Faculty Profiles - ALEKSIC Branko

Papers - ALEKSIC Branko

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【DSM-5】病因・病態研究から見たDSM-5 双極性障害とうつ病との分離の背景 Reviewed International journal

木村大樹, ブランコ・アレクシッチ, 尾崎紀夫

最新精神医学 Vol. 19 ( 5 ) page： 397 - 404 2014.9

The Polymorphism of YWHAE, a Gene Encoding 14-3-3Epsilon, and Brain Morphology in Schizophrenia: A Voxel-Based Morphometric Study Reviewed

Mikio Kido, Yukako Nakamura, Kiyotaka Nemoto, Tsutomu Takahashi, Branko Aleksic, Atsushi Furuichi, Yumiko Nakamura, Masashi Ikeda, Kyo Noguchi, Kozo Kaibuchi, Nakao Iwata, Norio Ozaki, Michio Suzuki

PLOS ONE Vol. 9 ( 8 ) page： e103571 2014.8

Language：English Publishing type：Research paper (scientific journal) Publisher：PUBLIC LIBRARY SCIENCE

Background: YWHAE is a possible susceptibility gene for schizophrenia that encodes 14-3-3epsilon, a Disrupted-in-Schizophrenia 1 (DISC1)-interacting molecule, but the effect of variation in its genotype on brain morphology remains largely unknown.
Methods: In this voxel-based morphometric magnetic resonance imaging study, we conducted whole-brain analyses regarding the effects of YWHAE single-nucleotide polymorphisms (SNPs) (rs28365859, rs11655548, and rs9393) and DISC1 SNP (rs821616) on gray matter volume in a Japanese sample of 72 schizophrenia patients and 86 healthy controls. On the basis of a previous animal study, we also examined the effect of rs28365859 genotype specifically on hippocampal volume.
Results: Whole-brain analyses showed no significant genotype effect of these SNPs on gray matter volume in all subjects, but we found significant genotype-by-diagnosis interaction for rs28365859 in the left insula and right putamen. The protective C allele carriers of rs28365859 had a significantly larger left insula than the G homozygotes only for schizophrenia patients, while the controls with G allele homozygosity had a significantly larger right putamen than the C allele carriers. The C allele carriers had a larger right hippocampus than the G allele homozygotes in schizophrenia patients, but not in healthy controls. No significant interaction was found between rs28365859 and DISC1 SNP on gray matter volume.
Conclusions: These different effects of the YWHAE (rs28365859) genotype on brain morphology in schizophrenia and healthy controls suggest that variation in its genotype might be, at least partly, related to the abnormal neurodevelopment, including in the limbic regions, reported in schizophrenia. Our results also suggest its specific role among YWHAE SNPs in the pathophysiology of schizophrenia.

DOI： 10.1371/journal.pone.0103571

Factor Structure of the Japanese Version of the Edinburgh Postnatal Depression Scale in the Postpartum Period Reviewed

Chika Kubota, Takashi Okada, Branko Aleksic, Yukako Nakamura, Shohko Kunimoto, Mako Morikawa, Tomoko Shiino, Ai Tamaji, Harue Ohoka, Naomi Banno, Tokiko Morita, Satomi Murase, Setsuko Goto, Atsuko Kanai, Tomoko Masuda, Masahiko Ando, Norio Ozaki

PLOS ONE Vol. 9 ( 8 ) page： e103941 2014.8

Language：English Publishing type：Research paper (scientific journal) Publisher：PUBLIC LIBRARY SCIENCE

Background: The Edinburgh Postnatal Depression Scale (EPDS) is a widely used screening tool for postpartum depression (PPD). Although the reliability and validity of EPDS in Japanese has been confirmed and the prevalence of PPD is found to be about the same as Western countries, the factor structure of the Japanese version of EPDS has not been elucidated yet.
Methods: 690 Japanese mothers completed all items of the EPDS at 1 month postpartum. We divided them randomly into two sample sets. The first sample set (n = 345) was used for exploratory factor analysis, and the second sample set was used (n = 345) for confirmatory factor analysis.
Results: The result of exploratory factor analysis indicated a three-factor model consisting of anxiety, depression and anhedonia. The results of confirmatory factor analysis suggested that the anxiety and anhedonia factors existed for EPDS in a sample of Japanese women at 1 month postpartum. The depression factor varies by the models of acceptable fit.
Conclusions: We examined EPDS scores. As a result, "anxiety" and "anhedonia" exist for EPDS among postpartum women in Japan as already reported in Western countries. Cross-cultural research is needed for future research.

DOI： 10.1371/journal.pone.0103941

Summaries of oral sessions at the XXI World Congress of Psychiatric Genetics, Boston, Massachusetts, 17-21 October 2013: state of the field Reviewed

Hilary Akpudo, Branko Aleksic, Anna Alkelai, Christie Burton, Tania Carillo Roa, David T. W. Chen, Min-Chih Cheng, Enrico Cocchi, Lea K. Davis, Isabele G. Giori, Leon M. Hubbard, Alison Merikangas, Nagaraj S. Moily, Adeniran Okewoleu, Emily Olfson, Irene Pappa, Markus Reitt, Ajeet B. Singh, Julia Steinberg, Jana Strohmaier, Te-Tien Ting, Kimm J. E. van Hulzen, Anne O'Shea, Lynn E. DeLisi

PSYCHIATRIC GENETICS Vol. 24 ( 4 ) page： 125 - 150 2014.8

Language：English Publishing type：Research paper (scientific journal) Publisher：LIPPINCOTT WILLIAMS & WILKINS

The XXI World Congress of Psychiatric Genetics (WCPG), sponsored by the International Society of Psychiatric Genetics (ISPG), took place in Boston, Massachusetts, on 17-21 October 2013. Approximately 900 participants gathered to discuss the latest findings in this rapidly advancing field. The following report was written by student travel awardees. Each was assigned one or more sessions as a rapporteur. This manuscript represents topics covered in most, but not all of the oral presentations during the conference, and contains some of the major notable new findings reported. (C) 2014 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.

DOI： 10.1097/YPG.0000000000000043

Effects of maternal depressive symptomatology during pregnancy and the postpartum period on infant-mother attachment

Harue Ohoka, Takayoshi Koide, Setsuko Goto, Satomi Murase, Atsuko Kanai, Tomoko Masuda, Branko Aleksic, Naoko Ishikawa, Kaori Furumura, Norio Ozaki

PSYCHIATRY AND CLINICAL NEUROSCIENCES Vol. 68 ( 8 ) page： 631 - 639 2014.8

Language：English Publishing type：Research paper (scientific journal) Publisher：WILEY-BLACKWELL

Aim: Postnatal depression has demonstrated long-term consequences on child cognitive and emotional development; however, the link between maternal and child pathology has not been clearly identified. We conducted a prospective study using self-rating questionnaires to clarify the association between bonding disorder and maternal mood during pregnancy and after childbirth.
Methods: A total of 389 women participated in this study and completed questionnaires. Participants were asked to complete the Edinburgh Postnatal Depression Scale (EPDS) and the Mother-to-Infant Bonding Scale four times during pregnancy and the postpartum period.
Results: We found statistically significant weak to moderate correlations (r = 0.14-0.39) between the EPDS and Mother-to-Infant Bonding Scale scores at each testing period. Women who experienced low mood tended to have stronger bonding disorder. Furthermore, the effectiveness of attachment between the mother and child was closely related to the mood of the mother as measured by the EPDS.
Conclusion: We observed different patterns of bonding and maternal mood. Distinct subtypes regarding maternal mood and formation of mother-to-infant attachment suggests that analysis of bonding disorder should be performed considering the course of maternal depressive symptoms.

DOI： 10.1111/pcn.12171

Novel rare variants in F-box protein 45 (FBXO45) in schizophrenia. Reviewed International journal

Chenyao Wang, Takayoshi Koide, Hiroki Kimura, Shohko Kunimoto, Akira Yoshimi, Yukako Nakamura, Itaru Kushima, Masahiro Banno, Naoko Kawano, Yuto Takasaki, Jingrui Xing, Yukihiro Noda, Akihiro Mouri, Branko Aleksic, Masashi Ikeda, Takashi Okada, Tetsuya Iidaka, Toshiya Inada, Nakao Iwata, Norio Ozaki

Schizophrenia research Vol. 157 ( 1-3 ) page： 149 - 156 2014.8

Language：English Publishing type：Research paper (scientific journal)

The ubiquitin ligase F-box protein 45 (FBXO45) is critical for synaptogenesis, neuronal migration, and synaptic transmission. FBXO45 is included in the 3q29 microdeletion region that confers a significant risk for schizophrenia, as shown by rare structural variant studies. Thus, FBXO45 is considered a prominent candidate for mediating schizophrenia pathogenesis. Here, we investigated rare, deleterious single nucleotide variants (SNVs) as well as small insertions and deletions (INDELs) in FBXO45 that may contribute to schizophrenia susceptibility. Using Sanger sequencing, we performed mutation screening in FBXO45 exon regions in 337 schizophrenia patients. Novel missense or nonsense variants were followed up with a genetic association study in an independent sample set of 601 schizophrenia patients and 916 controls, a case report for assessing the clinical consequence of the mutations, a pedigree study for measuring mutation inheritance in the proband's family, bioinformatics analyses for evaluating mutation effect on protein structure and function, and mRNA expression analysis for examining mutation transcriptional influence on FBXO45 expression. One heterozygous, novel, and rare missense mutation (R108C) was identified in a single schizophrenia patient and in his healthy mother. At age 20, this patient was diagnosed with paranoid schizophrenia and carried some clinical features of 3q29 deletion phenotypes, including premorbid IQ decline. With follow-up genotyping, this mutation was not found in either the schizophrenia group (0/601) or the healthy control group (0/916). Bioinformatics analyses predicted that R108C probably pathologically impacted the structure and function of the FBXO45 protein. The relative expression of FBXO45 in SCZ case with R108C mutation was relatively low when compared to 50 schizophrenia patients and 52 healthy controls. The R108C mutation in FBXO45 is a rare variant with a modest effect on schizophrenia risk that may disrupt the structure and function of the FBXO45 protein. Our findings also suggest that FBXO45 may be a new attractive candidate gene for schizophrenia.

DOI： 10.1016/j.schres.2014.04.032

Replication and Cross-Phenotype Study Based Upon Schizophrenia GWASs Data in the japanese Population: Support for Association of MHC Region with Psychosis

Takeo Saito, Kenji Kondo, Yoshimi Iwayama, Ayu Shimasaki, Branko Aleksic, Kazuo Yamada, Tomoko Toyota, Eiji Hattori, Kosei Esaki, Hiroshi Ujike, Toshiya Inada, Hiroshi Kunugi, Tadafumi Kato, Takeo Yoshikawa, Norio Ozaki, Masashi Ikeda, Nakao Iwata

AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS Vol. 165 ( 5 ) page： 421 - 427 2014.7

Language：English Publishing type：Research paper (scientific journal) Publisher：WILEY

Recent genome-wide association studies (GWASs) of schizophrenia (SCZ) identified several susceptibility genes and suggested shared genetic components between SCZ and bipolar disorder (BD). We conducted a genetic association study of single nucleotide polymorphisms (SNPs) selected according to previous SCZGWA Stargeting psychotic disorders (SCZ and BD) in the Japanese population. Fifty-one SNPs were analyzed in a two-stage design using first-set screening samples (all SNPs: 1,032 SCZ, 1,012 BD, and 993 controls) and second-set replication samples ("significant" SNPs in the first-set screening analysis: 1,808 SCZ, 821 BD, and 2,321 controls). We assessed allelic associations between the selected SNPs and the three phenotypes (SCZ, BD, and "psychosis" [SCZ + BD]). Nine SNPs revealed nominal association signals for all comparisons (P-uncorrected < 0.05), of which two SNPs located in the major histocompatibility complex region (rs7759855 in zincfinger and SCAN domain containing 31 [ZSCAN31] and rs1736913 in HLA-F antisense RNA1 [HLA-F-AS1]) were further assessed in the second-set replication samples. The associations were confirmed for rs7759855 (P-corrected = 0.026 for psychosis; P-corrected = 0.032 for SCZ), although the direction of effect was opposite to that in the original GWAS of the Chinese population. Finally, a meta-analysis was conducted using our two samples and using our data and data from Psychiatric GWAS Consortium (PGC), which have shown the same direction of effect. SNP in ZSCAN31 (rs7759855) had the strongest association with the phenotypes (best P = 6.8 x 10(-5) for psychosis: present plus PGC results). These data support shared risk SNPs between SCZ and BD in the Japanese population and association between MHC and psychosis. (C) 2014 Wiley Periodicals, Inc.

DOI： 10.1002/ajmg.b.32246

Social insecurity in relation to orbitofrontal activity in patients with eating disorders: a near-infrared spectroscopy study Reviewed

Hiroto Katayama, Kunihiro Kohmura, Satoshi Tanaka, Miho Imaeda, Naoko Kawano, Yukihiro Noda, Kazuo Nishioka, Masahiko Ando, Branko Aleksic, Tetsuya Iidaka, Norio Ozaki

BMC PSYCHIATRY Vol. 14 ( 1 ) page： 173 2014.6

Language：English Publishing type：Research paper (scientific journal) Publisher：BIOMED CENTRAL LTD

Background: Functional neuroimaging techniques are widely used to elucidate changes in brain activity, and various questionnaires are used to investigate psychopathological features in patients with eating disorders (ED). It is well known that social skills and interpersonal difficulties are strongly associated with the psychopathology of patients with ED. However, few studies have examined the association between brain activity and social relationships in patients with ED, particularly in patients with extremely low body weight.
Methods: In this study, 22-channel near-infrared spectroscopy was used to quantify regional hemodynamic changes during a letter fluency task (LFT) in 20 female patients with ED with a mean body mass index of 14.0 kg/m(2)and 31 female controls (CTLs). Symptoms were assessed using the Eating Disorder Inventory-2 and Beck Depression Inventory. We hypothesized that frontal activity in patients with ED would be lower than in CTLs and would show different correlations with psychopathological features compared with CTLs.
Results: The LFT performance and score on the social insecurity subscale of the Eating Disorder Inventory-2 were significantly higher in the ED group than in the CTL group. The mean change in oxygenated hemoglobin (oxy-Hb) in bilateral frontal regions during the LFT was significantly smaller in the ED group than in the CTL group. Social insecurity score was positively correlated with the concentration of oxy-Hb in the bilateral orbitofrontal cortex in the ED group but not in the CTL group.
Conclusions: These results suggest that activity of the orbitofrontal cortex is associated with social insecurity and disturbed in patients with ED. Therefore, disturbed orbitofrontal cortex activity may underlie the lack of insight and social isolation that is characteristic of patients with ED.

DOI： 10.1186/1471-244X-14-173

The polymorphism of YWHAE, a gene encoding 14-3-3epsilon, and orbitofrontal sulcogyral pattern in patients with schizophrenia and healthy subjects Reviewed

Tsutomu Takahashi, Yumiko Nakamura, Yukako Nakamura, Branko Aleksic, Yoichiro Takayanagi, Atsushi Furuichi, Mikio Kido, Mihoko Nakamura, Daiki Sasabayashi, Masashi Ikeda, Kyo Noguchi, Kozo Kaibuchi, Nakao Iwata, Norio Ozaki, Michio Suzuki

PROGRESS IN NEURO-PSYCHOPHARMACOLOGY & BIOLOGICAL PSYCHIATRY Vol. 51 page： 166 - 171 2014.6

Language：English Publishing type：Research paper (scientific journal) Publisher：PERGAMON-ELSEVIER SCIENCE LTD

An altered sulcogyral pattern in the orbitofrontal cortex (OFC) has been implicated in schizophrenia as a possible marker of abnormal neurodevelopment, while its genetic mechanism remains unknown. This magnetic resonance imaging study investigated the relationship between the polymorphism of YWHAE (rs28365859), a gene encoding 14-3-3epsilon that is a Disrupted-in-Schizophrenia 1 (DISC1)-interacting molecule associated with neuronal development, and the OFC subtypes of the 'H-shaped' sulcus (Types I, II, and III) in a Japanese sample of 72 schizophrenia patients and 86 healthy controls. The schizophrenia patients had significantly increased Type III (p = 0.004) and decreased Type I (p = 0.013) expression on the right hemisphere compared to the controls. The subjects carrying the protective C allele showed a decrease in Type III (p = 0.005) and an increase in Type I (p = 0.017) compared to the G allele homozygotes, especially for the healthy subjects in the left hemisphere. These results suggest a possible role for the YWHAE genotype in the early development of the OFC sulcogyral pattern, but its effect alone is not likely to explain the altered sulcogyral pattern in schizophrenia. (C) 2014 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.pnpbp.2014.02.005

Proteomic analysis of the lymphoblastoid cell line derived from Japanese schizophrenic patients Reviewed International journal

A. Yoshimi, S. Kunimoto, S. Yamada, B. Aleksic, A. Hirakawa, T. Nagai, N. Ozaki

INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY Vol. 17 page： 119 - 119 2014.6

Phase I Dose-escalation Clinical Trial of HF10 Oncolytic Herpes Virus in 17 Japanese Patients with Advanced Cancer Reviewed

Hideki Kasuya, Yasuhiro Kodera, Akimasa Nakao, Kazuo Yamamura, Tan Gewen, Wu Zhiwen, Yoshihiro Hotta, Suguru Yamada, Tsutomu Fujii, Saori Fukuda, Naoko Tsurumaru, Toshie Kuwahara, Toyone Kikumori, Yusuke Koide, Yasushi Fujimoto, Tsutomu Nakashima, Yoshiki Hirooka, Hiroshi Shiku, Maki Tanaka, Kazuto Takesako, Touru Kondo, Branko Aleksic, Hiroki Kawashima, Hidemi Goto, Yukihiro Nishiyama

HEPATO-GASTROENTEROLOGY Vol. 61 ( 131 ) page： 599 - 605 2014.5

Language：English Publishing type：Research paper (scientific journal) Publisher：H G E UPDATE MEDICAL PUBLISHING S A

Oncolytic virus therapy is a promising new therapeutic method, one of an eagerly anticipated class of biological therapies against cancer. There are many different classes of oncolytic virus. One of these, herpes oncolytic virus, is strongly oncolytic and has a large DNA genome as 150k bp. HF10 is a spontaneous mutant of herpes simplex virus -1 (HSV-1) that replicates within tumors and destroys cancers without damaging normal tissue and organs. Clinical trials of HF10 are underway in Japan and the United States. The first pilot study of HF10 was initiated in Japan in 2003. This study examined the safety and efficacy of HF10 in the treatment of breast cancer and head and neck cancers; the trial also included careful dose escalation studies. In 2005, a clinical trial using HF10 to treat pancreatic cancer was initiated. screened In this Japanese study, 17 patients received HF10 in their tumor sites. A clinical trial in the United States is also ongoing to evaluate safety, tolerability and evidence of antitumor activity in patients with refractory superficial solid tumors. Here, we report the evaluation of the 17 patients treated in Japan. Among the patients, 6 had recurrent breast cancer, 3 had recurrent head and neck cancer, and 8 had non-resectable pancreatic cancer. No severe adverse side effects have been observed, and some therapeutic potential has been reported based on pathological findings, tumor markers, and diagnostic radiography. Those results should encourage further clinical trials of HF10 around the world.

DOI： 10.5754/hge14104

Preoperative Level of Depression is a Predictor of Postoperative Levels of Depression in Patients with Head and Neck Cancer Reviewed

Yasunori Adachi, Hiroyuki Kimura, Naohiro Sato, Wataru Nagashima, Kouki Nakamura, Branko Aleksic, Keizo Yoshida, Yasushi Fujimoto, Tsutomu Nakashima, Norio Ozaki

JAPANESE JOURNAL OF CLINICAL ONCOLOGY Vol. 44 ( 4 ) page： 311 - 317 2014.4

Language：English Publishing type：Research paper (scientific journal) Publisher：OXFORD UNIV PRESS

Objective: Emotional distress is considered to be higher in patients with head and neck cancer than other types of cancer. The present study aimed to identify predictors of the postoperative levels of depression in patients with head and neck cancer who have undergone surgery.
Methods: Postoperative levels of depression were assessed at 3, 6 and 12 months after surgery. The preoperative factors that were significant predictors of the postoperative level of depression at each time point were extracted using multiple regression analyses.
Results: The preoperative level of depression was a significant predictor of the postoperative level of depression at the 3rd, 6th and 12th postoperative months. At the sixth postoperative month, negative adjustment to cancer at baseline was also a significant predictor of the postoperative level of depression.
Conclusion: Evaluating the level of depression and negative adjustment before surgery is considered to be effective for identifying patients who will develop depression after surgery.

DOI： 10.1093/jjco/hyu002

Copy-number variation in the pathogenesis of autism spectrum disorder

Emiko Shishido, Branko Aleksic, Norio Ozaki

PSYCHIATRY AND CLINICAL NEUROSCIENCES Vol. 68 ( 2 ) page： 85 - 95 2014.2

Language：English Publishing type：Research paper (scientific journal) Publisher：WILEY-BLACKWELL

Autism spectrum disorder is a neurodevelopmental disorder present in 1% of the population, characterized by impairments in reciprocal social interaction, communication deficits and restricted patterns of behavior. Approximately 10% of the autism spectrum disorder population is thought to have large chromosomal rearrangements. Copy-number variations (CNV) alter the genome structure either by duplication or deletion of a chromosomal region. The association between CNV and autism susceptibility has become more apparent through the use of methods based on comparative genomic hybridization in screening CNV. The nature of the high CNV rate in the human genome is partly explained by non-allelic homologous recombination between flanking repeated sequences derived from multiple copies of transposons or mobile genetic elements. There are hotspots for CNV in the human genome, such as 16p11.2 and 22q11.2. Genes involved in CNV are supposed to have copy-number dose-dependent effects on the behavior of affected individuals. Animal models give insight into the possible interactions between core genetic loci and additional factors contributing to the phenotypes of each individual. If affected genes code for cellular signaling molecules, reducing the dosage in the intracellular signaling pathway may result in the malfunction of the nervous system. The genetic background of autism spectrum disorder is highly heterogenic and most common or rare CNV do not lead to autism spectrum disorders in the majority of cases, but may occasionally increase the risk of developing an autism spectrum disorder.

DOI： 10.1111/pcn.12128

Genetic association study between the detected risk variants based upon type II diabetes GWAS and psychotic disorders in the Japanese population Reviewed

Yusuke Kajio, Kenji Kondo, Takeo Saito, Yoshimi Iwayama, Branko Aleksic, Kazuo Yamada, Tomoko Toyota, Eiji Hattori, Hiroshi Ujike, Toshiya Inada, Hiroshi Kunugi, Tadafumi Kato, Takeo Yoshikawa, Norio Ozaki, Masashi Ikeda, Nakao Iwata

JOURNAL OF HUMAN GENETICS Vol. 59 ( 1 ) page： 54 - 56 2014.1

Language：English Publishing type：Research paper (scientific journal) Publisher：NATURE PUBLISHING GROUP

Several epidemiological and genetic studies have suggested that the risk of type II diabetes (T2D) is likely to overlap with the susceptibility to psychotic disorders such as schizophrenia (SCZ) and bipolar disorder (BD). In this study, we aimed to examine the association of single-nucleotide polymorphisms (SNPs) detected in previous T2D genome-wide association studies (GWAS) with SCZ, BD and psychosis (SCZ plus BD). A total of 37 SNPs were selected from the literature. A two-stage analysis was conducted using a first set of screening samples (total N = 3037) and a second set of replication samples (N = 4950). None of the SNPs showed a significant association to the screening samples after correction for multiple testing. To avoid type II error, we genotyped the top three SNPs in BCL11A, HMG20A and HNF4A showing associations with any of the phenotypes (P-uncorrected<0.01) using independent samples to replicate the nominal associations. However, we were unable to find any significant associations based on the screening results (P-uncorrected>0.05). Our findings did not support the shared genetic risk between T2D and psychotic disorders in the Japanese population. However, further replication using a larger sample size is required.

DOI： 10.1038/jhg.2013.116

COMMON VARIANTS IN BCL9 GENE AND SCHIZOPHRENIA IN A JAPANESE POPULATION: ASSOCIATION STUDY, META-ANALYSIS AND COGNITIVE FUNCTION ANALYSIS

Tomoko Shiino, Takayoshi Koide, Itaru Kushima, Masashi Ikeda, Shohko Kunimoto, Yukako Nakamura, Akira Yoshimi, Branko Aleksic, Masahiro Banno, Tsutomu Kikuchi, Kunihiro Kohmura, Yasunori Adachi, Naoko Kawano, Takashi Okada, Toshiya Inada, Hiroshi Ujike, Tetsuya Iidaka, Michio Suzuki, Nakao Iwata, Norio Ozaki

JOURNAL OF MEDICAL BIOCHEMISTRY Vol. 32 ( 4 ) page： 361 - 367 2013.10

Language：English Publisher：VERSITA

Background: Schizophrenia is a relatively common disorder, with a lifetime prevalence of about 1%. Family history is the most important risk factor for schizophrenia, consistent with a genetic contribution to its etiology. Recent human genetic studies reported that some common variants located within BCL9 are associated with schizophrenia in the Chinese population, but not associated with bipolar disorder in the Caucasian population.
Methods: Single nucleotide variant (SNP) prioritization sample was comprised of 575 patients with schizophrenia and 564 healthy controls with no personal or family history of psychiatric illness. For SNP association analysis, we used an independent Japanese sample set (replication sample) comprising 1464 cases and 1171 controls. For the analysis of cognitive performance, we investigated 115 cases and 87 controls using Continuous Performance Test (CPT-IP) and the Wisconsin Card Sorting Test Keio version (WCST). Meta-analysis was performed using a combined Japanese total sample (N=3735) and a Chinese sample from a previous study.
Results: In the replication sample set, we did not detect any association in 2 SNPs (rs672607 and rs10494252) and schizophrenia. Meta-analysis of rs672607 showed significant association (p-value 0.012, odds ratio 0.855). There was a significant (p<0.01) difference between the A/A and G carrier group of rs672607 in CPT mean d' (p=0.0092).
Conclusions: We were able to detect evidence for an association between rs672607 in BCL9 and schizophrenia in the meta-analysis of Japanese and Chinese populations. Additionally, this common variant may affect cognitive performance, as measured by the CPT-IP in schizophrenia patients.

DOI： 10.2478/jomb-2013-0049

Definition and refinement of the 7q36.3 duplication region associated with schizophrenia. Reviewed International journal

Branko Aleksic, Itaru Kushima, Tamae Ohye, Masashi Ikeda, Shohko Kunimoto, Yukako Nakamura, Akira Yoshimi, Takayoshi Koide, Shuji Iritani, Hiroki Kurahashi, Nakao Iwata, Norio Ozaki

Scientific reports Vol. 3 page： 2587 - 2587 2013.9

Language：English Publishing type：Research paper (scientific journal)

Using a very high-resolution oligonucleotide array for copy number variant (CNV) screening of samples comprising schizophrenic patients, we detected a novel CNV within the critical region (NCBI36/hg18, Chr7: 158,630,410-158,719,410) previously shown to be associated with schizophrenia. We investigated the association between the novel CNV identified in the current study and schizophrenia. Three independent samples were used: (1) Screening set, 300 Japanese schizophrenic patients (53.28 ± 14.66 years); (2) Confirmation set, 531 schizophrenic patients (46.03 ± 12.15 years); and (3) 711 healthy controls (47.12 ± 11.03 years). All subjects enrolled in the study were Japanese. Chromosomal position was determined using fluorescence in situ hybridization. We identified a novel duplication within the region associated with schizophrenia identified on 7q36.3 that is adjacent to VIPR2 and is not associated with schizophrenia. In the Japanese population, the 35-kb region that harbors the common, novel CNV should be excluded from the region associated with schizophrenia on 7q36.3.

DOI： 10.1038/srep02587

Evidence for Shared Genetic Risk Between Methamphetamine-Induced Psychosis and Schizophrenia Reviewed

Masashi Ikeda, Yuko Okahisa, Branko Aleksic, Mujun Won, Naoki Kondo, Nobuya Naruse, Kumi Aoyama-Uehara, Ichiro Sora, Masaomi Iyo, Ryota Hashimoto, Yoshiya Kawamura, Nao Nishida, Taku Miyagawa, Masatoshi Takeda, Tsukasa Sasaki, Katsushi Tokunaga, Norio Ozaki, Hiroshi Ujike, Nakao Iwata

NEUROPSYCHOPHARMACOLOGY Vol. 38 ( 10 ) page： 1864 - 1870 2013.9

Language：English Publishing type：Research paper (scientific journal) Publisher：NATURE PUBLISHING GROUP

Methamphetamine (METH) use can provoke psychotic reactions requiring immediate treatment, namely METH-induced psychosis. Although the distinction between METH-induced and primary psychosis is important for understanding their clinical courses, we do not have clear diagnostic procedure by their symptoms. Not only are there similarities between the clinical features of METH-induced psychosis and schizophrenia (SCZ), but there is also epidemiological evidence of a shared genetic risk between 'METH-related' disorders and SCZ, which makes the differentiation of these two conditions difficult. In this study, we conducted a genome-wide association study (GWAS) targeting METH-dependent patients. The METH sample group, used in the METH-dependence GWAS, included 236 METH-dependent patients and 864 healthy controls. We also included a 'within-case' comparison between 194 METH-induced psychosis patients and 42 METH-dependent patients without psychosis in a METH-induced psychosis GWAS. To investigate the shared genetic components between METH dependence, METH-induced psychosis, and SCZ, data from our previous SCZ GWAS (total N = 1108) were re-analyzed. In the SNP-based analysis, none of the SNPs showed genome-wide significance in either data set. By performing a polygenic component analysis, however, we found that a large number of 'risk' alleles for METH-induced psychosis are over-represented in individuals with SCZ (P-best = 0.0090). Conversely, we did not detect enrichment either between METH dependence and METH-induced psychosis or between METH dependence and SCZ. The results support previous epidemiological and neurobiological evidence for a relationship between METH-induced psychosis and SCZ. These also suggest that the overlap between genes scored as positive in these data sets can have higher probability as susceptibility genes for psychosis.

DOI： 10.1038/npp.2013.94

Genetic Variants on 3q21 and in the Sp8 Transcription Factor Gene (SP8) as Susceptibility Loci for Psychotic Disorders: A Genetic Association Study Reviewed

Kenji Kondo, Masashi Ikeda, Yusuke Kajio, Takeo Saito, Yoshimi Iwayama, Branko Aleksic, Kazuo Yamada, Tomoko Toyota, Eiji Hattori, Hiroshi Ujike, Toshiya Inada, Hiroshi Kunugi, Tadafumi Kato, Takeo Yoshikawa, Norio Ozaki, Nakao Iwata

PLOS ONE Vol. 8 ( 8 ) page： e70964 2013.8

Language：English Publishing type：Research paper (scientific journal) Publisher：PUBLIC LIBRARY SCIENCE

Background: Recent genome-wide association studies (GWASs) investigating bipolar disorder (BD) have detected a number of susceptibility genes. These studies have also provided novel insight into shared genetic components between BD and schizophrenia (SCZ), two major psychotic disorders. To examine the replication of the risk variants for BD and the pleiotropic effect of the variants associated with BD, we conducted a genetic association study of single nucleotide polymorphisms (SNPs) that were selected based upon previous BD GWASs, which targeted psychotic disorders (BD and SCZ) in the Japanese population.
Methods: Forty-eight SNPs were selected based upon previous GWASs. A two-stage analysis was conducted using first-set screening (for all SNPs: BD = 1,012, SCZ = 1,032 and control = 993) and second-set replication samples (for significant SNPs in the screening analysis: BD = 821, SCZ = 1,808 and control = 2,149). We assessed allelic association between BD, SCZ, psychosis (BD+SCZ) and the SNPs selected for the analysis.
Results: Eight SNPs revealed nominal association signals for all comparisons (P-uncorrected<0.05). Among these SNPs, the top two SNPs (associated with psychosis: P-corrected = 0.048 and 0.037 for rs2251219 and rs2709722, respectively) were further assessed in the second-set samples, and we replicated the signals from the initial screening analysis (associated with psychosis: P-corrected = 0.0070 and 0.033 for rs2251219 and rs2709722, respectively). The meta-analysis between the current and previous GWAS results showed that rs2251219 in Polybromo1 (PBRM1) was significant on genome-wide association level (P = 5x10(-8)) only for BD (P = 9.4x10(-9)) and psychosis (P = 2.0x10(-10)). Although the association of rs2709722 in Sp8 transcription factor (SP8) was suggestive in the Asian population (P = 2.1x10(-7) for psychosis), this signal weakened when the samples size was increased by including data from a Caucasian population (P = 4.3x10(-3)).
Conclusions: We found 3p21.1 (including PBRM1, strong linkage disequilibrium made it difficult to pinpoint the risk genes) and SP8 as risk loci for BD, SCZ and psychosis. Further replication studies will be required for conclusive results.

DOI： 10.1371/journal.pone.0070964

Effectiveness of low-dose milnacipran for a patient suffering from pain disorder with delusional disorder (somatic type) in the orofacial region. International journal

Katsuyuki Ukai, Hiroyuki Kimura, Munetaka Arao, Branko Aleksic, Aya Yamauchi, Ryoko Ishihara, Shuji Iritani, Kenichi Kurita, Norio Ozaki

Psychogeriatrics : the official journal of the Japanese Psychogeriatric Society Vol. 13 ( 2 ) page： 99 - 102 2013.6

Language：English

Glossodynia is chronic pain localized around the tongue, with no perceivable organic abnormalities. In the fields of oral and maxillofacial surgery, it is categorized as an oral psychosomatic disease. In contrast, psychiatric nosology classifies glossodynia as a pain disorder among somatoform disorders, per the DSM-IV. The patient was a 71-year-old woman who developed symptoms of glossodynia, specifically a sore tongue. In the decade before she presented to us, she had had bizarre symptoms of oral cenesthopathy such as the sensation that her teeth had become 'limp and floppy' and that she needles in her mouth. Treatment was attempted using several psychotropic drugs, but no satisfactory response was noted. Because the patient was referred to our outpatient clinic, we tried psychotropic therapy again. Additionally, valproic acid, tandospirone and sertraline were administered (in this order), but the patient still showed no response. However, when sertraline was changed to milnacipran, all symptoms disappeared in a short period. We suggest that a small dose of milnacipran can be effective for controlling oral cenesthopathy as well as glossodynia.

DOI： 10.1111/j.1479-8301.2012.00430.x

Genome-Wide Association Study of Cognitive Decline in Schizophrenia Reviewed

Ryota Hashimoto, Masashi Ikeda, Kazutaka Ohi, Yuka Yasuda, Hidenaga Yamamori, Motoyuki Fukumoto, Satomi Umeda-Yano, Dwight Dickinson, Branko Aleksic, Masao Iwase, Hiroaki Kazui, Norio Ozaki, Daniel R. Weinberger, Nakao Iwata, Masatoshi Takeda

AMERICAN JOURNAL OF PSYCHIATRY Vol. 170 ( 6 ) page： 683 - 684 2013.6

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