions. An interaction of BDNF x COMT x gender was confirmed in the PD group by MANCOVA on STAI scores and NEO-PI-R Neuroticism and Extraversion scores, whereas no association of such interactions was observed in the healthy controls. The anxiety sensitivity of the COMT Met + BDNF Val/Val carriers was higher than that of the COMT Val/Val + BDNF Val/Val carriers by post hoc MANCOVA. A significant BDNF x COMT x gender interaction was observed in the PD patients but not in the controls. Our findings partly demonstrated the involvement of a gene x gene x gender interaction in the pathogenesis of PD. (C) 2014 Elsevier Inc. All rights reserved.
Scientific journal, English - Genetic influences on prefrontal activation during a verbal fluency task in adults: A twin study based on multichannel near-infrared spectroscopy
Eisuke Sakakibara; Ryu Takizawa; Yukika Nishimura; Shingo Kawasaki; Yoshihiro Satomura; Akihide Kinoshita; Shinsuke Koike; Kohei Marumo; Masaru Kinou; Mamoru Tochigi; Nao Nishida; Katsushi Tokunaga; Satoshi Eguchi; Syudo Yamasaki; Tatsunobu Natsubori; Norichika Iwashiro; Hideyuki Inoue; Yosuke Takano; Kunio Takei; Motomu Suga; Hidenori Yamasue; Junko Matsubayashi; Kenji Kohata; Chie Shimojo; Shiho Okuhata; Toshiaki Kono; Hitoshi Kuwabara; Ayaka Ishii-Takahashi; Yuki Kawakubo; Kiyoto Kasai
NEUROIMAGE, ACADEMIC PRESS INC ELSEVIER SCIENCE, 85, 508-517, Jan. 2014, Peer-reviwed, Near-infrared spectroscopy (NIRS) studies have reported that prefrontal hemodynamic dysfunction during executive function tasks may be a promising biomarker of psychiatric disorders, because its portability and noninvasiveness allow easy measurements in clinical settings. Here, we investigated the degree to which prefrontal NIRS signals are genetically determined. Using a 52-channel NIRS system, we monitored the oxy-hemoglobin (oxy-Hb) signal changes in 38 adult pairs of right-handed monozygotic (MZ) twins and 13 pairs of same-sex right-handed dizygotic (DZ) twins during a letter version of the verbal fluency task. Heritability was estimated based on a classical twin paradigm using structured equation modeling. Significant genetic influences were estimated in the right dorsolateral prefrontal cortex and left frontal pole. The degrees of heritability were 66% and 75% in the variances, respectively. This implies that the prefrontal hemodynamic dysfunction observed during an executive function task measured by NIRS may be an efficient endophenotype for large-scale imaging genetic studies in psychiatric disorders. (C) 2013 Elsevier Inc. All rights reserved.
Scientific journal, English - Association of decreased prefrontal hemodynamic response during a verbal fluency task with EGR3 gene polymorphism in patients with schizophrenia and in healthy individuals
Yukika Nishimura; Ryu Takizawa; Shinsuke Koike; Akihide Kinoshita; Yoshihiro Satomura; Shingo Kawasaki; Hidenori Yamasue; Mamoru Tochigi; Chihiro Kakiuchi; Tsukasa Sasaki; Yoshimi Iwayama; Kazuo Yamada; Takeo Yoshikawa; Kiyoto Kasai
NEUROIMAGE, ACADEMIC PRESS INC ELSEVIER SCIENCE, 85, 527-534, Jan. 2014, Peer-reviwed, The early growth response 3 (EGR3) gene is an immediate early gene that is expressed throughout the brain and has been suggested as a potential susceptibility gene for schizophrenia (SZ). EGR3 impairment is associated with various neurodevelopmental dysfunctions, and some animal studies have reported a role for EGR3 function in the prefrontal cortex. Therefore, EGR3 genotype variation may be reflected in prefrontal function. By using multichannel near-infrared spectroscopy (NIRS) in an imaging genetics approach, we tested for an association between the EGR3 gene polymorphism and prefrontal hemodynamic response during a cognitive task in patients with SZ. We assessed 73 chronic patients with SZ and 73 age-, gender-, and genotype-matched healthy controls (HC) who provided written informed consent. We used NIRS to measure changes in prefrontal oxygenated hemoglobin concentration (oxyHb) during the letter version of a verbal fluency task (VET). Statistical comparisons were performed among EGR3 genotype subgroups (rs35201266, GG/GA/AA). The AA genotype group showed significantly smaller oxyHb increases in the left dorsolateral prefrontal cortex (DLPFC) during the VFT than the GG and GA genotype groups; this was true for both patients with SZ and HC. Our findings provide in vivo human evidence of a significant influence of EGR3 polymorphisms on prefrontal hemodynamic activation level in healthy adults and in patients with SZ. Genetic variation in EGR3 may affect prefrontal function through neurodevelopment. This study illustrates the usefulness of NIRS in imaging genetics investigations on psychiatric disorders. (C) 2013 Elsevier Inc. All rights reserved.
Scientific journal, English - Gender-Specific Association between the COMT Val158Met Polymorphism and Openness to Experience in Panic Disorder Patients
Yoshiaki Konishi; Hisashi Tanii; Takeshi Otowa; Tsukasa Sasaki; Eishi Motomura; Asuna Fujita; Tadashi Umekage; Mamoru Tochigi; Hisanobu Kaiya; Yuji Okazak; Motohiro Okada
NEUROPSYCHOBIOLOGY, KARGER, 69, 3, 165-174, 2014, Peer-reviwed, Background: Because major depression and panic disorder are both more prevalent among females and since several lines of evidence suggest that genetic factors might influence an individual's vulnerability to panic disorder, gene-gender interactions are being examined in such psychiatric disorders and mental traits. A number of studies have suggested that specific genes, e.g. catechol-O-methyltransferase (COMT), might lead to distinct clinical characteristics of panic disorder. Method:We compared gender-specific personality-related psychological factors of 470 individuals with panic disorder and 458 healthy controls in terms of their COMT Val158Met polymorphism and their scores on the Revised NEO Personality Inventory (NEO PI-R) and State-Trait Anxiety Inventory (STAI) with a 1-way analysis of covariance. Results: In the male panic disorder patients, the NEO PI-R score for openness to experience was significantly lower in the Met/Met carrier group, whereas there was no such association among the female panic disorder patients or the male or female control groups. Conclusion: The gender-specific effect of the COMT genotype suggests that the COMT Val/Met genotype may influence a personality trait, openness to experience, in males with panic disorder. (C) 2014 S. Karger AG, Basel
Scientific journal, English - DNA methylation analysis of BDNF gene promoters in peripheral blood cells of schizophrenia patients
Tempei Ikegame; Miki Bundo; Fumiko Sunaga; Tatsuro Asai; Fumichika Nishimura; Akane Yoshikawa; Yoshiya Kawamura; Hiroyuki Hibino; Mamoru Tochigi; Chihiro Kakiuchi; Tsukasa Sasaki; Tadafumi Kato; Kiyoto Kasai; Kazuya Iwamoto
NEUROSCIENCE RESEARCH, ELSEVIER IRELAND LTD, 77, 4, 208-214, Dec. 2013, Peer-reviwed, Accumulating evidence suggests that epigenetic alterations in brain-derived neurotrophic factor (BDNF) promoters are associated with the pathophysiology of psychiatric disorders. Epigenetic changes in BDNF were reported not only in brain tissues but also in other tissues, including peripheral blood cells (PBC) and saliva. We examined DNA methylation levels ofBDNF promoters land IV using genomic DNA derived from PBC of healthy controls (n = 100), and patients with schizophrenia (n = 100), all from the Japanese population, by pyrosequencing. The examined CpG sites were chosen based on previous epigenetic studies that reported altered DNA methylation. We found a significantly higher level of methylation at BDNFpromoter I in patients with schizophrenia compared to controls, although the difference was small. Subsequent analysis revealed that in controls, the methylation level of BDNF promoters was associated with sex, and the methylation difference observed in promoter I was more prominent in male patients with schizophrenia. Epigenetic alteration ofBDNF in the PBC might reflect the pathophysiology of schizophrenia, and could be a potential biomarker. (c) 2013 Elsevier Ireland Ltd and the Japan Neuroscience Society. All rights reserved.
Scientific journal, English - Irritable bowel syndrome, its cognition, anxiety sensitivity, and anticipatory anxiety in panic disorder patients
Nagisa Sugaya; Eiji Yoshida; Shin Yasuda; Mamoru Tochigi; Kunio Takei; Toshiyuki Ohtani; Takeshi Otowa; Takanobu Minato; Tadashi Umekage; Yuji Sakano; Junwen Chen; Hironori Shimada; Shinobu Nomura; Yuji Okazaki; Hisanobu Kaiya; Hisashi Tanii; Tsukasa Sasaki
PSYCHIATRY AND CLINICAL NEUROSCIENCES, WILEY-BLACKWELL, 67, 6, 397-404, Sep. 2013, Peer-reviwed, Aim: The present study examined the effect of irritable bowel syndrome (IBS), cognitive appraisal of IBS, and anxiety sensitivity on anticipatory anxiety (AA) and agoraphobia (AG) in patients with panic disorder (PD).
Methods: We examined 244 PD patients who completed a set of questionnaires that included the Rome II Modular Questionnaire to assess the presence of IBS, the Anxiety Sensitivity Index (ASI), the Cognitive Appraisal Rating Scale (CARS; assessing the cognitive appraisal of abdominal symptoms in four dimensions: commitment, appraisal of effect, appraisal of threat, and controllability), and items about the severity of AA and AG. The Mini International Neuropsychiatric Interview was used to diagnose AG and PD.
Results: After excluding individuals with possible organic gastrointestinal diseases by using red flag items,' valid data were obtained from 174 participants, including 110 PD patients without IBS (PD/IBS[-]) and 64 with IBS (PD/IBS[+]). The PD/IBS[+] group had higher AA and higher comorbidity with AG than the PD/IBS[-] group. In the PD/IBS[+] group, the controllability score of CARS was significantly correlated with AA and ASI. Multiple regression analysis showed a significant effect of ASI but not of controllability on AA in PD/IBS[+] subjects.
Conclusion: This study suggested that the presence of IBS may be related to agoraphobia and anticipatory anxiety in PD patients. Cognitive appraisal could be partly related to anticipatory anxiety in PD patients with IBS with anxiety sensitivity mediating this correlation.
Scientific journal, English - Irritable bowel syndrome, its cognition, anxiety sensitivity, and anticipatory anxiety in panic disorder patients
Sugaya, Nagisa; Yoshida, Eiji; Yasuda, Shin; Tochigi, Mamoru; Takei, Kunio; Otani, Toshiyuki; Otowa, Takeshi; Minato, Takanobu; Umekage, Tadashi; Sakano, Yuji; Chen, Junwen; Shimada, Hironori; Nomura, Shinobu; Okazaki, Yuji; Kaiya, Hisanobu; Tanii, Hisashi; Sasaki, Tsukasa
Psychiatry and Clinical Neurosciences (Japanese Society of Psychiatry and Neurology), 67, 6, 397-404, Sep. 2013, Peer-reviwed, True, AIM: The present study examined the effect of irritable bowel syndrome (IBS), cognitive appraisal of IBS, and anxiety sensitivity on anticipatory anxiety (AA) and agoraphobia (AG) in patients with panic disorder (PD). METHODS: We examined 244 PD patients who completed a set of questionnaires that included the Rome II Modular Questionnaire to assess the presence of IBS, the Anxiety Sensitivity Index (ASI), the Cognitive Appraisal Rating Scale (CARS; assessing the cognitive appraisal of abdominal symptoms in four dimensions: commitment, appraisal of effect, appraisal of threat, and controllability), and items about the severity of AA and AG. The Mini International Neuropsychiatric Interview was used to diagnose AG and PD. RESULTS: After excluding individuals with possible organic gastrointestinal diseases by using 'red flag items,' valid data were obtained from 174 participants, including 110 PD patients without IBS (PD/IBS[-]) and 64 with IBS (PD/IBS[+]). The PD/IBS[+] group had higher AA and higher comorbidity with AG than the PD/IBS[-] group. In the PD/IBS[+] group, the controllability score of CARS was significantly correlated with AA and ASI. Multiple regression analysis showed a significant effect of ASI but not of controllability on AA in PD/IBS[+] subjects. CONCLUSION: This study suggested that the presence of IBS may be related to agoraphobia and anticipatory anxiety in PD patients. Cognitive appraisal could be partly related to anticipatory anxiety in PD patients with IBS with anxiety sensitivity mediating this correlation.
Scientific journal, English - An association analysis of the cardiomyopathy-associated 5 (CMYA5) gene with schizophrenia in a Japanese population
Masaomi Furukawa; Mamoru Tochigi; Takeshi Otowa; Tadao Arinami; Toshiya Inada; Hiroshi Ujike; Yuichiro Watanabe; Nakao Iwata; Masanari Itokawa; Hiroshi Kunugi; Ryota Hashimoto; Norio Ozaki; Chihiro Kakiuchi; Kiyoto Kasai; Tsukasa Sasaki
PSYCHIATRIC GENETICS, LIPPINCOTT WILLIAMS & WILKINS, 23, 4, 179-180, Aug. 2013, Peer-reviwed
Scientific journal, English - Genome-wide association study of schizophrenia using microsatellite markers in the Japanese population
Hiroki Shibata; Ken Yamamoto; Zhu Sun; Akira Oka; Hidetoshi Inoko; Tadao Arinami; Toshiya Inada; Hiroshi Ujike; Masanari Itokawa; Mamoru Tochigi; Yuichiro Watanabe; Toshiyuki Someya; Hiroshi Kunugi; Tatsuyo Suzuki; Nakao Iwata; Norio Ozaki; Yasuyuki Fukumaki
PSYCHIATRIC GENETICS, LIPPINCOTT WILLIAMS & WILKINS, 23, 3, 117-123, Jun. 2013, Peer-reviwed, Objectives To search for schizophrenia susceptibility loci, we carried out a case-control study using 28601 microsatellite markers distributed across the entire genome. Materials and methods To control the highly multiple testing, we designed three sequential steps of screening using three independent sets of pooled samples, followed by the confirmatory step using an independent sample set (>2200 case-control pairs). Results The first screening using pooled samples of 157 case-control pairs showed 2966 markers to be significantly associated with the disorder (P < 0.05). After the second and the third screening steps using pooled samples of 150 pairs each, 374 markers remained significantly associated with the disorder. We individually genotyped all screening samples using a total of 1536 tag single nucleotide polymorphisms (SNPs) located in the vicinity of similar to 200 kb from the 59 positive microsatellite markers. Of the 167 SNPs that replicated the significance, we selected 31 SNPs on the basis of the levels of P values for the confirmatory association test using an independent-sample set. The best association signal was observed in rs13404754, located in the upstream region of SLC23A3. We genotyped six additional SNPs in the vicinity of rs13404754. Significant associations were observed in rs13404754, rs6436122, and rs1043160 in the cumulative samples (2617 cases and 2698 controls) (P = 0.005, 0.035, and 0.011, respectively). These SNPs are located in the linkage disequilibrium block of 20 kb in size containing SLC23A3, CNPPD1, and FAM134A genes. Conclusion Genome-wide association study using microsatellite markers suggested SLC23A3, CNPPD1, and FAM134A genes as candidates for schizophrenia susceptibility in the Japanese population. Psychiatr Genet 23: 117-123 (C) 2013 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins. Psychiatric Genetics 2013, 23:117-123
Scientific journal, English - Prevalence of bipolar disorder in panic disorder patients in the Japanese population
Nagisa Sugaya; Eiji Yoshida; Shin Yasuda; Mamoru Tochigi; Kunio Takei; Toshiyuki Otani; Takeshi Otowa; Takanobu Minato; Tadashi Umekage; Yoshiaki Konishi; Yuji Sakano; Junwen Chen; Shinobu Nomura; Yuji Okazaki; Hisanobu Kaiya; Tsukasa Sasaki; Hisashi Tanii
JOURNAL OF AFFECTIVE DISORDERS, ELSEVIER SCIENCE BV, 147, 1-3, 411-415, May 2013, Peer-reviwed, Background: We examined the rate of bipolar I (BPD-I) and bipolar II disorders (BPD-II) in panic disorder (PD) patients, and compared clinical and psychological variables between PD patients with and without bipolar disorders (BPD).
Methods: Participants were 649 Japanese patients with PD (215 men and 434 women, 38.49 +/- 10.40 years) at outpatient clinics for anxiety disorders. Constructive interviews using the Mini-International Neuropsychiatric Interview (MINI) were conducted to confirm the diagnosis of PD, agoraphobia, and BPD, as well as the presence and severity of suicide risk in each subject. Clinical records were also reviewed to confirm the diagnosis of PD and BPD. Participants then completed several questionnaires, including the State Trait Anxiety Inventory-Trait scale, the Anxiety Sensitivity Index, and the Revised Neuroticism-Extraversion- Openness Personality Inventory (NEO-PI-R).
Results: We found that 22.34% of the PD patients had BPD (BPD-I: 5.24%, BPD-II: 17.10%). PD patients with BPD-I showed higher prevalence and severity of suicide risk, trait anxiety, anxiety sensitivity, and neuroticism, and lower agreeableness (subscales of the NEO-PI-R) than those with BPD-II and those without BPD.
Limitation: First, we could not investigate the order of the onset of PD and BPD. Second, BPD patients without PD were not studied as another control group for PD patients with BPD.
Conclusion: PD patients had high prevalence of BPD. Both PD patients with BPD-I and those with BPD-II had high severity of suicide risk, trait anxiety, anxiety sensitivity, neuroticism, and agreeableness, though these characteristics were more prominent in patients with BPD-I. (C) 2012 Elsevier B.V. All rights reserved.
Scientific journal, English - Season of birth effect on psychotic-like experiences in Japanese adolescents.
Mamoru Tochigi; Atsushi Nishida; Shinji Shimodera; Yuji Okazaki; Tsukasa Sasaki
European child & adolescent psychiatry, 2, 22, 2, 89-93, Feb. 2013, Peer-reviwed, True, A number of studies have investigated seasonality of birth in schizophrenia. Most of the studies have consistently observed an excess of winter births, often associated with decreased summer births. We postulated that psychotic-like experiences (PLEs), subclinical hallucinatory and delusional experiences, may also be affected by birth season. In the present study, we assessed the season of birth effect on the prevalence of PLEs using data from the cross-sectional survey of 19,436 Japanese adolescents. As a result, significant excess of winter births was observed in the prevalence of PLEs, accompanied by a decreased proportion of summer births. The odds ratios for the prevalence of PLEs were estimated to be 1.11, which was on the same order with those for the development of schizophrenia in the previous meta-analytic studies. To our knowledge, this is the first to show the seasonality of birth in the prevalence of PLEs and implicate the winter birth effect on subclinical stage of schizophrenia.
English - The suicidal feelings, self-injury, and mobile phone use after lights out in adolescents.
Norihito Oshima; Atsushi Nishida; Shinji Shimodera; Mamoru Tochigi; Shuntaro Ando; Syudo Yamasaki; Yuji Okazaki; Tsukasa Sasaki
Journal of pediatric psychology, 9, 37, 9, 1023-30, Oct. 2012, Peer-reviwed, True, OBJECTIVE: To study association between nocturnal mobile phone use and mental health, suicidal feelings, and self-injury in adolescents. METHODS: Associations of mobile phone use after lights out with mental health, suicidal feelings, and self-injury were cross-sectionally examined in 17,920 adolescents using a self-report questionnaire. A series of logistic regression analyses were separately conducted for early (grades 7-9) and late (grades 10-12) adolescents. RESULTS: Sleep length was significantly associated with the mobile phone use only in early adolescents. Logistic regression showed significant associations of the nocturnal mobile phone use with poor mental health, suicidal feelings, and self-injury after controlling for sleep length and other confounders. CONCLUSIONS: Mobile phone use after lights out may be associated with poor mental health, suicidal feelings, and self-injury in both early and late adolescents. Association between reduced sleep and the mobile phone use was confined to early adolescents.
English - 5-hmC in the brain is abundant in synaptic genes and shows differences at the exon-intron boundary
Tarang Khare; Shraddha Pai; Karolis Koncevicius; Mrinal Pal; Edita Kriukiene; Zita Liutkeviciute; Manuel Irimia; Peixin Jia; Carolyn Ptak; Menghang Xia; Raymond Tice; Mamoru Tochigi; Solange Morera; Anaies Nazarians; Denise Belsham; Albert H. C. Wong; Benjamin J. Blencowe; Sun Chong Wang; Philipp Kapranov; Rafal Kustra; Viviane Labrie; Saulius Klimasauskas; Arturas Petronis
NATURE STRUCTURAL & MOLECULAR BIOLOGY, NATURE PUBLISHING GROUP, 19, 10, 1037-U94, Oct. 2012, Peer-reviwed, The 5-methylcytosine (5-mC) derivative 5-hydroxymethylcytosine (5-hmC) is abundant in the brain for unknown reasons. Here we characterize the genomic distribution of 5-hmC and 5-mC in human and mouse tissues. We assayed 5-hmC by using glucosylation coupled with restriction-enzyme digestion and microarray analysis. We detected 5-hmC enrichment in genes with synapse-related functions in both human and mouse brain. We also identified substantial tissue-specific differential distributions of these DNA modifications at the exon-intron boundary in human and mouse. This boundary change was mainly due to 5-hmC in the brain but due to 5-mC in non-neural contexts. This pattern was replicated in multiple independent data sets and with single-molecule sequencing. Moreover, in human frontal cortex, constitutive exons contained higher levels of 5-hmC relative to alternatively spliced exons. Our study suggests a new role for 5-hmC in RNA splicing and synaptic function in the brain.
Scientific journal, English - A multi-tissue analysis identifies HLA complex group 9 gene methylation differences in bipolar disorder
Z. Kaminsky; M. Tochigi; P. Jia; M. Pal; J. Mill; A. Kwan; I. Ioshikhes; J. B. Vincent; J. L. Kennedy; J. Strauss; S. Pai; S. C. Wang; A. Petronis
Molecular Psychiatry, 17, 7, 728-740, Jul. 2012, Peer-reviwed, Epigenetic studies of DNA and histone modifications represent a new and important activity in molecular investigations of human disease. Our previous epigenome-wide scan identified numerous DNA methylation differences in post-mortem brain samples from individuals affected with major psychosis. In this article, we present the results of fine mapping DNA methylation differences at the human leukocyte antigen (HLA) complex group 9 gene (HCG9) in bipolar disorder (BPD). Sodium bisulfite conversion coupled with pyrosequencing was used to interrogate 28 CpGs spanning ∼700 bp region of HCG9 in 1402 DNA samples from post-mortem brains, peripheral blood cells and germline (sperm) of bipolar disease patients and controls. The analysis of nearly 40 000 CpGs revealed complex relationships between DNA methylation and age, medication as well as DNA sequence variation (rs1128306). Two brain tissue cohorts exhibited lower DNA methylation in bipolar disease patients compared with controls at an extended HCG9 region (P=0.026). Logistic regression modeling of BPD as a function of rs1128306 genotype, age and DNA methylation uncovered an independent effect of DNA methylation in white blood cells (odds ratio (OR)=1.08, P=0.0077) and the overall sample (OR=1.24, P=0.0011). Receiver operating characteristic curve A prime statistics estimated a 69-72% probability of correct BPD prediction from a case vs control pool. Finally, sperm DNA demonstrated a significant association (P=0.018) with BPD at one of the regions demonstrating epigenetic changes in the post-mortem brain and peripheral blood samples. The consistent multi-tissue epigenetic differences at HCG9 argue for a causal association with BPD. © 2012 Macmillan Publishers Limited All rights reserved.
Scientific journal, English - The suicidal feelings, self-injury, and mobile phone use after lights out in adolescents.
Oshima N; Nishida A; Shimodera S; Tochigi M; Ando S; Yamasaki S; Okazaki Y; Sasaki T
Journal of Pediatric Psychology, 37, 9, 1023-30, Jun. 2012, Peer-reviwed - A two-stage case-control association study between the tryptophan hydroxylase 2 (TPH2) gene and schizophrenia in a Japanese population
Yuichiro Watanabe; Jun Egawa; Yoshimi Iijima; Ayako Nunokawa; Naoshi Kaneko; Masako Shibuya; Tadao Arinami; Hiroshi Ujike; Toshiya Inada; Nakao Iwata; Mamoru Tochigi; Hiroshi Kunugi; Masanari Itokawa; Norio Ozaki; Ryota Hashimoto; Toshiyuki Someya
SCHIZOPHRENIA RESEARCH, ELSEVIER SCIENCE BV, 137, 1-3, 264-266, May 2012, Peer-reviwed
English - Association of SNPs linked to increased expression of SLC1A1 with schizophrenia
Yasue Horiuchi; Syuhei Iida; Minori Koga; Hiroki Ishiguro; Yoshimi Iijima; Toshiya Inada; Yuichiro Watanabe; Toshiyuki Someya; Hiroshi Ujike; Nakao Iwata; Norio Ozaki; Hiroshi Kunugi; Mamoru Tochigi; Masanari Itokawa; Makoto Arai; Kazuhiro Niizato; Shuji Iritani; Akiyoshi Kakita; Hitoshi Takahashi; Hiroyuki Nawa; Tadao Arinami
American Journal of Medical Genetics, Part B: Neuropsychiatric Genetics, 1, 159, 1, 30-37, Jan. 2012, Peer-reviwed, Glutamate is one of the key molecules involved in signal transduction in the brain, and dysfunction of glutamate signaling could be linked to schizophrenia. The SLC1A1 gene located at 9p24 encodes the glutamate transporter EAAT3/EAAC1. To investigate the association between the SLC1A1 gene and schizophrenia in the Japanese population, we genotyped 19 tagging single nucleotide polymorphisms (tagSNPs) in the SLC1A1 gene in 576 unrelated individuals with schizophrenia and 576 control subjects followed by replication in an independent case-control study of 1,344 individuals with schizophrenia and 1,344 control subjects. In addition, we determined the boundaries of the copy number variation (CNV) region in the first intron (Database of Genomic Variants, chr9:4516796-4520549) and directly genotyped the CNV because of significant deviation from the Hardy-Weinberg equilibrium. The CNV was not associated with schizophrenia. Four SNPs showed a possible association with schizophrenia in the screening subjects and the associations were replicated in the same direction (nominal allelic P<
0.05), and, among them, an association with rs7022369 was replicated even after Bonferroni correction (allelic nominal P=5×10-5, allelic corrected P=2.5×10-4, allelic odds ratio, 1.30
95% CI: 1.14-1.47 in the combined subjects). Expression analysis quantified by the real-time quantitative polymerase chain reaction in the postmortem prefrontal cortex of 43 Japanese individuals with schizophrenia and 11 Japanese control subjects revealed increased SLC1A1 expression levels in individuals homozygous for the rs7022369 risk allele (P=0.003). Our findings suggest the involvement of SLC1A1 in the pathogenesis of schizophrenia. © 2011 Wiley Periodicals, Inc.
Scientific journal, English - Irregular bedtime and nocturnal cellular phone usage as risk factors for being involved in bullying: a cross-sectional survey of Japanese adolescents.
Mamoru Tochigi; Atsushi Nishida; Shinji Shimodera; Norihito Oshima; Ken Inoue; Yuji Okazaki; Tsukasa Sasaki
PloS one, 9, 7, 9, e45736, 2012, Peer-reviwed, True, PURPOSE: A number of studies have tried to identify risk factors for being involved in bullying in order to help developing preventive measures; however, to our knowledge, no study has investigated the effect of nocturnal lifestyle behavior such as sleep pattern or cellular phone usage. In the present study, we aimed to investigate the relationship between school bullying and sleep pattern or nocturnal cellular phone usage in adolescents. The effect of school size on school bullying was also examined. METHODS: Data from the cross-sectional survey of psychopathologies conducted for 19,436 Japanese students from 45 public junior high schools (7(th)-9(th) grade) and 28 senior high schools (10(th)-12(th) grade) were analyzed. RESULTS: Bullying status was significantly associated with irregular bedtime (OR = 1.23 and 1.41 for pure bullies and bully-victims, respectively) and e-mail exchange or calling after lights-out (OR = 1.53 and 1.31 for pure bullies and bully-victims, respectively) after controlling domestic violence and substance usage. In addition, school size was significantly associated with the increased risk of bullying in junior high school students (OR = 1.13 for bully-victims). CONCLUSIONS: The present results suggested that sleep pattern and nocturnal cellular phone usage might be risk factors for being involved in school bullying in adolescents. Although further accumulation of data is needed, progressive trend towards nocturnal lifestyle and increasing usage of cellular phone might impair the well-being of adolescents. School-based interventions for lifestyle including sleep pattern and cellular phone usage may be encouraged to reduce school bullying.
English - Association of SNPs linked to increased expression of SLC1A1 with schizophrenia.
Horiuchi Yasue; Iida Syuhei; Koga Minori; Ishiguro Hiroki; Iijima Yoshimi; Inada Toshiya; Watanabe Yuichiro; Someya Toshiyuki; Ujike Hiroshi; Iwata Nakao; Ozaki Norio; Kunugi Hiroshi; Tochigi Mamoru; Itokawa Masanari; Arai Makoto; Niizato Kazuhiro; Iritani Shuji; Kakita Akiyoshi; Takahashi Hitoshi; Nawa Hiroyuki; Arinami Tadao
Am J Med Genet B Neuropsychiatr Genet, 159B, 1, 30-37, Jan. 2012, Peer-reviwed, Glutamate is one of the key molecules involved in signal transduction in the brain, and dysfunction of glutamate signaling could be linked to schizophrenia. The SLC1A1 gene located at 9p24 encodes the glutamate transporter EAAT3/EAAC1. To investigate the association between the SLC1A1 gene and schizophrenia in the Japanese population, we genotyped 19 tagging single nucleotide polymorphisms (tagSNPs) in the SLC1A1 gene in 576 unrelated individuals with schizophrenia and 576 control subjects followed by replication in an independent case-control study of 1,344 individuals with schizophrenia and 1,344 control subjects. In addition, we determined the boundaries of the copy number variation (CNV) region in the first intron (Database of Genomic Variants, chr9:4516796-4520549) and directly genotyped the CNV because of significant deviation from the Hardy-Weinberg equilibrium. The CNV was not associated with schizophrenia. Four SNPs showed a possible association with schizophrenia in the screening subjects and the associations were replicated in the same direction (nominal allelic P < 0.05), and, among them, an association with rs7022369 was replicated even after Bonferroni correction (a
Scientific journal, English - Meta-analysis of genome-wide association studies for panic disorder in the Japanese population
Otowa T; Kawamura Y; Nishida N; Sugaya N; Koike A; Yoshida E; Inoue K; Yasuda S; Nishimura Y; Liu X; Konishi Y; Nishimura F; Shimada T; Kuwabara H; Tochigi M; Kakiuchi C; Umekage T; Miyagawa T; Miyashita A; Shimizu E; Akiyoshi J; Someya T; Kato T; Yoshikawa T; Kuwano R; Kasai K; Kato N; Kaiya H; Tokunaga K; Okazaki Y; Tanii H; Sasaki T
Translational Psychiatry, 2, 2012, Peer-reviwed - Positive Association of Phencyclidine-Responsive Genes, PDE4A and PLAT, With Schizophrenia
Xiangdong Deng; Hiromi Takaki; Lixiang Wang; Tosihide Kuroki; Tatsuo Nakahara; Kijiro Hashimoto; Hideaki Ninomiya; Tadao Arinami; Toshiya Inada; Hiroshi Ujike; Masanari Itokawa; Mamoru Tochigi; Yuichiro Watanabe; Toshiyuki Someya; Hiroshi Kunugi; Nakao Iwata; Norio Ozaki; Hiroki Shibata; Yasuyuki Fukumaki
AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS, WILEY-BLACKWELL, 156B, 7, 850-858, Dec. 2011, Peer-reviwed, As schizophrenia-like symptoms are produced by administration of phencyclidine (PCP), a noncompetitive antagonist of N-methyl-D-aspartate (NMDA) receptors, PCP-responsive genes could be involved in the pathophysiology of schizophrenia. We injected PCP to Wistar rats and isolated five different parts of the brain in 1 and 4 hr after the injection. We analyzed the gene expression induced by the PCP treatment of these tissues using the AGILENT rat cDNA microarray system. We observed changes in expression level in 90 genes and 21 ESTs after the treatment. Out of the 10 genes showing >2-fold expressional change evaluated by qRT-PCR, we selected 7 genes as subjects for the locus-wide association study to identify susceptibility genes for schizophrenia in the Japanese population. In haplotype analysis, significant associations were detected in combinations of two SNPs of BTG2 (P = 1.4 x 10(-6)), PDE4A (P = 1.4 x 10(-6)), and PLAT (P = 1 x 10(-3)), after false discovery rate (FDR) correction. Additionally, we not only successfully replicated the haplotype associations in PDE4A (P = 6.8 x 10(-12)) and PLAT (P = 0.015), but also detected single-point associations of one SNP in PDE4A (P = 0.0068) and two SNPs in PLAT (P = 0.0260 and 0.0104) in another larger sample set consisting of 2,224 cases and 2,250 controls. These results indicate that PDE4A and PLAT may be susceptibility genes for schizophrenia in the Japanese population. (C) 2011 Wiley-Liss, Inc.
Scientific journal, English - A genome-wide CNV association study on panic disorder in a Japanese population
Yoshiya Kawamura; Takeshi Otowa; Asako Koike; Nagisa Sugaya; Eiji Yoshida; Shin Yasuda; Ken Inoue; Kunio Takei; Yoshiaki Konishi; Hisashi Tanii; Takafumi Shimada; Mamoru Tochigi; Chihiro Kakiuchi; Tadashi Umekage; Xiaoxi Liu; Nao Nishida; Katsushi Tokunaga; Ryozo Kuwano; Yuji Okazaki; Hisanobu Kaiya; Tsukasa Sasaki
JOURNAL OF HUMAN GENETICS, NATURE PUBLISHING GROUP, 56, 12, 852-856, Dec. 2011, Peer-reviwed, Family and twin studies have indicated that genetic factors have an important role in panic disorder (PD), whereas its pathogenesis has remained elusive. We conducted a genome-wide copy number variation (CNV) association study to elucidate the involvement of structural variants in the etiology of PD. The participants were 2055 genetically unrelated Japanese people (535 PD cases and 1520 controls). CNVs were detected using Genome-Wide Human SNP array 6.0, determined by Birdsuite and confirmed by PennCNV. They were classified as rare CNVs (found in <1% of the total sample) or common CNVs (found in >= 5%). PLINK was used to perform global burden analysis for rare CNVs and association analysis for common CNVs. The sample yielded 2039 rare CNVs and 79 common CNVs. Significant increases in the rare CNV burden in PD cases were not found. Common duplications in 16p11.2 showed Bonferroni-corrected P-values <0.05. Individuals with PD did not exhibit an increased genome-wide rare CNV burden. Common duplications were associated with PD and found in the pericentromeric region of 16p11.2, which had been reported to be rich in low copy repeats and to harbor developmental disorders, neuropsychiatric disorders and dysmorphic features. Journal of Human Genetics (2011) 56, 852-856; doi:10.1038/jhg.2011.117; published online 20 October 2011
Scientific journal, English - Reply to: Neurogenetic Effects of OXTR rs2254298 in the Extended Limbic System of Healthy Caucasian Adults
Yamasue Hidenori; Suga Motomu; Yahata Noriaki; Inoue Hideyuki; Tochigi Mamoru; Abe Osamu; Liu Xiaoxi; Kawamura Yoshiya; Rogers Mark A; Takei Kunio; Yamada Haruyasu; Aoki Shigeki; Sasaki Tsukasa; Kasai Kiyoto
BIOLOGICAL PSYCHIATRY, ELSEVIER SCIENCE INC, 70, 9, E41-E42, 01 Nov. 2011, Peer-reviwed
English - An association analysis of Per2 with panic disorder in the Japanese population
Takeshi Otowa; Mamoru Tochigi; Yoshiya Kawamura; Nagisa Sugaya; Eiji Yoshida; Ken Inoue; Shin Yasuda; Tadashi Umekage; Takashi Ebisawa; Hisashi Tanii; Hisanobu Kaiya; Yuji Okazaki; Nobumasa Kato; Tsukasa Sasaki
JOURNAL OF HUMAN GENETICS, NATURE PUBLISHING GROUP, 56, 10, 748-750, Oct. 2011, Peer-reviwed, Panic disorder (PD) is a severe and chronic psychiatric disorder, with genetic components underlying in its etiology. The PERIOD2 (Per2) gene has been reported to be associated with familial advanced sleep phase syndrome. Considering the high frequency of sleep disturbance in PD, Per2 may be a candidate gene for PD. Therefore, we conducted a two-stage case-control association study in the Japanese population. In the first screening sample of 203 patients and 409 controls, we investigated three single-nucleotide polymorphisms in Per2. We found a potential association in the screening sample (rs2304672, genotype P=0.046, uncorrected), whereas we could not replicate the association in the second sample of 460 patients and 460 controls. Our results suggest that Per2 may not have a major role in the pathogenesis of PD in the Japanese population. Journal of Human Genetics (2011) 56, 748-750; doi:10.1038/jhg.2011.94; published online 4 August 2011
Scientific journal, English - Effects of Metabotropic Glutamate Receptor 3 Genotype on Phonetic Mismatch Negativity
Yuki Kawakubo; Motomu Suga; Mamoru Tochigi; Masato Yumoto; Kenji Itoh; Tsukasa Sasaki; Yukiko Kano; Kiyoto Kasai
PLOS ONE, PUBLIC LIBRARY SCIENCE, 6, 10, e24929, Oct. 2011, Peer-reviwed, Background: The genetic and molecular basis of glutamatergic dysfunction is one key to understand schizophrenia, with the identification of an intermediate phenotype being an essential step. Mismatch negativity (MMN) or its magnetic counterpart, magnetic mismatch field (MMF) is an index of preattentive change detection processes in the auditory cortex and is generated through glutamatergic neurotransmission. We have previously shown that MMN/MMF in response to phoneme change is markedly reduced in schizophrenia. Variations in metabotropic glutamate receptor (GRM3) may be associated with schizophrenia, and has been shown to affect cortical function. Here we investigated the effect of GRM3 genotypes on phonetic MMF in healthy men.
Methods: MMF in response to phoneme change was recorded using magnetoencephalography in 41 right-handed healthy Japanese men. Based on previous genetic association studies in schizophrenia, 4 candidate SNPs (rs6465084, rs2299225, rs1468412, rs274622) were genotyped.
Results: GRM3 rs274622 genotype variations significantly predicted MMF strengths (p = 0.009), with C carriers exhibiting significantly larger MMF strengths in both hemispheres compared to the TT subjects.
Conclusions: These results suggest that variations in GRM3 genotype modulate the auditory cortical response to phoneme change in humans. MMN/MMF, particularly those in response to speech sounds, may be a promising and sensitive intermediate phenotype for clarifying glutamatergic dysfunction in schizophrenia.
Scientific journal, English - No association between CLOCK gene 3111C/T polymorphism and personality traits in healthy Japanese subjects.
Otowa T; Tochigi M; Umekage T; Ebisawa T; Kasai K; Kato N; Sasaki T
Psychiatry and clinical neurosciences, 65, 6, 604, Oct. 2011, Peer-reviwed - Association of RGS2 Variants With Panic Disorder in a Japanese Population
Takeshi Otowa; Takafumi Shimada; Yoshiya Kawamura; Nagisa Sugaya; Eiji Yoshida; Ken Inoue; Shin Yasuda; Xiaoxi Liu; Takanobu Minato; Mamoru Tochigi; Tadashi Umekage; Kiyoto Kasai; Hisashi Tanii; Yuji Okazaki; Hisanobu Kaiya; Tsukasa Sasaki
AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS, WILEY-BLACKWELL, 156B, 4, 430-434, Jun. 2011, Peer-reviwed, Panic disorder (PD) is a severe and chronic psychiatric disorder with significant genetic components underlying its etiology. The gene regulator of G protein signaling 2 (RGS2) has been reported to be associated with anxiety disorders. To confirm the association of RGS2 with PD, we investigated three single nucleotide polymorphisms (SNPs) of RGS2 (rs10801152, rs4606, and rs1819741) in 677 Japanese PD cases and 460 controls. The SNP rs10801152 was suggestive of an association with PD (allele P = 0.045 adjusted using sex and age as confounding factors). The three-SNP haplotype was significantly associated with PD (global permutation P=4 X 10(-4)). The haplotypes T-G-C and T-C-T showed significant association and protective effect on PD (T-G-C, permutation P = 0.038, OR = 0.80, 95% CI = 0.68-0.95; T-C-T, permutation P = 0.004, OR = 0.38, 95% CI = 0.21-0.70). These results provide support for an association of RGS2 with PD in a Japanese population. (C) 2011 Wiley-Liss, Inc.
Scientific journal, English - Association study of PDE4B with panic disorder in the Japanese population
Takeshi Otowa; Yoshiya Kawamura; Nagisa Sugaya; Eiji Yoshida; Takafumi Shimada; Xiaoxi Liu; Mamoru Tochigi; Tadashi Umekage; Taku Miyagawa; Nao Nishida; Hisanobu Kaiya; Yuji Okazaki; Katsushi Tokunaga; Tsukasa Sasaki
PROGRESS IN NEURO-PSYCHOPHARMACOLOGY & BIOLOGICAL PSYCHIATRY, PERGAMON-ELSEVIER SCIENCE LTD, 35, 2, 545-549, Mar. 2011, Peer-reviwed, Background: Panic disorder (PD) is a severe and chronic psychiatric disorder with genetic components underlying in its etiology. The Phosphodiesterase 4B (PDE4B) gene has been reported to be associated with several psychiatric disorders. Several studies indicated that PDE4B may be involved in the regulation of anxiety and depression. Therefore, we investigate the association of PDE4B with PD in the Japanese population.
Methods: We genotyped 14 single nucleotide polymorphisms (5NPs) of PDE4B in 231 PD cases (85 males and 146 females) and 407 controls (162 males and 245 females). Differences in the genotype, allele and haplotype frequencies between the two groups were compared.
Results: We found a significant association between PDE4B and PD in the haplotype analysis (haplotype C-T-T-A, permutation P=0.031, OR=1.81, 95% CI=1.30-2.51). Sex-specific analyses demonstrated that PDE4B was associated with PD in females in the allele/genotype and haplotype analyses (rs10454453, allele P=0.042, genotype P=0.0034; haplotype C-T-T-A, permutation P=0.028).
Conclusion: Our results suggest that PDE4B may play a role in the pathophysiology of PD in the Japanese population. Replication studies using larger samples will be needed for more reliable conclusions. (C) 2010 Elsevier Inc. All rights reserved.
English - Association Between the Oxytocin Receptor Gene and Amygdalar Volume in Healthy Adults
Hideyuki Inoue; Hidenori Yamasue; Mamoru Tochigi; Osamu Abe; Xiaoxi Liu; Yoshiya Kawamura; Kunio Takei; Motomu Suga; Haruyasu Yamada; Mark A. Rogers; Shigeki Aoki; Tsukasa Sasaki; Kiyoto Kasai
BIOLOGICAL PSYCHIATRY, ELSEVIER SCIENCE INC, 68, 11, 1066-1072, Dec. 2010, Peer-reviwed, Background: Recent studies have suggested that oxytocin affects social cognition and behavior mediated by the oxytocin receptor (OXTR) in amygdala in humans as well as in experimental animals. Genetic studies have revealed a link between the OXTR gene and the susceptibility to autism spectrum disorders (ASD), especially in the social dysfunctional feature of ASD.
Methods: We examined the relationship between amygdala volume measured with manual tracing methodology and seven single nucleotide polymorphisms and one haplotype-block in OXTR, which were previously reported to be associated with ASD, in 208 socially intact Japanese adults with no neuropsychiatric history or current diagnosis.
Results: The rs2254298A allele of OXTR was significantly associated with larger bilateral amygdala volume. The rs2254298A allele effect on amygdala volume varied in proportion to the dose of this allele. The larger the number of rs2254298A alleles an individual had, the larger their amygdala volume. Such an association was not observed with hippocampal volume or with global brain volumes, including whole gray, white matter, and cerebrospinal-fluid space. Furthermore, two three-single nucleotide polymorphism haplotypes, including rs2254298G allele, showed significant associations with the smaller bilateral amygdala volume.
Conclusions: The present results suggest that OXTR might be associated with the susceptibility to ASD, especially in its aspects of social interaction and communication mediated by a modulation of amygdala development, one of the most distributed brain regions with high density of OXTR. Furthermore, amygdala volume measured with magnetic resonance imaging could be a useful intermediate phenotype to uncover the complex link between OXTR and social dysfunction in ASD.
Scientific journal, English - Effect of tryptophan hydroxylase-2 gene variants on amygdalar and hippocampal volumes
Hideyuki Inoue; Hidenori Yamasue; Mamoru Tochigi; Kunio Takei; Motomu Suga; Osamu Abe; Haruyasu Yamada; Mark A. Rogers; Shigeki Aoki; Tsukasa Sasaki; Kiyoto Kasai
BRAIN RESEARCH, ELSEVIER SCIENCE BV, 1331, 51-57, May 2010, Peer-reviwed, Tryptophan hydroxylase (TPH) is the rate-limiting enzyme in the synthesis of serotonin (5-HT). Genetic variations in human TPH2, a newly identified isoform of TPH, have been shown to impact on enzymatic activity of TPH and to be associated with emotion-related personality traits and mood/anxiety disorders. Identification of an intermediate phenotype that bridges the relationship between genes and behavior may be of great importance in the further clarification of how hTPH2 contributes to emotional regulation. Previous studies have shown that a polymorphism in the upstream regulatory region of hTPH2 (SNP G-703T, rs4570625) correlates functional MRI response of the amygdala. In this study, we examined the effect of this genotype on amygdalar and hippocampal volumes in 208 mentally healthy individuals. To measure volumes of amygdala and hippocampus, gray matter regions of interest were outlined manually on three-dimensional MRI data obtained using a 1.5-T scanner. Additionally, personality traits were evaluated using the Temperament and Character Inventory (TCI). Those subjects with T allele carriers were associated with significantly smaller volumes in bilateral amygdala and hippocampus and higher reward dependence than those with G allele homozygotes. These results suggest that amygdalar and hippocampal volumes assessed using MRI may be a useful intermediate phenotype that will uncover the biological pathway linking 5-HT synthesis and emotional behaviors and affective disorders. (C) 2010 Elsevier B.V. All rights reserved.
Scientific journal, English - Association of the oxytocin receptor (OXTR) gene polymorphisms with autism spectrum disorder (ASD) in the Japanese population
Xiaoxi Liu; Yoshiya Kawamura; Takafumi Shimada; Takeshi Otowa; Shinko Koishi; Toshiro Sugiyama; Hisami Nishida; Ohiko Hashimoto; Ryoichi Nakagami; Mamoru Tochigi; Tadashi Umekage; Yukiko Kano; Taku Miyagawa; Nobumasa Kato; Katsushi Tokunaga; Tsukasa Sasaki
JOURNAL OF HUMAN GENETICS, NATURE PUBLISHING GROUP, 55, 3, 137-141, Mar. 2010, Peer-reviwed, The oxytocin receptor (OXTR) gene, which is located on chromosome 3p25.3, has been implicated as a candidate gene for susceptibility of autism spectrum disorder (ASD). Positive associations between OXTR and ASD have been reported in earlier studies. However, the results were inconsistent and demand further studies. In this study, we investigated the associations between OXTR and ASD in a Japanese population by analyzing 11 single-nucleotide polymorphisms (SNPs) using both family-based association test (FBAT) and population-based case-control test. No significant signal was detected in the FBAT test. However, significant differences were observed in allelic frequencies of four SNPs, including rs2254298 between patients and controls. The risk allele of rs2254298 was 'A', which was consistent with the previous study in Chinese, and not with the observations in Caucasian. The difference in the risk allele of this SNP in previous studies might be attributable to an ethnic difference in the linkage disequilibrium structure between the Asians and Caucasians. In addition, haplotype analysis exhibits a significant association between a five-SNP haplotype and ASD, including rs22542898. In conclusion, our study might support that OXTR has a significant role in conferring the risk of ASD in the Japanese population. Journal of Human Genetics (2010) 55, 137-141; doi: 10.1038/jhg.2009.140; published online 22 January 2010
Scientific journal, English - Replication of a genome-wide association study of panic disorder in a Japanese population
Takeshi Otowa; Hisashi Tanii; Nagisa Sugaya; Eiji Yoshida; Ken Inoue; Shin Yasuda; Takafumi Shimada; Yoshiya Kawamura; Mamoru Tochigi; Takanobu Minato; Tadashi Umekage; Taku Miyagawa; Nao Nishida; Katsushi Tokunaga; Yuji Okazaki; Hisanobu Kaiya; Tsukasa Sasaki
JOURNAL OF HUMAN GENETICS, NATURE PUBLISHING GROUP, 55, 2, 91-96, Feb. 2010, Peer-reviwed, Panic disorder (PD) is an anxiety disorder characterized by recurrent and unexpected panic attacks, subsequent worry and phobic avoidance. Although a number of association and linkage studies have been conducted, no gene has been identified as a susceptibility locus. We previously conducted a genome-wide association analysis of PD in 200 Japanese patients and the same number of controls, using a 500 K single nucleotide polymorphisms (SNPs) chip. In this study, we report a replication analysis of PD using the DigTag2 assay. The second stage sample consisted of 558 Japanese patients and 566 controls. Thirty-two markers were tested in a replication sample. As a result, no significant association was found after correction for multiple testing. However, the difference was observed at the nominal allele P-value <0.05 for two SNPs (rs6733840 and rs132617). We also conducted haplotype analyses of SNPs in the APOL3 and CLU genes. Our results failed to show any significant association with PD in these genes. Further studies on these variants with a larger sample size may be worth testing to confirm the results. Journal of Human Genetics (2010) 55, 91-96; doi: 10.1038/jhg.2009.127; published online 4 December 2009
Scientific journal, English - Association between the oxytocin receptor gene (OXTR) and amygdalar volume in healthy adults
Inoue Hideyuki; Yamasue Hidenori; Tochigi Mamoru; Abe Osamu; Takei Kunio; Suga Motomu; Yamada Haruyasu; Rogers Mark A; Aoki Shigeki; Liu Xiaoxi; Kawamura Yoshiya; Sasaki Tsukasa; Kasai Kiyoto
NEUROSCIENCE RESEARCH, 68, E205, 2010, Peer-reviwed - Functional (GT)n polymorphisms in promoter region of N-methyl-d-aspartate receptor 2A subunit (GRIN2A) gene affect hippocampal and amygdala volumes
Inoue H; Yamasue H; Tochigi M; Suga M; Iwayama Y; Abe O; Yamada H; Rogers M. A; Aoki S; Kato T; Sasaki T; Yoshikawa T; Kasai K
Genes Brain and Behavior, 9, 3, 269-275, 2010, Peer-reviwed - No association between the brain-derived neurotrophic factor gene and panic disorder in Japanese population
Takeshi Otowa; Takafumi Shimada; Yoshiya Kawamura; Xiaoxi Liu; Ken Inoue; Nagisa Sugaya; Takanobu Minato; Ryoichi Nakagami; Mamoru Tochigi; Tadashi Umekage; Kiyoto Kasai; Nobumasa Kato; Hisashi Tanii; Yuji Okazaki; Hisanobu Kaiya; Tsukasa Sasaki
JOURNAL OF HUMAN GENETICS, NATURE PUBLISHING GROUP, 54, 8, 437-439, Aug. 2009, Peer-reviwed, Panic disorder (PD) is a severe and chronic psychiatric disorder, with significant genetic components in the etiology. Brain-derived neurotrophic factor (BDNF) gene, which has regulatory effects on neurotransmitter systems such as serotonin and dopamine, is a candidate for susceptibility locus of PD. This study investigated three single-nucleotide polymorphisms (SNPs) of BDNF (rs6265 (Val66Met), rs11030104 and rs7103411) in Japanese patients with PD and controls. No significant association was observed between the three SNPs and PD. No association of the Val66Met was consistent with two small studies in Japanese and Chinese populations. We therefore conclude that the BDNF polymorphism may not play a major role in PD in the East Asian populations. Journal of Human Genetics (2009) 54, 437-439; doi: 10.1038/jhg.2009.46; published online 22 May 2009
Scientific journal, English - Association between Catechol-O-Methyltrasferase Val108/158Met Genotype and Prefrontal Hemodynamic Response in Schizophrenia
Ryu Takizawa; Mamoru Tochigi; Yuki Kawakubo; Kohei Marumo; Tsukasa Sasaki; Masato Fukuda; Kiyoto Kasai
PLOS ONE, PUBLIC LIBRARY SCIENCE, 4, 5, e5495, May 2009, Peer-reviwed, Background: "Imaging genetics'' studies have shown that brain function by neuroimaging is a sensitive intermediate phenotype that bridges the gap between genes and psychiatric conditions. Although the evidence of association between functional val108/158met polymorphism of the catechol-O-methyltransferase gene (COMT) and increasing risk for developing schizophrenia from genetic association studies remains to be elucidated, one of the most topical findings from imaging genetics studies is the association between COMT genotype and prefrontal function in schizophrenia. The next important step in the translational approach is to establish a useful neuroimaging tool in clinical settings that is sensitive to COMT variation, so that the clinician could use the index to predict clinical response such as improvement in cognitive dysfunction by medication. Here, we investigated spatiotemporal characteristics of the association between prefrontal hemodynamic activation and the COMT genotype using a noninvasive neuroimaging technique, near-infrared spectroscopy (NIRS).
Methodology/Principal Findings: Study participants included 45 patients with schizophrenia and 60 healthy controls matched for age and gender. Signals that are assumed to reflect regional cerebral blood volume were monitored over prefrontal regions from 52-channel NIRS and compared between two COMT genotype subgroups (Met carriers and Val/Val individuals) matched for age, gender, premorbid IQ, and task performance. The [oxy-Hb] increase in the Met carriers during the verbal fluency task was significantly greater than that in the Val/Val individuals in the frontopolar prefrontal cortex of patients with schizophrenia, although neither medication nor clinical symptoms differed significantly between the two subgroups. These differences were not found to be significant in healthy controls.
Conclusions/Significance: These data suggest that the prefrontal NIRS signals can noninvasively detect the impact of COMT variation in patients with schizophrenia. NIRS may be a promising candidate translational approach in psychiatric neuroimaging.
Scientific journal, English - Association between sigma-1 receptor gene polymorphism and prefrontal hemodynamic response induced by cognitive activation in schizophrenia
Ryu Takizawa; Kenji Hashimoto; Mamoru Tochigi; Yuki Kawakubo; Kohei Marumo; Tsukasa Sasaki; Masato Fukuda; Kiyoto Kasai
PROGRESS IN NEURO-PSYCHOPHARMACOLOGY & BIOLOGICAL PSYCHIATRY, PERGAMON-ELSEVIER SCIENCE LTD, 33, 3, 491-498, Apr. 2009, Peer-reviwed, The molecular biological role of the sigma-1 receptor (Sig-1R) has attracted much attention. Evidence suggests that the Sig-1R engaged in modulating NMDA and dopamine receptors is involved in the pathophysiology of schizophrenia and the mechanism of psychotropic drug efficacy. However, whether the Sig-1R genotype affects brain function in schizophrenia in vivo remains unknown. We investigated the association between Sig-1R functional polymorphism (GIn2Pro) and brain function in schizophrenia. The subjects were 40 patients with schizophrenia and 60 healthy controls, all right-handed, who gave written informed consent to participate. Signals, detected from prefrontal regions by 52-channel near-infrared spectroscopy (NIRS) during cognitive activation, were compared between two Sig1-R genotype subgroups (Gln/Gln individuals and Pro carriers) matched for age, gender, premorbid IQ and task performance. The prefrontal hemodynamic response of healthy controls during the verbal fluency task was higher than that of patients with schizophrenia. For the patients with schizophrenia, even after controlling the effect of medication, the [oxy-Hb] increase in the prefrontal cortex of the Gln/Gln genotype group was significantly greater than that of the Pro carriers (false discovery rate corrected p<0.05). Clinical symptoms were not significantly different between the two Sig-1R genotype subgroups. These differences were not significant in the healthy controls. This is the first functional imaging genetics study that implicated the association between Sig-1R genotype and prefrontal cortical function in schizophrenia in vivo. Our findings also suggest that the prefrontal hemodynamic response assessed by noninvasive and less demanding NIRS is a useful intermediate phenotype for translational research in schizophrenia. (C) 2009 Elsevier Inc. All rights reserved.
English - Genome-wide association study of panic disorder in the Japanese population
Takeshi Otowa; Eiji Yoshida; Nagisa Sugaya; Shin Yasuda; Yukika Nishimura; Ken Inoue; Mamoru Tochigi; Tadashi Umekage; Taku Miyagawa; Nao Nishida; Katsushi Tokunaga; Hisashi Tanii; Tsukasa Sasaki; Hisanobu Kaiya; Yuji Okazaki
JOURNAL OF HUMAN GENETICS, NATURE PUBLISHING GROUP, 54, 2, 122-126, Feb. 2009, Peer-reviwed, Panic disorder (PD) is an anxiety disorder characterized by panic attacks and anticipatory anxiety. Although a number of association studies have been conducted, no gene has been identified as a susceptibility locus. In this study, we conducted a genome-wide association study of PD in 200 Japanese patients and the same number of controls, using the GeneChip Human Mapping 500 K Array Set. Genotypes were determined using the Bayesian Robust Linear Model with Mahalanobis (BRLMM) genotype calling algorithm. The genotype data were data-cleaned using criteria for SNP call rate (>= 95%), Hardy-Weinberg equilibrium (P >= 0.1%) and minor allele frequency (>= 5%). The significance level of the allele P-value was set at 1.0 x 10(-6), to make false discovery rate (FDR) <0.05. As a result, seven SNPs were significantly associated with PD, which were located in or adjacent to genes including PKP1, PLEKHG1, TMEM16B, CALCOCO1, SDK2 and CLU (or APO-J). Studies with other samples are required to confirm the results.
Scientific journal, English - Association Study of the 15q11-q13 Maternal Expression Domain in Japanese Autistic Patients
Chieko Kato; Mamoru Tochigi; Jun Ohashi; Shinko Koishi; Yuki Kawakubo; Kenji Yamamoto; Hideo Matsumoto; Ohiko Hashimoto; Soo-Yung Kim; Keiichiro Watanabe; Yukiko Kano; Eiji Nanba; Nobumasa Kato; Tsukasa Sasaki
AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS, WILEY-LISS, 147B, 7, 1008-1012, Oct. 2008, Peer-reviwed, Chromosome 15q11-q13 has been a focus of genetic studies of autism susceptibility, because cytogenetic abnormalities are frequently observed in this region in autistic patients. An imprinted, maternally expressed gene within the region may have a role in autistic symptomatology. In the present study, we investigated the association between autism and the maternal expression domain (MED) in the region, containing the UBE3A and ATP10C genes, and the upstream imprinting center (IC), which mediates coordinate control of imprinted expression throughout the region. We analyzed 41 single nucleotide polymorphisms (SNPs) in 166 patients with autism and 416 controls from a Japanese population. As a result, a statistically significant difference after correction for multiple testing was observed between the patients and controls in the genotypic distribution of SNP rs7164989 (SNP8 in this study) located in SNRPN, whose promoter corresponds to the IC (P = 0.018, corrected for multiple testing). In the analysis of a four-marker haplotype located in ATP10C, a statistically significant difference after correction for multiple testing was observed in the frequency of one haplotype between male patients and controls (permutation P = 0.033, corrected for multiple testing). Thus, the present study may suggest the association between autism and the MED or the upstream IC in chromosome 15q11-q13 in the Japanese population. (C) 2008 Wiley-Liss, Inc.
Scientific journal, English - Association and interaction analyses of NRG1 and ERBB4 genes with schizophrenia in a Japanese population
Sae Shiota; Mamoru Tochigi; Hiroko Shimada; Jun Ohashi; Kiyoto Kasai; Nobumasa Kato; Katsushi Tokunaga; Tsukasa Sasaki
JOURNAL OF HUMAN GENETICS, NATURE PUBLISHING GROUP, 53, 10, 929-935, Oct. 2008, Peer-reviwed, Neuregulin 1 (NRG1) is one of the most promising candidate genes for schizophrenia. A number of replication studies have been conducted, although the results were inconsistent and no susceptible variant has yet been identified. The inconsistency might be attributed to the ethnic difference in allele and haplotype frequencies. However, it is equally possible that one or more genes interacting with NRG1 may also be implicated in schizophrenia and attribute to the inconsistency. To test the hypothesis, we conducted an interaction analysis between NRG1 and one of its receptor's (ERBB4) polymorphisms as well as the association analysis of the two genes associated with schizophrenia in Japanese. We observed no significant difference between patients and controls in allele frequencies or genotypic distributions of the 18 polymorphisms of the genes. The permutation test showed no significant differences in estimated haplotype frequencies between patients and controls, including the haplotype HAP(ICE). In the interaction analysis, significant interaction was observed between rs2919381 in NRG1 and rs7560730 in ERBB4 (P = 0.047, corrected). Thus, our results suggest the possibility that interaction between variants in NRG1 and ERBB4 might contribute to susceptibility for schizophrenia in a Japanese population. Further investigation may be necessary to confirm our results.
Scientific journal, English - Up-regulation of ADM and SEPX1 in the lymphoblastoid cells of patients in monozygotic twins discordant for schizophrenia
Chihiro Kakiuchi; Mizuho Ishiwata; Shinichiro Nanko; Norio Ozaki; Nakao Iwata; Tadashi Umekage; Mamoru Tochigi; Kazuhisa Kohda; Tsukasa Sasaki; Akira Imamura; Yuji Okazaki; Tadafumi Kato
AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS, WILEY-LISS, 147B, 5, 557-564, Jul. 2008, Peer-reviwed, The contribution of genetic factors to schizophrenia is well established and recent studies have indicated several strong candidate genes. However, the pathophysiology of schizophrenia has not been totally elucidated yet. To date, studies of monozygotic twins discordant for schizophrenia have provided insight into the pathophysiology of this illness; this type of study can exclude interindividual variability and confounding factors such as effects of drugs. In this study we used DNA microarray analysis to examine the mRNA expression patterns in the lymphoblastoid (LB) cells derived from two pairs of monozygotic twins discordant for schizophrenia. From five independent replicates for each pair of twins, we selected five genes, which included adrenomedullin (ADM) and selenoprotein X1 (SEPX1), as significantly changed in both twins with schizophrenia. Interestingly, ADM was previously reported to be upregulated in both the LB cells and plasma of schizophrenic patients, and SEPX1 was included in the list of genes up-regulated in the peripheral blood cells of schizophrenia patients by microarray analysis. Then, we performed a genetic association study of schizophrenia in the Japanese population and examined the copy number variations, but observed no association. These findings suggest the possible role of ADM and SEPX1 as biomarkers of schizophrenia. The results also support the usefulness of gene expression analysis in LB cells of monozygotic twins discordant for an illness. (C) 2007 Wiley-Liss, Inc.
Scientific journal, English - Association study of the commonly recognized breakpoints in chromosome 15q11-q13 in Japanese autistic patients
Chieko Kato; Mamoru Tochigi; Shinko Koishi; Yuki Kawakubo; Kenji Yamamoto; Hideo Matsumoto; Ohiko Hashimoto; Soo-Yung Kim; Keiichiro Watanabe; Yukiko Kano; Eiji Nanba; Nobumasa Kato; Tsukasa Sasaki
PSYCHIATRIC GENETICS, LIPPINCOTT WILLIAMS & WILKINS, 18, 3, 133-136, Jun. 2008, Peer-reviwed, Objective Chromosome 15q11-q13 has been proposed to harbor a gene for autism susceptibility because deletions of the region lead to Prader-Willi syndrome and Angelman syndrome, whose phenotypes overlap with autism. These deletions generally occur with the use of three commonly recognized breakpoints (BP1, BP2, and BP3); therefore, it may be possible that genes located in the breakpoints are impaired and contribute to autism susceptibility. No study, however, has investigated the genetic association between the breakpoints and autism, to our knowledge. Here, we investigated the association between the common breakpoints of chromosome 15q11-q13 and autism in a Japanese population.
Methods We genotyped 12 single nucleotide polymorphisms (SNPs) in 166 patients with autistic disorder and 415 healthy controls. The SNPs are located in two additional distal breakpoints (BP4 and BP5), involved in duplications and triplications of the region, as well as in BP1 and BP3.
Results No significant difference was observed between the controls and patients in allelic frequencies or genotypic distributions of the 12 SNPs. In the analyses of the suggested five haplotypes, no significant difference between the controls and patients was observed in the distributions of any estimated haplotypes. When confining the patients to only males, a difference was observed in a two-marker haplotype in BP3 between the controls and patients (global permutation P value= 0.006), although the statistical level became insignificant after correction for multiple testing.
Conclusion This study provides no positive evidence of the association between the common breakpoints of chromosome 15q11-q13 and autism in the Japanese population.
Scientific journal, English - No association between the ryanodine receptor 3 gene and autism in a Japanese population
Mamoru Tochigi; Chieko Kato; Jun Ohashi; Shinko Koishi; Yuki Kawakubo; Kenji Yamamoto; Hideo Matsumoto; Ohiko Hashimoto; Soo-Yung Kim; Keiichiro Watanabe; Yukiko Kano; Eiji Nanba; Nobumasa Kato; Tsukasa Sasaki
PSYCHIATRY AND CLINICAL NEUROSCIENCES, WILEY-BLACKWELL, 62, 3, 341-344, Jun. 2008, Peer-reviwed, Aim: Autism is a neurodevelopmental disorder with a complex genetic etiology. Chromosome 15q11-q14 has been proposed to harbor a gene for autism susceptibility because deletion of the region leads to Prader-Willi syndrome or Angelman syndrome, having phenotypic overlap with autism. Here we studied the association between autism and the ryanodine receptor 3 (RyR3) gene, which is located in the region. This is the first study, to our knowledge, that has investigated the association.
Methods: We genotyped 14 tag single nucleotide polymorphisms (SNPs) in 166 Japanese patients with autism and 375 controls.
Results: No significant difference was observed between the patients and controls in allelic frequencies or genotypic distributions of the 14 SNPs. Analysis after confining the subjects to males showed similar results.
Conclusions: The present study provides no positive evidence for the association between the RyR3 gene and autism in the Japanese population.
Scientific journal, English - Characteristics of fatigue in panic disorder patients
Hisanobu Kaiya; Nagisa Sugaya; Reiko Iwasa; Mamoru Tochigi
PSYCHIATRY AND CLINICAL NEUROSCIENCES, BLACKWELL PUBLISHING, 62, 2, 234-237, Apr. 2008, Peer-reviwed, It was suggested that fatigue is one of characteristics of panic disorder. Fatigue was assessed in 360 patients with panic disorder using the Japanese version of the Multidimensional Fatigue Inventory (MFI-J). The scores for general fatigue and reduced activity were significantly higher in the patients than in the controls. These tendencies were also observed in men when the subject group was differentiated according to sex, but not in women. In contrast, the trend for higher score for physical fatigue was observed only in the female patients. Thus, the present study suggests that the characteristics of fatigue vary with sex in panic disorder.
Scientific journal, English - Methylation status of the reelin promoter region in the brain of schizophrenic patients
Mamoru Tochigi; Kazuya Iwamoto; Miki Bundo; Atsuko Komori; Tsukasa Sasaki; Nobumasa Kato; Tadafumi Kato
BIOLOGICAL PSYCHIATRY, ELSEVIER SCIENCE INC, 63, 5, 530-533, Mar. 2008, Peer-reviwed, Background: Hypermethylation of the reelin (RELN) promoter region and the reduced levels of its messenger RNA and protein have been implicated in the pathophysiology of schizophrenia. We intended a technical replication of recent studies that observed hypermethylation of CpG or CpNpG sites in the RELN promoter region in the brain of schizophrenic patients.
Methods: The DNA methylation status of the promoter region of RELN was examined by using the pyrosequencing method in the prefrontal cortices of 14 patients with schizophrenia and 13 control subjects.
Results: All of the CpG and two proposed CpNpG sites analyzed showed no detectable DNA methylation (< 5%) in both control subjects and patients with schizophrenia. No detectable DNA methylation was observed in both gray and white matter, excluding the possibility of cellular heterogeneity of start materials.
Conclusions: We did not confirm the hypermethylation of the RELN promoter region in the brains of schizophrenic patients, suggested in the previous studies.
Scientific journal, English - Gene expression profiling of major depression and suicide in the prefrontal cortex of postmortem brains
Mamoru Tochigi; Kazuya Iwamoto; Miki Bundo; Tsukasa Sasaki; Nobumasa Kato; Tadafumi Kato
NEUROSCIENCE RESEARCH, ELSEVIER IRELAND LTD, 60, 2, 184-191, Feb. 2008, Peer-reviwed, Genome-wide gene expression analysis using DNA microarray has a great advantage to identify the genes or specific molecular cascades involved in mental diseases, including major depression and suicide. In the present study, we conducted DNA microarray analysis of major depression using postmortem prefrontal cortices. The gene expression patterns were compared between the controls and subjects with major depression. As a result, 99 genes were listed as the differentially expressed genes in major depression, of which several genes such as FGFR1, NCAM1, and CAMK2A were of interest. Gene ontology analysis suggested an overrepresentation of genes implicated in the downregulation or inhibition of cell proliferation. The present results may support the hypothesis that major depression is associated with impaired cellular proliferation and plasticity. Comparison between the controls and suicide victims with major depression, bipolar disorder, or schizophrenia was also conducted in the present study. Two genes, CAD and ATP1A3, were differentially expressed in the three comparisons in the same direction. Interestingly, these two genes were also included in the differentially expressed 99 genes in major depression. It may be worth investigating the genes in relation to suicide or major depression. (C) 2007 Published by Elsevier Ireland Ltd and the Japan Neuroscience Society.
Scientific journal, English - The association between the val158met polymorphism of the catecol-O-methyl transferase gene and morphological abnormalities of the brain in patients with schizophrenia
Suga M; Yamasue H; Tochigi M; Inoue H; Iwayama Y; Abe O; Yamada H; Aoki S; Kato T; Sasaki T; Yoshikawa T; Kasai K
PSYCHIATRY AND CLINICAL NEUROSCIENCES, 62, 1, S7, Feb. 2008, Peer-reviwed - Schizophrenia susceptibility genes and the volume of hippocampus
Inoue H; Yamasue H; Tochigi M; Suga M; Abe O; Yamada H; Aoki S; Sasaki T; Kasai K
PSYCHIATRY AND CLINICAL NEUROSCIENCES, 62, 1, S9, Feb. 2008, Peer-reviwed - Gender-common and -specific neuroanatomical basis of human anxiety-related personality traits
Hidenori Yamasue; Osamu Abe; Motomu Suga; Haruyasu Yamada; Hideyuki Inoue; Mamoru Tochigi; Mark Rogers; Shigeki Aoki; Nobumasa Kato; Kiyoto Kasai
CEREBRAL CORTEX, OXFORD UNIV PRESS INC, 18, 1, 46-52, Jan. 2008, Peer-reviwed, Exploration of the relationships between regional brain volume and anxiety-related personality traits is important for understanding preexisting vulnerability to depressive and anxiety disorders. However, previous studies on this topic have employed relatively limited sample sizes and/or image processing methodology, and they have not clarified possible gender differences. In the present study, 183 (male/female: 117/66) right-handed healthy individuals in the third and fourth decades of life underwent structural magnetic resonance imaging scans and Temperament and Character Inventory. Neuroanatomical correlates of individual differences in the score of harm avoidance (HA) were examined throughout the entire brain using voxel-based morphometry. We found that higher scores on HA were associated with smaller regional gray matter volume in the right hippocampus, which was common to both genders. In contrast, female-specific correlation was found between higher anxiety-related personality traits and smaller regional brain volume in the left anterior prefrontal cortex. The present findings suggest that smaller right hippocampal volume underlies the basis for higher anxiety-related traits common to both genders, whereas anterior prefrontal volume contributes only in females. The results may have implications for why susceptibility to stress-related disorders such as anxiety disorders and depression shows gender and/or individual differences.
Scientific journal, English - Global hypomethylation of peripheral leukocyte DNA in male patients with schizophrenia: A potential link between epigenetics and schizophrenia
Morihiro Shimabukuro; Tsukasa Sasaki; Akira Imamura; Takahiro Tsujita; Chiaki Fuke; Tadashi Umekage; Mamoru Tochigi; Kennichi Hiramatsu; Tetsuji Miyazaki; Takaya Oda; Jun Sugimoto; Yoshihiro Jinno; Yuji Okazaki
JOURNAL OF PSYCHIATRIC RESEARCH, PERGAMON-ELSEVIER SCIENCE LTD, 41, 12, 1042-1046, Dec. 2007, Peer-reviwed, Genetic and epigenetic factors can potentially alter susceptibility to psychiatric disorders such as schizophrenia. In order to explore the effect of epigenetics on the pathogenesis of schizophrenia, we examined the global methylation level of leukocyte DNA from 210 patients with schizophrenia (124 males and 86 females) and 237 healthy subjects (108 males and 129 females). Methylated deoxycytidine (mC) content in peripheral leukocyte DNA was measured by high performance liquid chromatography (HPLC). We confirmed in the healthy subjects our previous finding that there are sex-dependent differences in mC content (males > females; beta = 0.319, p < 0.001), in addition to the effect of age (beta = -0.141, p = 0.022). We therefore used multiple regression to analyze the data from all subjects by sex, with age as a co-variant. In males, a tendency was observed toward lower mC content in patients than in controls (beta = -0.115, p = 0.075), with a significant effect of age (beta = -0.212, p < 0.001). This difference was more prominent in younger individuals. In females, no effect of age or disease status on mC content was observed. These results established that there is significant sex-dependent difference in the mC content of human peripheral leukocyte DNA, and raise the possibility that alterations in DNA methylation state are present in patients with schizophrenia. (c) 2006 Elsevier Ltd. All rights reserved.
Scientific journal, English - No evidence for significant association between GABA receptor genes in chromosome 15q11-q13 and autism in a Japanese population
Mamoru Tochigi; Chieko Kato; Shinko Koishi; Yuki Kawakubo; Kenji Yamamoto; Hideo Matsumoto; Ohiko Hashimoto; Soo-Yung Kim; Keiichiro Watanabe; Yukiko Kano; Eiji Nanba; Nobumasa Kato; Tsukasa Sasaki
JOURNAL OF HUMAN GENETICS, SPRINGER TOKYO, 52, 12, 985-989, Dec. 2007, Peer-reviwed, The gamma-aminobutyric acid (GABA) receptor genes GABRB3, GABRA5, and GABRG3 located on chromosome 15q11-q13 have been major candidates for susceptibility genes for autism, a neurodevelopmental disorder with a complex genetic etiology. In this study, we first investigated the association between the GABA receptor genes and autism in a Japanese population by analyzing 11 single nucleotide polymorphisms (SNPs). Intron 3 of GABRB3 was densely mapped because the previous studies observed the association of the microsatellite 155CA-2 located in the region. We observed no significant difference in allelic frequencies or genotypic distributions of the 11 SNPs between patients and controls. A permutation test showed no significant global differences in estimated haplotype frequencies between patients and controls. Analysis after confining the subjects to males showed similar results. Thus, this study provides no positive evidence of an association between the GABA receptor genes and autism in a Japanese population. However, in a SNP (rs3212337) located near the microsatellite 155CA-2, a significant deviation from the Hardy-Weinberg equilibrium was observed in patients (p = 0.029, corrected for multiple testing). This finding may suggest further studies around the markers for more definitive conclusions.
Scientific journal, English - Association analysis of HSP90B1 with bipolar disorder
Chihiro Kakiuchi; Mizuho Ishiwata; Shinichiro Nanko; Hiroshi Kunugi; Yoshio Minabe; Kazuhiko Nakamura; Norio Mori; Kumiko Fujii; Tadashi Umekage; Mamoru Tochigi; Kazuhisa Kohda; Tsukasa Sasaki; Kazuo Yamada; Takeo Yoshikawa; Tadafumi Kato
JOURNAL OF HUMAN GENETICS, SPRINGER TOKYO, 52, 10, 794-803, Oct. 2007, Peer-reviwed, Pathophysiological role of endoplasmic reticulum (ER) stress response signaling has been suggested for bipolar disorder. The goal of this study was to test the genetic association between bipolar disorder and an ER chaperone gene, HSP90B1 (GRP94/gp96), which is located on a candidate locus, 12q23.3. We tested the genetic association between bipolar disorder and HSP90B1 by case-control studies in two independent Japanese sample sets and by a transmission disequilibrium test (TDT) in NIMH Genetics initiative bipolar trio samples (NIMH trios). We also performed gene expression analysis of HSP90B1 in lymphoblastoid cells. Among the 11 SNPs tested, rs17034977 showed significant association in both Japanese sample sets. The frequency of the SNP was lower in NIMH samples than in Japanese samples and there was no significant association in NIMH trios. Gene expression analysis of HSP90B1 in lymphoblastoid cells suggested a possible relationship between the associated SNP and mRNA levels. HSP90B1 may have a pathophysiological role in bipolar disorder in the Japanese population, though further study will be needed to understand the underlying functional mechanisms.
Scientific journal, English - Association study of monoamine oxidase and catechol-O-methyltransferase genes with smoking behavior
Mamoru Tochigi; Kentaro Suzuki; Chieko Kato; Takeshi Otowa; Hiroyuki Hibino; Tadashi Umekage; Nobumasa Kato; Tsukasa Sasaki
PHARMACOGENETICS AND GENOMICS, LIPPINCOTT WILLIAMS & WILKINS, 17, 10, 867-872, Oct. 2007, Peer-reviwed, Objective The genes of catalytic enzymes of dopamine, including monoamine oxidase (MAOA and MAOB) and catechol-O-methyltransferase (COMT), have been major candidates for genes that affect smoking behavior. In this study, we investigated the relationship between smoking behavior and four polymorphisms of these genes, the MAOA variable number tandem repeat polymorphism, the MAOA 1460 T/C polymorphism, the MAOB intron 13 G/A polymorphism, and the COMT Val158Met polymorphism. The association between the MAOB polymorphism and personality traits was also explored.
Participants and methods The polymorphisms were genotyped in 451 healthy Japanese volunteers. Data on smoking habits were obtained from structured interviews. In addition to testing the association between each polymorphism and smoking status, epistatic and additive effects between two polymorphisms were also investigated.
Results A significant association was observed between the COMT Val158Met polymorphism and smoking status. Male participants with the Val/Val genotype had a significantly higher risk of heavy smoking compared with those with other genotypes, although no significant association was observed in female participants. No evidence was obtained for an association between the MAO genes and smoking behavior, including epistatic or additive effects. No significant association was observed between the MAOB polymorphism and personality traits.
Conclusion This study may suggest a role of the COMT Val158Met polymorphism in smoking behavior in Japanese individuals.
Scientific journal, English - 躁うつ病関連遺伝子多型であるmtDNA10398Aをもつ健常者では扁桃体・被殻が大きく前頭前野白質体積が小さい
井上 秀之; 山末 英典; 栃木 衛; 佐々木 司; 加藤 進昌; 笠井 清登; 阿部 修; 山田 晴耕; 青木 茂樹; 加藤 忠史; 垣内 千尋
Bipolar Disorder, アルタ出版(株), 5, 90-92, May 2007, Peer-reviwed, 双極性障害患者と遺伝素因を共有する非罹患同胞で認められる皮殻・前頭前野白質・梁下野・扁桃体などの脳構造異常が、双極性障害リスクアレルであるミトコンドリア遺伝子10398Aでも健常者でも認められるか、海馬・扁桃体に関心領域を設定したROI(region of interest)法とVBM(voxel-based morphometry)を併用して検討した。その結果、健常者でも双極性障害のリスクアレルを有しているだけで扁桃体体積・皮殻が大きく、左前頭前野白質が小さくなることが明らかとなった。以上より、大きな皮殻と小さな左前頭前野白質が双極性障害の遺伝因子の表現型となり得ることが示唆された。
Japanese - Effect of COMT (val/met) genotype on prefrontal function in schizophrenia; A multi-channel NIRS study
Takizawa Ryu; Tochigi Mamoru; Marumo Kohei; Kawakubo Yuki; Suga Motomu; Yamasue Hidenori; Sasaki Tsukasa; Kasai Kiyoto
BIOLOGICAL PSYCHIATRY, 61, 8, 252S, 15 Apr. 2007, Peer-reviwed - Gender-common and -specific neuroanatomical basis of human anxiety-related personality traits
Yamasue Hidenori; Abe Osamu; Suga Motomu; Yamade Haruyasu; Inoue Hideyuki; Tochigi Mamoru; Rogers Mark; Aoki Shigeki; Kato Nobumasa; Kasai Kiyoto
BIOLOGICAL PSYCHIATRY, 61, 8, 132S, 15 Apr. 2007, Peer-reviwed - Functional (GT)N polymorphisms in the promoter region of N-methyl-D-aspartate receptor 2A subunit (GRIN2A) gene affects hippocampal and amygdala volume in humans
Inoue Hideyuki; Yamasue Hidenori; Tochigi Mamoru; Suga Motomu; Iwayama Yoshimi; Abe Osamu; Yamada Haruyasu; Mark Rogers; Aoki Shigeki; Kato Nobumasa; Kato Tadafumi; Sasaki Tsukasa; Kasai Kiyoto; Yoshikawa Takeo
BIOLOGICAL PSYCHIATRY, 61, 8, 156S-157S, 15 Apr. 2007, Peer-reviwed - Association study between the TNXB locus and schizophrenia in a Japanese population
Mamoru Tochigi; Xuan Zhang; Jun Ohashi; Hiroyuki Hibino; Takeshi Otowa; Mark Rogers; Tadafumi Kato; Yuji Okazaki; Nobumasa Kato; Katsushi Tokunaga; Tsukasa Sasaki
AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS, WILEY-LISS, 144B, 3, 305-309, Apr. 2007, Peer-reviwed, The chromosome 6p21-24 region, which contains the human leukocyte antigen (HILA) region, has been suggested as an important locus for a susceptibility gene for schizophrenia. Recently, a significant association between schizophrenia and the TNXB locus, located immediately telomeric of the NOTCH4 locus in the HLA region, was observed. Few studies have further investigated the region in schizophrenia. In the present study, we investigated the region in a Japanese population. Subjects included 241 patients with schizophrenia and 290 controls. Twenty-six single nucleotide polymorphisms (SNPs) and the corresponding haplotypes were analyzed. As a result, exactly the same SNPs in the TNXB locus (rs1009382 and rs204887) as in the previous study were associated with schizophrenia (P = 0.034 and 0.034, respectively, uncorrected). A SNP (rs2071287) in the NOTCH4 locus and haplotype around it were also suggested to associate with the disease, consistent with another previous study (P = 0.041 and permutation P = 0.024, respectively, uncorrected). Although these associations became insignificant after Bonferroni correction, the findings might provide support for the association of the TNXB locus or its adjacent region of the NOTCH4 locus with schizophrenia. (c) 2006 Wiley-Liss, Inc.
Scientific journal, English - Association study between the cholecystokinin A receptor gene and schizophrenia in the Japanese population
Takanobu Minato; Mamoru Tochigi; Nobumasa Kato; Tsukasa Sasaki
PSYCHIATRIC GENETICS, LIPPINCOTT WILLIAMS & WILKINS, 17, 2, 117-119, Apr. 2007, Peer-reviwed, Cholecystokinin A receptor (CCK-AR) has been implicated in the pathophysiology of schizophrenia through its mediation of dopamine-release in the central nervous system. Several studies have observed the association between the CCK-AR gene and schizophrenia. Especially, the association has been repeatedly observed between the 779T/C polymorphism and auditory hallucinations or positive symptoms of schizophrenia. In this study, we investigated the association between the 779T/C polymorphism of the CCK-AR gene and schizophrenia in 290 Japanese patients with schizophrenia and 290 controls. As a result, no significant difference was observed in genotypic distributions or allelic frequencies between the patients and controls, although there was a trend for the association between the C allele of the polymorphism and hallucination (P=0.024) or hallucinatory-paranoid state (P=0.049). In conclusion, the present results may not provide evidence for the association between the CCK-AR gene and schizophrenia in the Japanese population.
Scientific journal, English - Neurotrophic factor genotypes and regional brain volume measured with manually-traced volumetry as well as voxel-based morphometry
Yamasue H; Tochigi M; Kakiuchi C; Suga M; Inoue H; Kasai K; Kato T; Sasaki T
PSYCHIATRY AND CLINICAL NEUROSCIENCES, 61, 2, S1-S2, Apr. 2007, Peer-reviwed - Effect of catechol-O-methyltranseferese (Val/Met) genotype on prefrontal function in schizophrenia: a multi-channel near-infrared spectroscopy study
Takizawa R; Kasai K; Tochigi M; Marumo K; Kawakubo Y; Suga M; Yamasue H; Fukuda M; Kato N; Sasaki T
PSYCHIATRY AND CLINICAL NEUROSCIENCES, 61, 2, S4, Apr. 2007, Peer-reviwed - The brain-derived neurotrophic factor val66met polymorphism and amygdala and hippcampal volumes
Inoue H; Yamasue H; Tochigi M; Suga M; Minato T; Abe O; Yamada H; Aoki S; Kato N; Kasai K; Sasaki T
PSYCHIATRY AND CLINICAL NEUROSCIENCES, 61, 2, S4, Apr. 2007, Peer-reviwed - Human brain structural change related to acute single exposure to sarin
Hidenori Yamasue; Osamu Abe; Kiyoto Kasai; Motomu Suga; Akira Iwanami; Haruyasu Yamada; Mamoru Tochigi; Toshlyuki Ohtani; Mark A. Rogers; Tsukasa Sasaki; Shigeki Aoki; Tadafumi Kato; Nobumasa Kato
ANNALS OF NEUROLOGY, WILEY-LISS, 61, 1, 37-46, Jan. 2007, Peer-reviwed, Objective: This study aimed to identify persistent morphological changes subsequent to an acute single-time exposure to satin, a highly poisonous organophosphate, and the neurobiological basis of long-lasting somatic and cognitive symptoms in victims exposed to satin.
Methods: Thirty-eight victims of the 1995 Tokyo subway satin attack, all of whom had been treated in an emergency department for satin intoxication, and 76 matched healthy control subjects underwent T1-weighted and diffusion tensor magnetic resonance imaging (DTI) in 2000 to 2001. Serum cholinesterase (ChE) levels measured immediately and longitudinally after the exposure and the current severity of chronic reports in the victims were also evaluated.
Results: The voxel-based morphometry exhibited smaller than normal regional brain volumes in the insular cortex and neighboring white matter, as well as in the hippocampus in the victims. The reduced regional white matter volume correlated with decreased serum cholinesterase levels and with the severity of chronic somatic complaints related to interoceptive awareness. Voxel-based analysis of diffusion tensor magnetic resonance imaging further demonstrated an extensively lower than normal fractional anisotropy in the victims. All these findings were statistically significant (corrected p < 0.05).
Interpretation: Sarin intoxication might be associated with structural changes in specific regions of the human brain, including those surrounding the insular cortex, which might be related to elevated subjective awareness of internal bodily status in exposed individuals.
Scientific journal, English - No association between the metabotropic glutamate receptor type 3 gene (GRM3) and schizophrenia in a Japanese population
Mamoru Tochigi; Motomu Suga; Jun Ohashi; Takeshi Otowa; Hidenori Yamasue; Kiyoto Kasai; Tadafumi Kato; Yuji Okazaki; Nobumasa Kato; Tsukasa Sasaki
SCHIZOPHRENIA RESEARCH, ELSEVIER SCIENCE BV, 88, 1-3, 260-264, Dec. 2006, Peer-reviwed, Several lines of evidence have suggested that the metabotropic glutamate receptor 3 (GRM3) gene is a candidate susceptibility gene for schizophrenia. To our knowledge, six studies have investigated the genetic association between GRM3 and schizophrenia, although the results have been quite controversial. In the present study, we investigated the association between the GRM3 gene and schizophrenia in 402 Japanese people by analyzing 10 single nucleotide polymorphisms (SNPs), including all SNPs that showed significant results in previous studies. We observed no significant difference in allelic frequencies or genotypic distributions of the 10 SNPs between the controls and patients. A permutation test showed no significant global differences in estimated haplotype frequencies between the controls and patients. Thus, the present study provides no positive evidence of an association between the GRM3 gene and schizophrenia in the Japanese population. (c) 2006 Elsevier B.V. All rights reserved.
Scientific journal, English - Insertional polymorphism of endogenous retrovirus HERV-K115 in schizophrenia
Takeshi Otowa; Mamoru Tochigi; Mark Rogers; Tadashi Umekage; Nobumasa Kato; Tsukasa Sasaki
NEUROSCIENCE LETTERS, ELSEVIER IRELAND LTD, 408, 3, 226-229, Nov. 2006, Peer-reviwed, Retroviruses are implicated in the pathogenesis of schizophrenia. Human endogenous retrovirus type KI 15 (HERV-KI 15) is a full-length, potentially transcriptional retrovirus and is also polymorphic. We investigated the frequency of HERV-KI 15 in Japanese schizophrenia patients and healthy controls. No difference was found in the frequency between patients and controls (8.4% versus 9.4%, respectively). However, a marginal difference was observed in age at onset between the HERV-K positive and negative patients (p = 0.057). The HERV-KI 15 insertion appeared to be more frequent in patients with younger onset than those with later onset. These results preliminarily suggest that HERV-KI 15 may not be associated with schizophrenia in general, but that it could play a partial role in early precipitation of the disease. (c) 2006 Elsevier Ireland Ltd. All rights reserved.
Scientific journal, English - No association between the metabotropic glutamate receptor type 3 gene (GRM3) and schizophrenia in a Japanese population
Tochigi Mamoru; Suga Motomu; Ohashi Jun; Otowa Takeshi; Yamasue Hidenori; Kasai Kiyoto; Kato Tadafumi; Okazaki Yuji; Kato Nobumasa; Sasaki Tsukasa
AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS, 141B, 7, 792, 05 Oct. 2006, Peer-reviwed - No association of DRD2, DRD3, and tyrosine hydroxylase gene polymorphisms with personality traits in the Japanese population
Hiroyuki Hibino; Mamoru Tochigi; Takeshi Otowa; Nobumasa Kato; Tsukasa Sasaki
Behavioral and Brain Functions, 2, 32, 03 Oct. 2006, Peer-reviwed, Background: Dopamine D2 receptor (DRD2) and dopamine D3 receptor (DRD3) genes could be candidates for personality-related genes considering their pharmacological profiles or structures. However, a limited number of studies have investigated the association between these genes and personality traits. In the present study, we investigated the DRD2, DRD3, and tyrosine hydroxylase (TH) genes in relation to personality traits in the Japanese population. Epistasis (gene-gene interaction) among the genes was extensively analyzed, in addition to the analysis based on each gene. Methods: The -241A/G, - 141C Ins/Del, and Ser311Cys polymorphisms in the DRD2 gene, the Ser9Gly polymorphism of the DRD3 gene, and the Va181 Met and Pstl site polymorphisms in the TH gene were genotyped in 257 healthy Japanese subjects. Personality traits were evaluated by using the Revised NEO Personality Inventory (NEO PI-R) and the State-Trait Anxiety Inventory (STAI). The associations between gene polymorphisms and the scores for NEO PI-R or Trait Anxiety of STAI were statistically analyzed by one-way analysis of covariance (ANCOVA) adjusting sex and age. Epistasis was assessed using two-way ANCOVA between the polymorphisms of independent two genes. Results: In the analysis based on each gene, trends for association were observed between State Anxiety and the DRD2-141C Ins/Del polymorphism (p = 0.031, uncorrected), and between Trait Anxiety and the DRD2 Ser311Cys or TH Pstl site polymorphism (p = 0.048 and 0.041, respectively, uncorrected). In epistatic analysis, a trend for interaction was observed on the scores for Neuroticism and Trait Anxiety between the DRD2-141C Ins/Del and TH Va181 Met polymorphisms (p = 0.015 and 0.010, respectively, uncorrected). However, these differences were insignificant after Bonferroni correction. Conclusion: The present study did not provide evidence for the association between these dopamine-related genes and personality traits in the Japanese population. © 2006 Hibino et al
licensee BioMed Central Ltd.
Scientific journal, English - No evidence for an association between the BDNF Val66Met polymorphism and schizophrenia or personality traits
Mamoru Tochigi; Takeshi Otowa; Motomu Suga; Mark Rogers; Takanobu Minato; Hidenori Yamasue; Kiyoto Kasai; Nobumasa Kato; Tsukasa Sasaki
SCHIZOPHRENIA RESEARCH, ELSEVIER SCIENCE BV, 87, 1-3, 45-47, Oct. 2006, Peer-reviwed, Brain-derived neurotrophic factor (BDNF) is a member of the nerve growth factor family, which plays a critical role in neurodevelopment. Based on the neurodevelopmental hypothesis, the BDNF gene has been a candidate locus for schizophrenia. In Caucasians, recent studies identified an association with the Val66Met polymorphism, which has been suggested to affect episodic memory and hippocampal function in humans. However, in other populations, the association has not been replicated. In the present study, we investigated the association between the Val66Met polymorphism of the gene and schizophrenia in 401 Japanese patients with schizophrenia and 569 controls. As a result, we did not observe a significant difference in genotypic distribution or allele frequencies between the patients and controls (chi(2) = 0.56, df = 2, p = 0.76 and chi(2) = 0.39, df = 1, p = 0.53, respectively). We also investigated the association between the polymorphism and personality traits in the controls; however, no significant association was observed. Thus, the present study did not provide evidence for an association between the BDNF gene and schizophrenia or personality traits in the Japanese population. (c) 2006 Elsevier B.V. All rights reserved.
Scientific journal, English - Association study of the dysbindin (DTNBP1) gene in schizophrenia from the Japanese population
Mamoru Tochigi; Xuan Zhang; Jun Ohashi; Hiroyuki Hibino; Takeshi Otowa; Mark Rogers; Tadafumi Kato; Yuji Okazaki; Nobumasa Kato; Katsushi Tokunaga; Tsukasa Sasaki
NEUROSCIENCE RESEARCH, ELSEVIER IRELAND LTD, 56, 2, 154-158, Oct. 2006, Peer-reviwed, Dysbindin (DTNBP1: dystrobrevin binding protein 1), located on 6p22.3, is a candidate susceptibility gene for schizophrenia. Several studies, mostly in Caucasians, have provided evidence for an association between schizophrenia and the gene, although no common polymorphism or haploytpe has been established. In Asian populations, two studies investigated a limited number of single nucleotide polymorphisms (SNPs) of dysbindin and observed support for the association. In the present study, we investigated 12 SNPs of dysbindin, including those examined in previous Asian studies, and the corresponding haplotypes in a Japanese people with schizophrenia. As a result, no significant difference was observed between patients and controls in allelic frequencies or genotypic distributions of the 12 SNPs. Permutation test however showed significant differences in frequencies of the estimated 10-marker haplotypes between patients and controls (global p = 0.006). The present study may provide further support for an association between dysbindin and schizophrenia in Asian populations. The results might be similar to a previous Asian study, but specific haplotypes suggested for the association differed between the studies. Studies with more markers and subjects may be required before firm conclusions can be reached. (c) 2006 Elsevier Ireland Ltd and the Japan Neuroscience Society. All rights reserved.
Scientific journal, English - Clinical features of soft bipolarity in major depressive inpatients
Takeshi Utsumi; Tsukasa Sasaki; Iwao Shimada; Mayuko Mabuchi; Takuro Motonaga; Toshiyuki Ohtani; Mamoru Tochigi; Nobumasa Kato; Shinichiro Nanko
PSYCHIATRY AND CLINICAL NEUROSCIENCES, BLACKWELL PUBLISHING, 60, 5, 611-615, Oct. 2006, Peer-reviwed, Because of the difficulties of ascertaining episode of hypomania by past history of the patients, it is of clinical value to find variables which predict the development of bipolar II disorder in depressive patients. Taking advantage of relatively long hospitalization, the authors tried to elucidate fine clinical features of the soft bipolarity. The subjects were 39 patients with Major Depressive Episode, diagnosed according to the 4th edition of the Diagnostic and Statistical Manual criteria. Among them, 15 patients were diagnosed as bipolar II disorder (BPII), whereas 24 patients were with unipolar depression (UP), using a structured clinical interview to assess the mood spectrum (SCI-MOODS). In addition to ordinary clinical and demographic variables, the authors studied fine symptomatology of depression, premorbid personality, and interpersonal relationship. Continuous variables were analyzed by t-test. Categorical variables were tested by chi(2) analysis. In terms of premorbid personality, manic type (Zerssen) was found more frequently in BPII (UP 2/24, BPII 9/15, P < 0.05). Patients with BPII tended to show apparently quick disappearance of depressive symptoms (UP 2/24, BPII 9/15, P = 0.01). The most prominent result was a high prevalence of comorbidity of borderline personality disorder (BPD) among BPII (UP 0/24, BPII 6/15, P = 0.02). As Akiskal indicated that mood lability represents the most powerful predictor of hypomanias, patients with BPII showed quick response in mood to admission. The current subjects with BPII had high frequency of manic type of premorbid personality, indicating the usefulness of this variable for the prediction of hypomanias. Finally, the authors could observe development of BPD during hospitalization exclusively among BPII, to support the possibility of BPD as a state effect of BPII.
Scientific journal, English - No association between the CNTF null mutation and schizophrenia or personality
Jun Nishiyama; Mamoru Tochigi; Shin Itoh; Takeshi Otowa; Chieko Kato; Tadashi Umekage; Kazuhisa Kohda; Takashi Ebisawa; Nobumasa Kato; Tsukasa Sasaki
PSYCHIATRIC GENETICS, LIPPINCOTT WILLIAMS & WILKINS, 16, 5, 217-219, Oct. 2006, Peer-reviwed, The ciliary neurotrophic factor (CNTF) is a neurotrophic cytokine that plays a critical role in neurodevelopment. On the basis of neurodevelopmental hypothesis, the CNTF gene has been a candidate locus for schizophrenia. Several studies have investigated the association between the null mutation of the gene and schizophrenia, however, with inconsistent results. In the present study, we investigated the association in 222 Japanese patients with schizophrenia and 237 controls. The association between the mutation and personality traits was also studied, to investigate the effect of the mutation in participants from the general population. As a result, no association was observed between the mutation and schizophrenia nor personality traits, evaluated by using the Revised NEO Personality Inventory scores. The present study did not provide evidence for the association between the CNTF gene and schizophrenia or personality traits in the Japanese population. Psychiatr Genet 16:217-219 (c) 2006 Lippincott Williams & Wilkins.
Scientific journal, English - No association between the Clara cell secretory protein (CC16) gene polymorphism and personality traits
Mamoru Tochigi; Takeshi Otowa; Hiroyuki Hibino; Chieko Kato; Tetsuya Marui; Toshiyuki Ohtani; Tadashi Umekage; Nobumasa Kato; Tsukasa Sasaki
PROGRESS IN NEURO-PSYCHOPHARMACOLOGY & BIOLOGICAL PSYCHIATRY, PERGAMON-ELSEVIER SCIENCE LTD, 30, 6, 1122-1124, Aug. 2006, Peer-reviwed, Clara cell secretory protein (CC16) is an anti-inflammatory protein expressed in the respiratory tract. Several studies have suggested the association between CC16 and mental disturbances, such as schizophrenia, depression, and post-traumatic stress disorder. In the present study, we investigated the association between the CC16 gene A38G polymorphism and personality traits in 214 healthy Japanese subjects. Personality traits were evaluated by using the Revised NEO Personality Inventory (NEO PI-R) and the State-Trait Anxiety Inventory (STAI). As a result, no significant association was observed between the genotypes and the scores of the NEO PI-R. or the STAI. The present results suggest that CC16 may not have a major role in the development of personality traits. (c) 2006 Elsevier Inc. All rights reserved.
English - Association between corticotropin-releasing hormone receptor 2 (CRHR2) gene polymorphism and personality traits
Mamoru Tochigi; Chieko Kato; Takeshi Otowa; Hiroyuki Hibino; Tetsuya Marui; Toshiyuki Ohtani; Tadashi Umekage; Nobumasa Kato; Tsukasa Sasaki
PSYCHIATRY AND CLINICAL NEUROSCIENCES, BLACKWELL PUBLISHING, 60, 4, 524-526, Aug. 2006, Peer-reviwed, Corticotropin-releasing hormone (CRH) has been implicated in the pathophysiology of anxiety disorders and depression. Corticotropin-releasing hormone receptor 2 (CRHR2) is one of the receptors that mediate CRH signal. The purpose of the present study was to investigate the association between the CRHR2 gene and personality traits, evaluated using the Revised NEO Personality Inventory (NEO PI-R), in 243 healthy Japanese subjects. As a result, significant association was observed between the polymorphism in intron 2 (rs2267717) and Openness (P = 0.004, uncorrected, ANOVA), while no relationship was observed concerning Neuroticism. The present result suggests an association between CRHR2 and the personality trait of Openness.
Scientific journal, English - ミトコンドリアComplex Iサブユニット遺伝子(NDUFV2)と統合失調症との関連
鷲塚 伸介; 亀谷 瑞枝; 梅景 正; 栃木 衛; 幸田 和久; 佐々木 司; 加藤 忠史
神経化学, (一社)日本神経化学会, 45, 2-3, 471-471, Aug. 2006
Japanese - パニック障害と時計関連遺伝子
音羽 健司; 栃木 衛; 梅 景正; 海老澤 尚; 菅谷 渚; 井上 顕; 吉田 栄二; 谷井 久志; 岡崎 祐士; 加藤 進昌; 貝谷 久宣; 佐々木 司
神経化学, 日本神経化学会, 45, 2-3, 390-390, Aug. 2006
Japanese - No association of 5-HT2C, 5-HT6, and tryptophan hydroxylase-1 gene polymorphisms with personality traits in the Japanese population
Mamoru Tochigi; Hiroyuki Hibino; Takeshi Otowa; Toshiyuki Ohtani; Takashi Ebisawa; Nobumasa Katoa; Tsukasa Sasaki
NEUROSCIENCE LETTERS, ELSEVIER IRELAND LTD, 403, 1-2, 100-102, Jul. 2006, Peer-reviwed, Serotonin 2C receptor (5-HT2C), serotonin 6 receptor (5-HT6), and tryptophan hydroxylase-1 (TPH1) genes could be candidates for personality-related genes considering the role of serotonin in various mental functions and behavior. However, a limited number of studies have investigated the association between these genes and personality traits. In the present study, we investigated the three serotonin-related genes, 5-HT2C, 5-HT6, and TPH1 genes, in relation to personality traits in the Japanese population. The Cys23Ser polymorphisms in the 5-HT2C gene, the 267T/C polymorphism of the 5-HT6 gene, and the 779A/C polymorphisms in the TPH1 gene were genotyped in 253 healthy Japanese subjects. Personality traits were evaluated by using the Revised NEO Personality Inventory (NEO PI-R) and the State-Trait Anxiety Inventory (STAI). As a result, no significant association was observed between the polymorphisms and the NEO PI-R or the STAI scores. The present results did not provide evidence for the association between the three serotonin-related genes and personality traits. The genes might not have major role in the development of personality traits, although further investigation with larger sample size may be recommended for conclusion. (c) 2006 Elsevier Ireland Ltd. All rights reserved.
Scientific journal, English - Association between dopamine D4 receptor (DRD4) exon III polymorphism and Neuroticism in the Japanese population
M Tochigi; H Hibino; T Otowa; C Kato; T Marui; T Ohtani; T Umekage; N Kato; T Sasaki
NEUROSCIENCE LETTERS, ELSEVIER IRELAND LTD, 398, 3, 333-336, May 2006, Peer-reviwed, The association between the dopamine D4 receptor (DRD4) exon III polymorphism and personality trait of novelty seeking (NS) has been studied intensively. In the Japanese population, the results of the previous studies did not always coincide. In the present study, we investigated the association between the polymorphism and personality traits evaluated by using the Revised NEO Personality Inventory (NEO PI-R) and State-Trait Anxiety Inventory (STAI) in 196 Japanese subjects. A meta-analysis of the present and previous Japanese studies was also conducted regarding NS. As a result, significant association was observed between the polymorphism and personality traits evaluated by using NEO PI-R as a whole (p = 0.022, MANCOVA). Subsequent analyses showed a significant association between short alleles (2-4 repeats) and higher scores for Neuroticism or its subscales, Anxiety, Depression, and Vulnerability (p = 0.015, 0.039, 0.021, and 0.008, respectively, uncorrected). No other significant difference in the scores for NEO PI-R was observed in the subsequent analyses. Significant association was also observed between the polymorphism and scores for STAI as a whole (p = 0.004, MANCOVA). Subsequent analyses did not show significant association, although a weak trend for the relation between the genotype consisting of short alleles and Trait Anxiety was observed (p = 0.10, uncorrected). The meta-analysis showed no significant association between the polymorphism and NS. Thus, the present study suggested the association between the short allele of the DRD4 exon III polymorphism and personality trait of Neuroticism in Japanese subjects. (c) 2006 Elsevier Ireland Ltd. All rights reserved.
Scientific journal, English - Association of mitochondrial complex I subunit gene NDUFV2 at 18p11 with schizophrenia in the Japanese population
S Washizuka; M Kametani; T Sasaki; M Tochigi; T Umekage; K Kohda; T Kato
AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS, WILEY-LISS, 141B, 3, 301-304, Apr. 2006, Peer-reviwed, Schizophrenia and bipolar disorder share common genetic background. Several loci such as 18p11, 13q32, and 22q11-13 were commonly linked with these diseases. Since mitochondrial dysfunction has been suggested in both of these disorders, NDUFV2 at 18p11, encoding a subunit of the complex 1, NADH ubiquinone oxidoreductase, is a candidate gene for these diseases. We previously reported that single nucleotide polymorphisms (SNPs) in the upstream region of NDUFV2 were associated with bipolar disorder in Japanese. The association of haplotype consisting of two SNPs, -3542G > A and -602G > A, with bipolar disorder was also seen both in Japanese and the National Institute of Mental Health Pedigrees trios. In this study, 2 polymorphisms, -3542G > A and -602G > A, were investigated in 229 schizophrenic patients as compared with controls. Individual genotypes were not associated with schizophrenia. However, the haplotype consisting of these two SNPs were significantly associated with schizophrenia. These results suggested that inter-individual variation of the genomic sequence of the promoter region of NDUFV2 might be a genetic risk factor common to bipolar disorder and schizophrenia. (c) 2006 Wiley-Liss, Inc.
Scientific journal, English - Combined analysis of association between personality traits and three functional polymorphisms in the tyrosine hydroxylase,) monoamine oxidase A, and catechol-O-methyltransferase genes
M Tochigi; T Otowa; H Hibino; C Kato; T Otani; T Umekage; T Utsumi; N Kato; T Sasaki
NEUROSCIENCE RESEARCH, ELSEVIER IRELAND LTD, 54, 3, 180-185, Mar. 2006, Peer-reviwed, Several molecular genetic studies have been conducted with regard to the association between catecholamine-related genes and personality traits. However, the results of replication studies did not always coincide. One of the possible reasons may be that the effect exerted by the individual gene is small. In the present study, we investigated the association between personality traits and systematic combination of functional polymorphisms in three genes that regulate the metabolism of catecholantines, namely, tyrosine hydroxylase (TH), monoamine oxidase A (MAOA), and catechol-O-methyltransferase (COMT). The (TCAT)(n) repeat in the TH gene, the promoter variable number tandem repeat (VNTR) in the MAOA gene, and Val 158Met in the COMT gene were genotyped in 256 healthy Japanese volunteers. Personality traits were evaluated using the NEO Personality Inventory-Revised (NEO PI-R). As a result, the score for Neuroticism increased, and those for Extraversion and Conscientiousness decreased according to the degree of functional polymorphic change, i.e., the lower synthesis/higher catalysis of catecholamines. A statistically significant difference was observed in the change of Extraversion (p = 0.04, after Bonferroni correction). These results may provide evidence for the association between metabolic change of catecholamines and personality traits, which may be due to the additive effect of the three genes. (c) 2005 Elsevier Ireland Ltd and the Japan Neuroscience Society. All rights reserved.
Scientific journal, English - Association study of the DISC1/TRAX locus with schizophrenia in a Japanese population
Zhang, X; M Tochigi; J Ohashi; K Maeda; T Kato; Y Okazaki; N Kato; K Tokunaga; A Sawa; T Sasaki
SCHIZOPHRENIA RESEARCH, ELSEVIER SCIENCE BV, 79, 2-3, 175-180, Nov. 2005, Peer-reviwed, Disrupted-in-Schizophrenia-1 (DISC1), identified by cytogenetic approaches in a pedigree with familial psychosis, is considered a candidate susceptibility gene for schizophrenia in some populations. In the pedigree, the TRAX gene, located adjacent to DISC1 on the disrupted chromosome 1, may also contribute to the pathophysiology of the familial schizophrenia. We studied association of the DISC1 and TRAX genes with schizophrenia in 338 Japanese by analyzing 15 single nucleotide polymorphisms (SNPs), including 12 SNPs in DISC1 and three in TRAX, respectively. No significant difference was observed between the patients and controls in allelic frequencies or genotypic distributions of 15 SNPs. A weak trend for the association in genotypic distribution of one SNP in TRAX (major homo/hetero/minor homo: 0.324/0.431/0.245 vs. 0.293/0.526/0.181 for patients vs controls, p = 0.039 in the 2 X 3 comparison) turned out to be insignificant after Bonferroni correction. Haplotype analysis did not support the association between the patients and controls. The present study suggests that the DISC1/TRAX locus may not have a major role in Japanese schizophrenia. (c) 2005 Elsevier B.V All rights reserved.
Scientific journal, English - Functional polymorphisms of HSPA5: Possible association with bipolar disorder
C Kakiuchi; M Ishiwata; S Nanko; H Kunugi; Y Minabe; K Nakamura; N Mori; K Fujii; T Umekage; M Tochigi; K Kohda; T Sasaki; K Yamada; T Yoshikawa; T Kato
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, ACADEMIC PRESS INC ELSEVIER SCIENCE, 336, 4, 1136-1143, Nov. 2005, Peer-reviwed, Altered endoplasmic reticulum stress (ER) response signaling is suggested in bipolar disorder. Previously, we preliminarily reported the genetic association of HSPA5 (GRP78/BiP) with bipolar disorder. Here, we extended our analysis by increasing the number of Japanese case-control samples and NIMH Genetics Initiative bipolar trio samples (NIMH trios), and also analyzed schizophrenia samples. In Japanese, nominally significant association of one haplotype was observed in extended samples of bipolar disorder but not in schizophrenia. In NIMH trios, no association was found in total samples. However, an exploratory analysis suggested that the other haplotype was significantly over-transmitted to probands only from the paternal side. The associated haplotype in Japanese or NIMH pedigrees shared three common polymorphisms in the promotor, which was found to alter promotor activity. These findings suggested promotor polymorphisms of HSPA5 may affect the interindividual variability of ER stress response and may confer a genetic risk factor for bipolar disorder.(c) 2005 Elsevier Inc. All rights reserved.
Scientific journal, English - Mitochondrial DNA sequence analysis of patients with 'atypical psychosis'
AA Kazuno; K Munakata; K Mori; M Tanaka; S Nanko; H Kunugi; T Umekage; M Tochigi; K Kohda; T Sasaki; T Akiyama; S Washizuka; N Kato; T Kato
PSYCHIATRY AND CLINICAL NEUROSCIENCES, BLACKWELL PUBLISHING, 59, 4, 497-503, Aug. 2005, Peer-reviwed, Although classical psychopathological studies have shown the presence of an independent diagnostic category, 'atypical psychosis', most psychotic patients are currently classified into two major diagnostic categories, schizophrenia and bipolar disorder, by the Diagnostic and Statistical Manual of Mental Disorders (4th edn; DSM-IV) criteria. 'Atypical psychosis' is characterized by acute confusion without systematic delusion, emotional instability, and psychomotor excitement or stupor. Such clinical features resemble those seen in organic mental syndrome, and differential diagnosis is often difficult. Because patients with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) sometimes show organic mental disorder, 'atypical psychosis' may be caused by mutations of mitochondrial DNA (mtDNA) in some patients. In the present study whole mtDNA was sequenced for seven patients with various psychotic disorders, who could be categorized as 'atypical psychosis'. None of them had known mtDNA mutations pathogenic for mitochondrial encephalopathy. Two of seven patients belonged to a subhaplogroup F1b1a with low frequency. These results did not support the hypothesis that clinical presentation of some patients with 'atypical psychosis' is a reflection of subclinical mitochondrial encephalopathy. However, the subhaplogroup F1b1a may be a good target for association study of 'atypical psychosis'.
Scientific journal, English - XBP1 gene polymorphism (-116C/G) and personality
C Kato; C Kakiuchi; T Umekage; M Tochigi; N Kato; T Kato; T Sasaki
AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS, WILEY-LISS, 136B, 1, 103-105, Jul. 2005, Peer-reviwed, Recently, a polymorphism. of the XBP1 gene (-116 C/G) was observed to play a significant role in the development of bipolar mood disorder from the Japanese population. The present study investigated a role of the polymorphism in the development of personality in healthy Japanese volunteers (n = 195). Personality traits were evaluated using NEO Personality Inventory-Revised (NEO PI-R). As a result, a statistical trend for association between the polymorphism (genotype) and the NEO PI-R scores of agreeableness and neuroticism was observed (ANOVA, P = 0.01 and 0.006, respectively). Subjects with the G allele, especially those with G-G genotype, tended to show lower neuroticism and higher agreeableness in the present study. The result is provisional and should be interpreted with caution, partly because the previous study suggested the allele as a risk allele for bipolar disorder. Further studies are required to confirm the results. (c) 2005 Wiley-Liss, Inc.
Scientific journal, English - Support for relationship between serum cholinesterase and post-traumatic stress disorder; 5-year follow-ups of victims of the Tokyo subway sarin poisoning
M Tochigi; T Otani; H Yamasue; K Kasai; N Kato; T Sasaki; T Kato; A Iwanami
NEUROSCIENCE RESEARCH, ELSEVIER IRELAND LTD, 52, 2, 129-131, Jun. 2005, Peer-reviwed
English - Seasonality of schizophrenia births in the Japanese population: increased winter births possibly confined to the north area
M Tochigi; T Onai; K Narita; H Hibino; M Rogers; T Umekage; K Kohda; T Otani; R Kanamori; N Kato; T Sasaki
SCHIZOPHRENIA RESEARCH, ELSEVIER SCIENCE BV, 75, 2-3, 433-438, Jun. 2005, Peer-reviwed, A number of North American and European studies have observed a higher proportion of winter births in schizophrenia patients. Thus, seasonal fluctuation of unknown environmental factors may affect brain development in ways that alter susceptibility to schizophrenia. Specification of these factors may help elucidate the etiopathological mechanism of the disease, about which little is certain. A small number of studies have investigated this issue in Asian populations, and the findings are not as consistent as those of Western populations. No remarkable excess of winter births has been observed in Japanese or Korean studies, while some studies have reported a significant decrease of summer births. We further investigated the issue in Japanese patients with schizophrenia (n = 3927). No significant excess of winter births was observed, but a decrease in the summer births was found in male subjects. This is largely consistent with previous Japanese studies; however, when the subjects were confined to those born in a colder and higher latitude area of Japan (n = 1338), a consistent trend for both a winter increase, and a summer decrease, was found. However, the results did not consistently reach statistical significance, possibly due to the lack of statistical power. Environmental factors that correlate with latitude might play a role in the development of the seasonality of births in schizophrenia. Further studies in a larger sample size are required to test these possibilities. (c) 2004 Elsevier B.V. All rights reserved.
Scientific journal, English - Serotonin 2A receptor gene polymorphism and personality traits: no evidence for significant association
M Tochigi; T Umekage; C Kato; T Marui; T Otowa; H Hibino; T Otani; K Kohda; N Kato; T Sasaki
PSYCHIATRIC GENETICS, LIPPINCOTT WILLIAMS & WILKINS, 15, 1, 67-69, Mar. 2005, Peer-reviwed, A number of studies have observed associations between the serotonin 2A (5-HT2A) receptor and mental disorders. Here, we investigated correlations between polymorphisms (-1438G/A and 102T/C) of the 5-HT2A gene and personality traits in healthy Japanese volunteers (n=239). The personality traits were evaluated using the Revised NEO Personality Inventory (NEO PI-R). The -1438G/A and 102T/C were in complete linkage disequilibrium. There was a tendency for associations between the genotype and the scores for Agreeableness, Conscientiousness and Neuroticism of the NEO PI-R (P=0.028, 0.039 and 0.062, respectively; analysis of variance, uncorrected for multiple testing). Subjects with the A/A of -1438G/A (or T/T of 102T/C) appeared to be lower in Neuroticism and higher in Conscientiousness than the rest of the subjects. However, the results were statistically non-significant after Bonferroni's correction for multiple testing of the five scales of the NEO PI-R. Thus, the present study provided no evidence for statistically significant associations between the 5-HT2A polymorphisms and the personality traits. (c) 2005 Lippincott Williams A Wilkins.
Scientific journal, English - Association between the neurofibromatosis-1 (NF1) locus and autism in the Japanese population
Tetsuya Marui; Ohiko Hashimoto; Eiji Nanba; Chieko Kato; Mamoru Tochigi; Tadashi Umekage; Michiko Ishijima; Kazuhisa Kohda; Nobumasa Kato; Tsukasa Sasaki
American Journal of Medical Genetics - Neuropsychiatric Genetics, 1, 131, 1, 43-47, 15 Nov. 2004, Peer-reviwed, Autistic patients have a 100 to 190-fold increased risk of neurofibromatosis compared to the general population. This suggests that the two diseases may share a common etiological background. Recently, a new allele (or the six-repeat allele) of the (AAAT)n repeat polymorphism in an Alu sequence in the neurofibromatosis-1 (NF1) gene was observed exclusively in severe autistic patients, not in controls, in Caucasians of French ancestry. This suggests a role of the NF1 gene in the development of autism. We investigated three microsatellite polymorphisms within the intron-27b and intron-38 of the NF1 region, including the (AAAT)n and two (CA)n repeat polymorphisms, in Japanese subjects with autism (n = 74) and controls (n = 122). The six-repeat allele of the (AAAT)n polymorphism was not found either in patients or controls, possibly indicating an ethnic difference in the polymorphism. However, significant differences were observed in the allele distributions of the (AAAT)n and a (CA)n, which were located at intron-27b, between patients and controls, although an association was not significant between autism and another polymorphism at intron-38. This may suggest an involvement of the NF1 locus in susceptibility to autism, although further investigations are recommended. © 2004 Wiley-Liss, Inc.
Scientific journal, English - Association between the neurofibromatosis-1 (NF1) locus and autism in the Japanese population
T Marui; O Hashimoto; E Nanba; C Kato; M Tochigi; T Umekage; M Ishijima; K Kohda; N Kato; T Sasaki
AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS, WILEY-LISS, 131B, 1, 43-47, Nov. 2004, Peer-reviwed, Autistic patients have a 100 to 190-fold increased risk of neurofibromatosis compared to the general population. This suggests that the two diseases may share a common etiological background. Recently, a new allele (or the six-repeat allele) of the (AAAT)(n) repeat polymorphism in an Alu sequence in the neurofibromatosis-1 (NF1) gene was observed exclusively in severe autistic patients, not in controls, in Caucasians of French ancestry. This suggests a role of the NF1 gene in the development of autism. We investigated three microsatellite polymorphisms within the intron-27b and intron-38 of the NF1 region, including the (AAAT)(n) and two (CA)n repeat polymorphisms, in Japanese subjects with autism (n=74) and controls (n=122). The six-repeat allele of the (AAAT)(n) polymorphism was not found either in patients or controls, possibly indicating an ethnic difference in the polymorphism. However, significant differences were observed in the allele distributions of the (AAAT)(n) and a (CA)(n), which were located at intron-27b, between patients and controls, although an association was not significant between autism and another polymorphism at intron-38. This may suggest an involvement of the NF1 locus in susceptibility to autism, although further investigations are recommended. (C) 2004 Wiley-Liss, Inc.
Scientific journal, English - Association of the XBP1-116C/G polymorphism with schizophrenia in the Japanese population
C Kakiuchi; M Ishiwata; T Umekage; M Tochigi; K Kohda; T Sasaki; T Kato
PSYCHIATRY AND CLINICAL NEUROSCIENCES, BLACKWELL PUBLISHING ASIA, 58, 4, 438-440, Aug. 2004, Peer-reviwed, Schizophrenia and bipolar disorder share some clinical features and linkage studies have shown that several loci are common. Recently, the authors found that the -116C-->G substitution in the promotor region of XBP1, a pivotal gene in endoplasmic reticulum (ER) stress response, causes the impairment of ER stress response, and that the -116C/C genotype is a protective factor; in other words the presence of the G allele increases the risk for bipolar disorder. The gene is located on 22q12.1, which is also linked with schizophrenia. The polymorphisms were investigated in 234 schizophrenic patients as compared with controls. Significant difference of genotype distribution was observed, which suggested that the -116C/C genotype is a protective factor for both of the major mental disorders.
Scientific journal, English - Association of six polymorphisms of the NOTCH4 gene with schizophrenia in the Japanese population
Mamoru Tochigi; Xuan Zhang; Tadashi Umekage; Jun Ohashi; Chieko Kato; Tetsuya Marui; Takeshi Otowa; Hiroyuki Hibino; Toshiyuki Otani; Kazuhisa Kohda; Shuzheng Liu; Nobumasa Kato; Katsushi Tokunaga; Tsukasa Sasaki
American Journal of Medical Genetics - Neuropsychiatric Genetics, 1, 128, 1, 37-40, 01 Jul. 2004, Peer-reviwed, The NOTCH4 gene is located at 6p21.3 and involved in the development and patterning of the central nervous systems. Recently, Wei and Hemmings [2000] observed that the gene was associated with schizophrenia. Subsequent to the report, several studies investigated the gene in schizophrenia, with controversial and inconclusive results. In the present study, we investigated six polymorphisms (SNPs 1-5 and a CTG repeat) of the gene in Japanese subjects with schizophrenia (n = 284) and the same number of controls. The polymorphisms include SNP5, which has been observed to be associated with schizophrenia in a Chinese population and two new SNPs 3-4 adjacent to SNP5, in addition to the SNPs 1-2 and the CTG repeat, which were suggested for the association with the disease in the previous study. As a result, no significant difference in genotypic distributions or allelic frequencies of the six polymorphisms of the gene was observed between the patients and the controls. Also, no significant difference was found in frequencies of haplotypes of the six polymorphisms between the patients and the controls. However, the distribution of SNP2 was significantly deviated from Hardy-Weinberg equilibrium in the patients (P = 0.000986), not in the controls, which could be a chance or due to an association of SNP2 with the disease. In conclusion, the present study provided no clear evidence for an association between the NOTCH4 gene and schizophrenia in the Japanese population. © 2004 Wiley-Liss, Inc.
Scientific journal, English - Season of birth effect on personality in a general population
M Tochigi; K Marumo; H Hibino; T Otowa; C Kato; T Marui; T Araki; T Otani; T Umekage; N Kato; T Sasaki
NEUROSCIENCE LETTERS, ELSEVIER SCI IRELAND LTD, 365, 2, 120-123, Jul. 2004, Peer-reviwed, Seasonality of births in schizophrenia and other mental disorders has been consistently observed. This may be through effects of unknown environmental factors that seasonally fluctuate on the brain development. The effects may affect cognitive function of the brain and behavioral characteristics that might be correlated with the development of personality not only in patients with mental disorders but also in healthy subjects. We, therefore, investigated the effects of season of birth on personality traits in healthy Japanese adults (n = 397). Personality traits were evaluated using the NEO Personality Inventory-Revised (NEO PI-R). A trend for lower Agreeableness in subjects born during winter (December to February) than other subjects was observed (P = 0.036, after correction for the multiple testing, multiple regression analysis adjusting for age and sex). Other major factors of the NEO PI-R, including Neuroticism, Extraversion, Openness and Conscientiousness, were not affected by season of birth. Further studies may be recommended to confirm the results, considering the relatively limited sample size. Evaluation of cognitive functions and behaviors using other measures including event-related potentials and functional MRI may also help the interpretation of the present result. (C) 2004 Elsevier Ireland Ltd. All rights reserved.
Scientific journal, English - Association of six polymorphisms of the NOTCH4 gene with schizophrenia in the Japanese population
M Tochigi; Zhang, X; T Umekage; J Ohashi; C Kato; T Marui; T Otowa; H Hibino; T Otani; K Kohda; SZ Liu; N Kato; K Tokunaga; T Sasaki
AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS, WILEY-LISS, 128B, 1, 37-40, Jul. 2004, Peer-reviwed, The NOTCH4 gene is located at 6p21.3 and involved in the development and patterning of the central nervous systems. Recently, Wei and Hemmings [2000] observed that the gene was associated with schizophrenia. Subsequent to the report, several studies investigated the gene in schizophrenia, with controversial and inconclusive results. In the present study, we investigated six polymorphisms (SNPs 1-5 and a CTG repeat) of the gene in Japanese subjects with schizophrenia (n = 284) and the same number of controls. The polymorphisms include SNP5, which has been observed to be associated with schizophrenia in a Chinese population and two new SNPs 3-4 adjacent to SNP5, in addition to the SNPs 1-2 and the CTG repeat, which were suggested for the association with the disease in the previous study. As a result, no significant difference in genotypic distributions or allelic frequencies of the six polymorphisms of the gene was observed between the patients and the controls. Also, no significant difference was found in frequencies of haplotypes of the six polymorphisms between the patients and the controls. However, the distribution of SNP2 was significantly deviated from Hardy-Weinberg equilibrium in the patients (P = 0.000986), not in the controls, which could be a chance or due to an association of SNP2 with the disease. In conclusion, the present study provided no clear evidence for an association between the NOTCH4 gene and schizophrenia in the Japanese population. (C) 2004 Wiley-Liss, Inc.
Scientific journal, English - Mitochondrial DNA polymorphisms and extraversion
C Kato; T Umekage; M Tochigi; T Otowa; H Hibino; T Ohtani; K Kohda; N Kato; T Sasaki
AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS, WILEY-LISS, 128B, 1, 76-79, Jul. 2004, Peer-reviwed, Mitochondria is the major site of energy production in cells, therefore, mitochondrial abnormality may affect functions of organs including the brain, which constantly requires high levels of energy consumption. Previous studies have suggested a role of mitochondria and their DNA polymorphisms in neuro-psychiatric disorders, including Alzheimer's disease, Parkinson's disease, schizophrenia and bipolar mood disorder. Thus, we hypothesized that mitochondrial DNA polymorphisms might be related with the development of personality. The present study investigated a role of two mitochondrial DNA polymorphisms, the C5178A and A10398G, in personality traits evaluated using the NEO PI-R scores in 238 healthy Japanese volunteers. Subjects with the 5178A genotype showed significantly higher extraversion score than those with the 5178C genotype (P = 0.027), while no significant association was observed between the C5178A polymorphism and other scores. No significant association was found between the A10398G polymorphism and any scores Regarding the 5178-10398 haplotype, the score of extraversion, not other scores, was significantly associated with the A-G haplotype (P = 0.042). Although further studies are recommended for the confirmation, the result may suggest a role of the mitochondrial DNA polymorphism in the personality trait. (C) 2004 Wiley-Liss, Inc.
Scientific journal, English - Mitochondrial DNA polymorphisms and extraversion.
Kato C; Umekage T; Tochigi M; Otowa T; Hibino H; Ohtani T; Kohda K; Kato N; Sasaki T
American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics, 128B, 1, 76-79, Jul. 2004, Peer-reviwed, True, Mitochondria is the major site of energy production in cells, therefore, mitochondrial abnormality may affect functions of organs including the brain, which constantly requires high levels of energy consumption. Previous studies have suggested a role of mitochondria and their DNA polymorphisms in neuro-psychiatric disorders, including Alzheimer's disease, Parkinson's disease, schizophrenia and bipolar mood disorder. Thus, we hypothesized that mitochondrial DNA polymorphisms might be related with the development of personality. The present study investigated a role of two mitochondrial DNA polymorphisms, the C5178A and A10398G, in personality traits evaluated using the NEO PI-R scores in 238 healthy Japanese volunteers. Subjects with the 5178A genotype showed significantly higher extraversion score than those with the 5178C genotype (P = 0.027), while no significant association was observed between the C5178A polymorphism and other scores. No significant association was found between the A10398G polymorphism and any scores. Regarding the 5178-10398 haplotype, the score of extraversion, not other scores, was significantly associated with the A-G haplotype (P = 0.042). Although further studies are recommended for the confirmation, the result may suggest a role of the mitochondrial DNA polymorphism in the personality trait.
Scientific journal, English - What causes seasonality of birth in schizophrenia?
M Tochigi; Y Okazaki; N Kato; T Sasaki
NEUROSCIENCE RESEARCH, ELSEVIER SCI IRELAND LTD, 48, 1, 1-11, Jan. 2004, Peer-reviwed, An excess of winter-spring births (and/or a decrease of summer births) has consistently been observed in schizophrenia (SCZ). This observation may provide a significant clue about the causes of the disease if specific factors which cause the phenomenon can be determined. This paper reviews several studies which investigated factors correlated with this observation in SCZ, in an attempt to determine which factors more likely cause the seasonality. Among the candidates of the factors are meteorological variables (such as ambient temperature), several infections, maternal hormones, sperm quality, nutrition and external toxins. A variation of procreation might also have an effect. Among the factors, the most extensively studied are temperature and viral infections. Some of them have appeared promising, but further studies are definitely required. Several challenges, including complicated correlations of the factors and determination of the susceptible period during pregnancy, need to be overcome. Comparisons of the data from areas and cohorts with different patterns of the candidate factors may be helpful. Animal studies may also help investigate the molecular and physiological mechanisms of the phenomenon. (C) 2003 Published by Elsevier Ireland Ltd and The Japan Neuroscience Society.
English - Gastrin-releasing peptide receptor (GRPR) locus in Japanese subjects with autism
T Marui; O Hashimoto; E Nanba; C Kato; M Tochigi; T Umekage; N Kato; T Sasaki
BRAIN & DEVELOPMENT, ELSEVIER SCIENCE BV, 26, 1, 5-7, Jan. 2004, Peer-reviwed, Gastrin-releasing peptide receptor (GRPR) gene is considered a candidate locus for infantile autism for several reasons. The present study investigated two polymorphic sites (C/450/T and C/661/T) in the second exon of the GRPR gene in Japanese patients with autism (DSM-IV) and healthy subjects. The two polymorphic sites were at high linkage disequilirium, consistent with a previous study in a North American population. The C450-C661 allele, which was observed in one-third of the chromosomes from the North American subjects, was less frequent (6-7%) in the Japanese subjects, suggesting a large ethnic difference in the frequency of the polymorphism. The allele frequencies and genotype distributions were not significantly different between the patients and controls. However, further studies are required to exclude the GRPR locus as a candidate locus for autism, considering the low frequency of the polymorphism in the Japanese subjects. (C) 2003 Elsevier B.V. All rights reserved.
Scientific journal, English - Voxel-based analysis of MRI reveals anterior cingulate gray-matter volume reduction in posttraumatic stress disorder due to terrorism
Yamasue H; Kasai K; Iwanami A; Ohtani T; Yamada H; Abe O; Kuroki N; Fukuda R; Tochigi M; Furukawa S; Sadamatsu M; Sasaki T; Aoki S; Ohtomo K; Asukai N; Kato N
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 100, 15, 9039-9043, 22 Jul. 2003, Peer-reviwed - Serotonin transporter-linked promoter region polymorphism and personality traits in a Japanese population
T Umekage; M Tochigi; T Marui; C Kato; H Hibino; T Otani; K Kohda; N Kato; T Sasaki
NEUROSCIENCE LETTERS, ELSEVIER SCI IRELAND LTD, 337, 1, 13-16, Jan. 2003, Peer-reviwed, Serotonin transporter gene may play a critical role in a regulation of mood and other aspects of mental status. A large number of association studies have investigated a correlation between the polymorphism in the serotonin transporter-linked promoter region (5-HTTLPR) and anxiety-related personality traits. The results, however, have been inconsistent. Heterogeneity of subjects regarding gender, occupation, social-class and other environmental factors, in addition to effects of other genes, might have confounded the results. Here, we studied an association between the 5-HTTLPR polymorphism and personality traits in primarily female (78%) healthy subjects (n = 244), who had homogeneous backgrounds regarding ethnicity (Japanese) and occupation. Personality traits of the subjects were assessed with the revised NEO Personality Inventory. No significant association was observed between the polymorphism and neuroticism or other personality traits, in all subjects, all females (n = 190) or female nurses (n = 159). Thus, our findings provided no evidence for an association between the 5-HTTLPR polymorphism and anxiety-related or other personality traits. (C) 2002 Elsevier Science Ireland Ltd. All rights reserved.
Scientific journal, English - Serum cholesterol, uric acid and cholinesterase in victims of the Tokyo subway sarin poisoning: A relation with post-traumatic stress disorder
M Tochigi; T Umekage; T Otani; T Kato; A Iwanami; N Asukai; T Sasaki; N Kato
NEUROSCIENCE RESEARCH, ELSEVIER SCI IRELAND LTD, 44, 3, 267-272, Nov. 2002, Peer-reviwed, Cholesterol and uric acid, which might correlate with steroidogenesis and monoamine functions, may change under emotionally stressful conditions and in mental disturbances. Among anxiety disorders, an increase of serum cholesterol has been observed in panic disorder. However, the issue has not been adequately investigated in other anxiety disorders, including post-traumatic stress disorder (PTSD). The present study investigated serum cholesterols, uric acid and cholinesterase in victims of the Tokyo subway sarin poisoning, 1995, in a series of 5-year follow-ups. Cholinesterase was studied, in relevance with serum lipid changes and symptoms of PTSD, and also in light of a biological effect of satin. Out of 34 victims, eight developed PTSD and two were currently diagnosed with PTSD using the Clinician-Administered PTSD Scale (CAPS). No significant relationship was observed between PTSD and serum cholesterols or uric acid. Several factors including co-occurrence of other mental disturbances with PTSD, in addition to the limited sample size, might have affected the result. In contrast, serum cholinesterase level was significantly reduced in the victims with the development of PTSD, compared with the matched controls (P < 0.02, t-test). This might partly reflect a long-term remnant effect of satin intoxication, although an effect of the psychological experience could not be totally excluded. (C) 2002 Elsevier Science Ireland Ltd. and the Japan Neuroscience Society. All rights reserved.
Scientific journal, English - Molecular genetic studies of schizophrenia: challenges and insights
C Kato; A Petronis; Y Okazaki; M Tochigi; T Umekage; T Sasaki
NEUROSCIENCE RESEARCH, ELSEVIER SCI IRELAND LTD, 43, 4, 295-304, Aug. 2002, Peer-reviwed, Schizophrenia (SCZ) is a mental disease that affects approximately 1% of the population with life-long devastating consequences. Based on evidence for a major contribution of genetic factors, a decade of extensive efforts has been dedicated to the search of DNA sequence variations that increase the risk to SCZ. Search for genes in rare multiplex SCZ families with a large number of affected individuals and quasi-Mendelian mode of inheritance using genetic linkage methodology has been one of the favorite strategies in psychiatric genetics. Although several genomic regions were suggested for linkage to SCZ, not a single gene causing or predisposing to SCZ has been identified thus far. Furthermore, it is not clear whether the genes of familial SCZ are also involved in sporadic cases that represent the overwhelming majority of SCZ patients. For sporadic cases, genetic association studies comparing the distribution of allelic frequencies of candidate genes in SCZ patients and controls have been performed but the outcome of such studies has also been quite modest. Several factors such as possible involvement of numerous interactive genes of minor effect, yet unknown environmental effects and diagnostic ambiguities of the disease have made genetic studies in SCZ quite unproductive. In terms of future studies, a genome-wide association search is a promising approach; however, this approach requires genotyping of thousands of genetic markers in large samples. In addition, a detailed analysis of the genes, expression of which changes under the influence of environmental factors, can indicate good candidates for genetic association studies. In this connection, investigations of the epigenetic regulation of genes and not only the DNA sequence variation, may be necessary for complete understanding of the etiopathogenic mechanisms of SCZ. (C) 2002 Published by Elsevier Science Ireland Ltd. and the Japan Neuroscience Society.
English - Human leukocyte antigen-A specificities and its relation with season of birth in Japanese patients with schizophrenia
M Tochigi; J Ohashi; T Umekage; K Kohda; H Hibino; T Otowa; T Mauri; K Masui; Y Sugahara; R Kanamori; T Juji; N Kato; K Tokunaga; T Sasaki
NEUROSCIENCE LETTERS, ELSEVIER SCI IRELAND LTD, 329, 2, 201-204, Aug. 2002, Peer-reviwed, Several studies, including one from Japan, have observed an increase of Human Leukocyte Antigen (HLA)-A24 and A26 in schizophrenia, although others failed to observe the increase. No use of systematic diagnostic criteria and a not-adequately reliable typing technique might have affected the results in the previous studies. We investigated HLA-A specificities in Japanese patients with schizophrenia (DSM-IV), recruited from the same area as in the early Japanese study. A DNA-based technique (polymerase chain reaction-microtiter plate hybridization) was employed. No significant difference was observed in frequencies of any HLA-A specificities between patients and controls, including A24 and A26. No significant association was found between the HLA-A and birth-season in patients. Thus, no evidence was obtained for an association between HLA-A and schizophrenia from the Japanese population. (C) 2002 Published by Elsevier Science Ireland Ltd.
Scientific journal, English - インフルエンザ脳炎後に側頭葉症状を呈した小児の1症例
荒木 剛; 栃木 衛; 渡辺 慶一郎; 大野 孝浩; 野瀬 孝彦; 黒木 規臣; 天野 直二; 加藤 進昌
東京精神医学会誌, 東京精神医学会, 18, 1, 37-38, Dec. 2000
Japanese
MISC
- 経過中にパーキンソニズムを呈し治療に難渋したうつ病の1例
永井 誠一; 金田 渉; 赤羽 晃寿; 森岡 久雄; 渡邊 公聡; 金井 理恵; 栃木 衛; 林 直樹
(公社)日本精神神経学会, Jan. 2020, 精神神経学雑誌, 122, 1, 54-55, Japanese, 0033-2658, U131080011 - 認知症の現状と課題 診断・対策・ケア 帝京大学医学部附属病院メンタルヘルス科「物忘れ検査入院」の取り組み
栃木 衛; 赤羽 晃寿; 林 直樹; 池淵 恵美
(公社)板橋区医師会, May 2018, 板橋区医師会医学会誌, 22, 105-106, Japanese, 1342-9795, 2018268683 - 治療に心理教育が有効であったバセドウ精神病の1例
渡邊 公聡; 金田 渉; 赤羽 晃寿; 栃木 衛; 林 直樹; 池淵 恵美
(公社)日本精神神経学会, Dec. 2017, 精神神経学雑誌, 119, 12, 941-941, Japanese, 0033-2658, 2018109308 - 明らかな幻覚・妄想を欠いた超急速交代型双極性障害の病像を呈した覚醒剤精神病の1例
井川 春樹; 金田 渉; 赤羽 晃寿; 栃木 衛; 林 直樹; 池淵 恵美
(公社)日本精神神経学会, Dec. 2017, 精神神経学雑誌, 119, 12, 945-945, Japanese, 0033-2658, 2018109324 - 当事者・家族・支援者が共有する,ポートフォリオ型リカバリープロセス評価ツールの開発
金田渉; 稲垣晃子; 栃木衛; 池淵恵美
01 Mar. 2017, 統合失調症研究, 7, 1, 121, Japanese, 201702269764541906 - 研究と報告 汎発性皮膚そう痒症を合併した老年期うつ病にmirtazapineが奏効した1例
佐藤 研一; 赤羽 晃寿; 栃木 衛; 林 直樹; 池淵 恵美
汎発性皮膚そう痒症を合併した老年期うつ病の症例を経験した。その病像の中心はうつ病およびその身体症状(痒み)による不快感から生じた焦燥であり,これらの症状に対してmirtazapineが著効を示した。一方,その治療過程において,後に治療者の焦燥に対する認識と治療薬の選択,そして精神疾患に関連する皮膚症状についての知識といった問題点が浮き彫りになり,このことが寛解までに費やした時間に影響を及ぼした可能性があると考えられた。痒みはきわめて不快な感覚であり,速やかにかつ適切に対処すべき症状である。器質的な皮膚病変を認めない皮膚そう痒症は精神皮膚科学(psychodermatology)の対象疾患であり,治療には精神医学的介入が重要であることを本症例から学んだ。(著者抄録), (株)医学書院, Mar. 2017, 精神医学, 59, 3, 259-264, Japanese, 0488-1281, 2017170903, 40021134288, AN00127676 - 入院治療が奏効した不登校を繰り返す思春期女性の1例
矢倉 朱緒; 金井 理恵; 渡邊 由香子; 栃木 衛; 林 直樹; 池淵 恵美
(公社)日本精神神経学会, Sep. 2016, 精神神経学雑誌, 118, 9, 721-722, Japanese, 0033-2658, 2017008238 - 【地下鉄サリン事件から20年:被害は過去のものとなったのか?】湾岸戦争病からみたサリン後遺症
栃木 衛
湾岸戦争病は、湾岸戦争終了後の多国籍軍側の帰還兵士にみられた関節痛、疲労、筋肉痛、頭痛、忘れやすさ、集中困難、気分の落ち込み、不眠、発疹などの種々の症状に対して、欧米を中心とするマスコミが呼称しはじめたものである。化学兵器への曝露やその予防薬、感染症や多種ワクチンの同時接種、砂漠に特有の諸環境、劣化ウランへの被曝、炎上した油井からの煙の吸入、精神的ストレスなどが原因として検討されてきたが、原因は未だ不明であり、湾岸戦争に由来する特異な病態ないし、新規の疾患の存在自体を疑問視する向きもあるのが現状である。一方、帰還兵に対して行われている追跡調査からは、低用量の神経剤曝露の長期的な影響が改めて問題とされている。本稿では、化学兵器曝露、中でもサリンへの低用量曝露と、精神的ストレス、とりわけ心的外傷後ストレス障害(PTSD)の影響という2つの観点から湾岸戦争病とサリン後遺症の共通点について考察した。(著者抄録), 日本生物学的精神医学会, Jun. 2016, 日本生物学的精神医学会誌, 27, 2, 84-87, Japanese, 2186-6619, 2016339110, 40020895281, AA12468060 - 悪性高熱症合併患者へのロクロニウムによる修正型電気痙攣療法
島田 巌; 中込 翔; 原島 敏也; 原 芳樹; 栃木 衛; 池淵 恵美
(公社)日本精神神経学会, Jun. 2016, 精神神経学雑誌, 2016特別号, S641-S641, Japanese, 0033-2658, 2016391367 - 心因性多飲症による水中毒で脳浮腫を繰り返した患者の社会復帰
汐月 治実; 赤羽 晃寿; 栃木 衛; 林 直樹; 池淵 恵美
(公社)日本精神神経学会, Nov. 2015, 精神神経学雑誌, 117, 11, 942-942, Japanese, 0033-2658, 2016103502 - 地下鉄サリン事件から20年 被害は過去のものとなったのか? 湾岸戦争病からみたサリン後遺症
栃木 衛
日本生物学的精神医学会・日本神経精神薬理学会, Sep. 2015, 日本生物学的精神医学会・日本神経精神薬理学会合同年会プログラム・抄録集, 37回・45回, 112-112, English, 2016064938 - 大脳皮質形成異常(異所性灰白質,多小脳回)を伴ったバセドウ精神病の1例
押久保 岳; 赤羽 晃寿; 栃木 衛; 林 直樹; 池淵 恵美
幻覚妄想状態を呈し,墜落外傷により搬送されたバセドウ精神病の40歳女性の症例を報告した。頭部MRIにて右側頭葉多小脳回,右海馬および扁桃体異形成を認め,多小脳回を伴う片側性脳室周囲結節状異所性灰白質(unilateral periventricular nodular heterotopia;PNH)と考えられた。PNHは好発部位にあり,IQ85,社会適応不良で,典型的な所見を示したが,てんかん発作や明らかな神経学的異常は認めなかった。バセドウ精神病で異所性灰白質を伴う症例は我々の知る限り本報告が初めてである。本症例では,処理速度低下などのPNHと関連すると考えられる所見がバセドウ精神病発症の素因となっていた可能性が指摘される。今後,バセドウ精神病とPNHの関連について検討を進める必要がある。(著者抄録), (株)医学書院, Aug. 2015, 精神医学, 57, 8, 661-664, Japanese, 0488-1281, 2015324664, 40020561930, AN00127676 - 【明日からできる強迫症/強迫性障害の診療II】 強迫症状の軽快した後も生活機能の全般的低下が持続している強迫性障害の1例
汐月 治実; 赤羽 晃寿; 金井 理恵; 栃木 衛; 林 直樹
ここに提示するのは、薬物治療や行動療法的介入によって強迫症状が軽快した後も、思考や行動の緩慢さから生活機能の低下が持続している強迫性障害の40代の女性症例である。本症例は、生活歴に高校入学後の学業成績の低下、20歳頃の著明な体重減少のエピソードがあるものの、発病以前には安定した職業生活を送るなど良好な適応状態を保持していた。40代前半の失恋を機に発症した強迫性障害には、確認強迫といった強迫症状と同時に、思考・動作の緩慢さが認められており、強迫症状の軽快後も生活機能の低下が生じていた。経過中に明確な精神病症状は認められていない。本症例の緩慢さは自発的行動や日常行為全般に広がっており、強迫症状に由来しない一次性強迫性緩慢であると評価される。統合失調症や薬剤の副作用である過鎮静、アパシー症候群との鑑別も重要な検討課題である。(著者抄録), (株)星和書店, May 2015, 精神科臨床サービス, 15, 2, 213-219, Japanese, 1883-0463, 2015242249 - 【地下鉄サリン事件から20年:被害は過去のものとなったのか?】 湾岸戦争病からみたサリン後遺症
栃木 衛
(有)科学評論社, May 2015, 精神科, 26, 5, 342-345, Japanese, 1347-4790, 2015257329, 40020459074, AA11667414 - 大脳皮質形成異常(異所性灰白質、多小脳回)を伴ったバセドウ精神病の1例
押久保 岳; 赤羽 晃寿; 栃木 衛; 林 直樹; 池淵 恵美
(公社)日本精神神経学会, Feb. 2015, 精神神経学雑誌, 117, 2, 152-153, Japanese, 0033-2658, 2015200721 - 発生初期の環境とその後の成長・発達・健康 出生の季節・場所と精神疾患
栃木衛
(有)科学評論社, 28 Mar. 2014, 月刊精神科, 24, 3, 318-321, Japanese, 1347-4790, 2014177029, 201402258870502043, 40020023169, AA11667414 - Birth season/place and mental disorders
栃木 衛
科学評論社, Mar. 2014, 精神科, 24, 3, 318-321, Japanese, 1347-4790, 40020023169, AA11667414 - 統合失調症病態におけるNMDA受容体スイッチング制御因子の遺伝学的検討
吉川茜; 西村文親; 稲井彩; 西岡将基; 江里口陽介; 高屋淳彦; 栃木衛; 河村代志也; 梅景正; 加藤佳代子; 佐々木司; 笠井清登; 垣内千尋
2014, 日本生物学的精神医学会誌, 513, Japanese, 2186-6619, 201402256698277315 - OXSR1遺伝子及びWNK3遺伝子と統合失調症との関連研究
吉川茜; 西村文親; 栃木衛; 河村代志也; 梅景正; 佐々木司
Sep. 2012, 日本生物学的精神医学会誌, 23, Supplement, 198, Japanese, 2186-6619, 201202206640509567 - ダイオキシン関連遺伝子の多型が自閉症スペクトラムの重症度に及ぼす影響
藤澤隆史; 西谷正太; 岩永竜一郎; 松崎淳子; 川崎千里; 栃木衛; 加藤進昌; 佐々木司; 篠原一之
Sep. 2012, 日本生物学的精神医学会誌, 23, Supplement, 169, Japanese, 2186-6619, 201202260593418170 - Effect of Bdnf Gene Polymorphism on Cerebral Blood Flow in Cognitive Task; A Nirs Study
Akihide Kinoshita; Ryu Takizawa; Yukika Nishimura; Mamoru Tochigi; Tsukasa Sasaki; Kiyoto Kasai
ELSEVIER SCIENCE INC, Apr. 2012, BIOLOGICAL PSYCHIATRY, 71, 8, 268S-268S, English, Summary international conference, 0006-3223, WOS:000302466001159 - 意味カテゴリー流暢性課題施行時の脳血流変化及びGRM3遺伝子多型との関連:多チャンネルNIRS研究
木下晃秀; 滝沢龍; 西村幸香; 丸茂浩平; 栃木衛; 佐々木司; 笠井清登
May 2011, 日本生物学的精神医学会誌, 22, Supplement, 132, Japanese, 2186-6619, 201102207303304502 - エクソンシーケンスを用いた自閉症スペクトラム障害家系の遺伝解析
桑原斉; 島田隆史; 文東美紀; 垣内千尋; 岩本和也; 栃木衛; 佐々木司; 金生由紀子; 笠井清登
May 2011, 日本生物学的精神医学会誌, 22, Supplement, 103, Japanese, 2186-6619, 201102212512772010 - CD200遺伝子と統合失調症との関連研究
西村文親; 西村文親; 吉川茜; 吉川茜; 栃木衛; 河村代志也; 梅景正; 梅景正; 佐々木司; 佐々木司; 笠井清登; 垣内千尋
May 2011, 日本生物学的精神医学会誌, 22, Supplement, 123, Japanese, 2186-6619, 201102267026086015 - Casein Kinase 2と統合失調症の遺伝学的関連
吉川茜; 吉川茜; 西村文親; 西村文親; 栃木衛; 河村代志也; 梅景正; 梅景正; 佐々木司; 笠井清登; 垣内千尋
May 2011, 日本生物学的精神医学会誌, 22, Supplement, 122, Japanese, 2186-6619, 201102297870225043 - Association between EGR3 gene polymorphism and prefrontal hemodynamic response during cognitive task in patients with schizophrenia
Yukika Nishimura; Ryu Takizawa; Shinsuke Koike; Mamoru Tochigi; Tsukasa Sasaki; Takeo Yoshikawa; Kiyoto Kasai
ELSEVIER IRELAND LTD, 2011, NEUROSCIENCE RESEARCH, 71, E395-E395, English, Summary international conference, 0168-0102, WOS:000308218102204 - Effect of GRM3 gene polymorphism on cerebral blood flow in category fluencytask: A NIRS study
Akihide Kinoshita; Ryu Takizawa; Yukika Nishimura; Kouhei Marumo; Mamoru Tochigi; Tsukasa Sasaki; Kiyoto Kasai
ELSEVIER IRELAND LTD, 2011, NEUROSCIENCE RESEARCH, 71, E393-E393, English, Summary international conference, 0168-0102, WOS:000308218102196 - SLC1A1遺伝子多型と統合失調症との関連解析
飯田周平; 堀内泰江; 飯嶋良味; 石黒浩毅; 稲田俊也; 渡部雄一郎; 染矢俊幸; 氏家寛; 岩田仲生; 尾崎紀夫; 功刀浩; 栃木衛; 糸川昌成; 糸川昌成; 新井誠; 新里和弘; 入谷修司; 柿田明美; 高橋均; 那波宏之; 有波忠雄
2011, 日本人類遺伝学会大会プログラム・抄録集, 56th, 173, Japanese, 201202219195795109 - オキシトシン受容体遺伝子多型(OXTR)が扁桃体体積に与える影響(Association between the oxytocin receptor gene (OXTR) and amygdalar volume in healthy adults)
井上 秀之; 山末 英典; 栃木 衛; 阿部 修; 武井 邦夫; 管 心; 山田 晴耕; Rogers Mark A; 青木 茂樹; 劉 暁渓; 河村 代志也; 佐々木 司; 笠井 清登
日本神経化学会, Aug. 2010, 神経化学, 49, 2-3, 591-591, English, 0037-3796, 2011205030 - 拒否する患者に受診/入院をどう勧めるか・進めるか 外来で夕方,どう対応したらよいか
栃木衛
科学評論社, 28 Jun. 2010, 月刊精神科, 16, 6, 562-564, Japanese, 1347-4790, 201002278878690029, 40017161379, AA11667414 - Treatment of outpatients in the evening
栃木 衛
科学評論社, Jun. 2010, Psychiatry, 16, 6, 562-564, Japanese, 1347-4790, 40017161379, AA11667414 - 関連遺伝子と精神疾患―全ゲノム解析はどこまでわかったか―全ゲノム関連遺伝子解析の基礎知識
栃木衛
28 Feb. 2010, 月刊精神科, 16, 2, 137-144, Japanese, 1347-4790, 201002272978636627 - Genome-wide association study: basics and theory
栃木 衛
科学評論社, Feb. 2010, Psychiatry, 16, 2, 137-144, Japanese, 1347-4790, 40016992088, AA11667414 - 統合失調症の脳科学最前線 第7回 統合失調症とRNA編集,エピジェネティクス
栃木衛; 栃木衛; 栃木衛
20 Jan. 2009, Schizophrenia Front, 10, 1, 63-68, Japanese, 1345-8639, 200902212716304131 - Effect of BDNF val66met genetic variation on prefrontal hemodynamic response in human
Shinsuke Koike; Ryu Takizawa; Mamoru Tochigi; Kohei Marumo; Yuki Kawakubo; Masaru Kinou; Tsukasa Sasaki; Kiyoto Kasai
ELSEVIER IRELAND LTD, 2009, NEUROSCIENCE RESEARCH, 65, S225-S225, English, Summary international conference, 0168-0102, WOS:000272421101621 - Effect of sigma-1 receptor gene polymorphism on prefrontal hemodynamic response in schizophrenia; a multi-channel NIRS study
Ryu Takizawa; Mamoru Tochigi; Yuki Kawakubo; Kohei Marumo; Tsukasa Sasaki; Masato Fukuda; Kenji Hashimoto; Kiyoto Kasai
ELSEVIER SCIENCE INC, Apr. 2008, BIOLOGICAL PSYCHIATRY, 63, 7, 272S-273S, English, Summary international conference, 0006-3223, WOS:000254163700867 - Effect of polymorphism of susceptibility genes on prefrontal function in schizophrenia; a NIRS study
R. Takizawa; M. Tochigi; K. Marumo; M. Kinou; Y. Kawakubo; M. Suga; T. Sasaki; K. Kasai
BLACKWELL PUBLISHING, Feb. 2008, PSYCHIATRY AND CLINICAL NEUROSCIENCES, 62, 1, S10-S10, English, Summary international conference, 1323-1316, WOS:000253258400055 - Molecular genetics of personality
栃木 衛
科学評論社, Sep. 2007, Psychiatry, 11, 3, 196-200, Japanese, 1347-4790, 40015630824, AA11667414 - Epigenetics of mental disorders
栃木 衛
科学評論社, Sep. 2007, Psychiatry, 11, 3, 213-217, Japanese, 1347-4790, 40015630827, AA11667414 - Differential effect of GRM3 and BDNF genotypes on auditory cortical response to phoneme change
Y. Kawakubo; M. Tochigi; M. Suga; M. Kato; M. Yumoto; K. Itoh; T. Sasaki; N. Kato; K. Kasai
BLACKWELL PUBLISHING, Apr. 2007, PSYCHIATRY AND CLINICAL NEUROSCIENCES, 61, 2, S17-S18, English, Summary international conference, 1323-1316, WOS:000244600300081 - ここが知りたい他科知識 耳鼻咽喉科医が知っておきたい疾患の知識 パニック障害
貝谷久宣; 井上顕; 井上顕; 横山知加; 横山知加; 土田英人; 土田英人; 山中学; 山中学; 梅景正; 梅景正; 栃木衛; 栃木衛
2007, JOHNS, 23, 3, 0910-6820, 200902247149019267 - 統合失調症とNeuregulin1遺伝子の関連解析
塩田早恵; 栃木衛; 大橋順; 音羽健司; 笠井清登; 加藤進昌; 徳永勝士; 佐々木司; 佐々木司
2007, 日本人類遺伝学会大会プログラム・抄録集, 52nd, 200902209253800524 - パニック障害の治療法の最適化と治療ガイドラインの策定 パニック障害の感受性遺伝子探索と症状の季節性変動に関する研究
佐々木司; 谷井久志; 音羽健司; 大渓俊幸; 栃木衛; 梅景正; 野村忍; 菅谷渚; 穐吉條太郎; 清水栄司; 貝谷久宣; 吉田栄治; 安田新; 井上顕; 岡崎祐士
2007, パニック障害の治療法の最適化と治療ガイドラインの策定に関する研究 平成16-18年度 総括・総合研究報告書, 31-35, Japanese, 200902262851917043 - パニック障害の治療法の最適化と治療ガイドラインの策定に関する研究 パニック障害の疾患感受性遺伝子の探索
佐々木司; 谷井久志; 音羽健司; 大渓俊幸; 栃木衛; 梅景正; 野村忍; 菅谷渚; 穐吉條太郎; 清水栄司; 貝谷久宣; 吉田栄治; 安田新; 井上顕; 岡崎祐士
2007, パニック障害の治療法の最適化と治療ガイドラインの策定に関する研究 平成18年度 総括・分担研究報告書, 25-27, Japanese, 200902289704774550 - 慢性疲労の薬物療法 (特集2 慢性疲労を治す)
梅景 正; 栃木 衛; 吉田 栄治
科学評論社, Nov. 2006, 精神科, 9, 5, 418-422, Japanese, 1347-4790, 40015183207, AA11667414 - Association of mitochondrial complex I subunit gene NDUFV2 at 18P11 with schizophrenia
Shinsuke Washizuka; Mizue Kametani; Mamoru Tochigi; Tadashi Umekage; Kazuhisa Kohda; Tsukasa Sasaki; Tadafumi Kato
WILEY-LISS, Oct. 2006, AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS, 141B, 7, 780-780, English, Summary international conference, 1552-4841, WOS:000240877700427 - Circadian Clock-Related Polymorphisms in Panic Disorder
音羽健司; 音羽健司; 栃木衛; 梅景正; 海老澤尚; 菅谷渚; 菅谷渚; 井上顕; 吉田栄二; 谷井久志; 岡崎祐士; 岡崎祐士; 加藤進昌; 貝谷久宣; 佐々木司
2006, 神経化学, 45, 2/3, 0037-3796, 200902204016839570 - Search for schizophrenia genes on 6P21-24 and LQ42 in the Japanese population
M Tochigi; Zhang, X; J Ohashi; H Hibino; T Otowa; N Kato; K Tokunaga; T Sasaki
ELSEVIER SCIENCE BV, Jan. 2006, SCHIZOPHRENIA RESEARCH, 81, 196-196, English, Summary international conference, 0920-9964, WOS:000235524701041 - Panic disorders
梅景 正; 栃木 衛; 竹内 龍雄
アークメディア, 2006, Japanese journal of clinical psychiatry, 35, 0, 126-133, Japanese, 0300-032X, 40015363458, AN00253400 - Evidence for association between the dysbindin (DTNBP1) gene and schizophrenia: A case-control study from the Japanese population
M Tochigi; Zhang, X; J Ohashi; H Hibino; T Otowa; T Kato; Y Okazaki; N Kato; K Tokunaga; T Sasaki
WILEY-LISS, Sep. 2005, AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS, 138B, 1, 52-52, English, Summary international conference, 1552-4841, WOS:000232357300184 - 統合失調症における精神生理学的および神経画像にもとづいたエンドフェノタイプ (特集 精神疾患のエンドフェノタイプ)
切原 賢治; 管 心; 栃木 衛
先端医学社, Apr. 2005, 分子精神医学, 5, 2, 113-125, Japanese, 1345-9082, 40006725846, AA11500190 - 物質的環境が統合失調症へどう影響するか (特集2.物質的環境が精神機能へどう影響するか)
栃木 衛
科学評論社, Mar. 2005, 精神科, 6, 3, 252-255, Japanese, 1347-4790, 40006693931, AA11667414 - Association studies of the NOTCH4 locus and the TNXB locus with schizophrenia in Chinese and Japanese populations
Zhang, X; M Tochigi; L Liu; S Liu; Li, X; Y Yu; J Shi; J Wei; K Tokunaga; T Sasaki
ELSEVIER SCIENCE BV, Feb. 2004, SCHIZOPHRENIA RESEARCH, 67, 1, 62-62, English, Summary international conference, 0920-9964, WOS:000188788100144 - 統合失調症の病因としての感染と免疫
音羽 健司; 加藤 千枝子; 栃木 衛
科学評論社, Sep. 2003, 精神科, 3, 3, 306-314, Japanese, 1347-4790, 40005977051, AA11667414 - What causes seasonality of birth in schizophrenia?
Tochigi Mamoru; Okazaki Yuji; Kato Nobumasa
精神医学研究所, 2003, 精神医学研究所業績集, 40, 140-156, English, 0080-8547, 40006746924, AN00127698 - PTSDと遺伝子多型 (特集 PTSDの分子生物学)
梅景 正; 栃木 衛; 河村 直樹
先端医学社, Jul. 2002, 分子精神医学, 2, 3, 236-242, Japanese, 1345-9082, 40005593489, AA11500190
Courses
Affiliated academic society
Research Themes
- The role of a candidate gene in the etiology of autism spectrum disorder
YASUDA Shin; TOCHIGI Mamoru
Japan Society for the Promotion of Science, Grants-in-Aid for Scientific Research, Tokyo Metropolitan Institute of Medical Science, Grant-in-Aid for Scientific Research (C), Dendritic filopodia are most abundant during early phase of synaptogenesis, but the number of filopodia declines thereafter. When filopodia contact presynaptic sites and form synapses, filopodia convert into dendritic spines. Normal dendritic spinogenesis may be related to learning and memory function, and abnormal spine formation may cause the autistic spectrum disorder (ASD).TAO2b is a p38 MAP kinase kinase kinase, which binds to a protocadherin arcadlin at its cytoplasmic region. The gene encoding TAO2b is known to be located on chromosome 16p11.2, a region has been shown to carry substantial susceptibility to ASD. To address if TAO2b variants are associated with ASD, we sequenced TAO2b in patients and unaffected individuals. We identified two rare TAO2b variants in ASD individuals. Overexpression of each variant caused dendritic spine abnormality in cultured hippocampal neurons. We generated TAO2b knock mice. Tao2b knockout induced aberrant spine morphology and ASD-like behavior., 24500452
01 Apr. 2012 - 31 Mar. 2016 - Search for the candidate genes for mental and developmental disorders by analyzing family and discordant twin samples
Tochigi Mamoru; SASAKI Tsukasa; IKEBUCHI Emi; AKAHANE Akihisa
Japan Society for the Promotion of Science, Grants-in-Aid for Scientific Research, Teikyo University, Grant-in-Aid for Scientific Research (C), Principal investigator, We collected the DNA samples of the family, sporadic, and discordant twin patients of mental and developmental disorders, including schizophrenia, bipolar disorder, panic disorder, autism, and Tourette disorder. Through analyzing exome sequencing by using next-generation sequencer and microarray, the several candidate genes were collected for schizophrenia and Tourette disorder., 26461725
2014 - 2016 - Search for the candidate genes for autism by the DNA methylation microarray analysis of sperm cells
TOCHIGI Mamoru
Japan Society for the Promotion of Science, Grants-in-Aid for Scientific Research, 東京大学, Grant-in-Aid for Young Scientists (B), Principal investigator, The utility of sperm cells in the epgenetic studies of autism was reviewed. It was concluded that sperm cells from the patients' fathers may be helpful for identifying the candidate genes for autism. It was also tried to establish the method of evaluating the genome-wide DNA methylation status by using microarrays, and investigate the DNA methylation status by using blood cells as a pilot study. As a result, the reproducibility of the method was not enough, and further improvement of the assessment procedure was recommended., 24791197
2012 - 2013 - Target resequencing of the candidate region of the susceptibility gene for autism by using the next-generation sequencer
Mamoru TOCHIGI
Ministry of Education, Culture, Sports, Science and Technology, Grants-in-Aid for Scientific Research(若手研究(B)), 東京大学, 若手研究(B), Principal investigator, As a result of the exome sequencing of a four-generation-extending autism spectrum disorder(ASD) family, several candidate genes, which completely co-segregate with the disease, were found and may lead to a new finding. In the copy number variation(CNV) analysis of 163 trios of ASD, eight de novo CNVs(> 500kb) were found in seven trios, one of which was duplication in 15q11. 2., 22791107
2010 - 2011 - A Search for Risk Genes of Psychiatric Disorders
OKAZAKI Yuji
Japan Society for the Promotion of Science, Grants-in-Aid for Scientific Research, Grant-in-Aid for Scientific Research on Priority Areas, Panic disorder (PD) is characterized by the recurrence of anxiety attacks and anticipatory anxiety that causes extensive restriction in daily activities. It is known that 2% of general population suffers from the disorder and genetic factor plays a role in the causation. We have established the largest DNA sample in the world, and searched risk SNPs, CNVs and micro chromosomal abnormalities for PD using 900k SNPs chip and CGH arrays. Common CNVs on chromosome 11, 14, 19 were found to be associated with PD and further analysis is in progress. We also found hypo-activation of prefrontal cortex is a trait and intermediate phenotype of PD, through NIRS measurements comparing between twins from identical twin pairs discordant for PD and between PD patients with and without family history., 17019029
2005 - 2009