Faculty Profiles - ALEKSIC Branko

Papers - ALEKSIC Branko

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A Case Control Association Study and Cognitive Function Analysis of Neuropilin and Tolloid-Like 1 Gene and Schizophrenia in the Japanese Population Reviewed

Masahiro Banno, Takayoshi Koide, Branko Aleksic, Kazuo Yamada, Tsutomu Kikuchi, Kunihiro Kohmura, Yasunori Adachi, Naoko Kawano, Itaru Kushima, Masashi Ikeda, Toshiya Inada, Takeo Yoshikawa, Nakao Iwata, Norio Ozaki

PLOS ONE Vol. 6 ( 12 ) page： e28929 2011.12

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

Background: Using a knock-out mouse model, it was shown that NETO1 is a critical component of the NMDAR complex, and that loss of Neto1 leads to impaired hippocampal long term potentiation and hippocampal-dependent learning and memory. Moreover, hemizygosity of NETO1 was shown to be associated with autistic-like behavior in humans.
Purpose of the Research: We examined the association between schizophrenia and the neuropilin and tolloid-like 1 gene (NETO1). First, we selected eight single nucleotide polymorphisms (SNPs) within the NETO1 locus, based on the Japanese schizophrenia genome wide association study (JGWAS) results and previously conducted association studies. These SNPs were genotyped in the replication sample comprised of 963 schizophrenic patients and 919 healthy controls. We also examined the effect of associated SNPs on scores in the Continuous Performance Test and the Wisconsin Card Sorting Test Keio version (schizophrenic patients 107, healthy controls 104).
Results: There were no significant allele-wise and haplotype-wise associations in the replication analysis after Bonferroni correction. However, in meta-analysis (JGWAS and replication dataset) three association signals were observed (rs17795324: p = 0.028, rs8098760: p = 0.017, rs17086492: p = 0.003). These SNPs were followed up but we could not detect the allele-specific effect on cognitive performance measured by the Continuous performance test (CPT) and Wisconsin Card Sorting test (WCST).
Major Conclusions: We did not detect evidence for the association of NETO1 with schizophrenia in the Japanese population. Common variants within the NETO1 locus may not increase the genetic risk for schizophrenia in the Japanese population. Additionally, common variants investigated in the current study did not affect cognitive performance, as measured by the CPT and WCST.

DOI： 10.1371/journal.pone.0028929

Loss of Function Studies in Mice and Genetic Association Link Receptor Protein Tyrosine Phosphatase alpha to Schizophrenia Invited Reviewed

Nagahide Takahashi, Karin Sandager Nielsen, Branko Aleksic, Steffen Petersen, Masashi Ikeda, Itaru Kushima, Nathalie Vacaresse, Hiroshi Ujike, Nakao Iwata, Veronique Dubreuil, Naheed Mirza, Takeshi Sakurai, Norio Ozaki, Joseph D. Buxbaum, Jan Sap

BIOLOGICAL PSYCHIATRY Vol. 70 ( 7 ) page： 626 - 635 2011.10

Language：English Publisher：ELSEVIER SCIENCE INC

Background: Solid evidence links schizophrenia (SZ) susceptibility to neurodevelopmental processes involving tyrosine phosphorylation-mediated signaling. Mouse studies implicate the Ptpra gene, encoding protein tyrosine phosphatase RPTP alpha, in the control of radial neuronal migration, cortical cytoarchitecture, and oligodendrocyte differentiation. The human gene encoding RPTP alpha, PTPRA, maps to a chromosomal region (20p13) associated with susceptibility to psychotic illness.
Methods: We characterized neurobehavioral parameters, as well as gene expression in the central nervous system, of mice with a null mutation in the Ptpra gene. We searched for genetic association between polymorphisms in PTPRA and schizophrenia risk (two independent cohorts, 1420 cases and 1377 controls), and we monitored PTPRA expression in prefrontal dorsolateral cortex of SZ patients (35 cases, 2 control groups of 35 cases).
Results: We found that Ptpra(-/-) mice reproduce neurobehavioral endophenotypes of human SZ: sensitization to methamphetamine-induced hyperactivity, defective sensorimotor gating, and defective habituation to a startle response. Ptpra loss of function also leads to reduced expression of multiple myelination genes, mimicking the hypomyelination-associated changes in gene expression observed in postmortem patient brains. We further report that a polymorphism at the PTPRA locus is genetically associated with SZ, and that PTPRA mRNA levels are reduced in postmortem dorsolateral prefrontal cortex of subjects with SZ.
Conclusions: The implication of this well-studied signaling protein in SZ risk and endophenotype manifestation provides novel entry points into the etiopathology of this disease.

DOI： 10.1016/j.biopsych.2011.06.016

Prospective study of maternal depressive symptomatology among Japanese women Reviewed

Naoko Ishikawa, Setsuko Goto, Satomi Murase, Atsuko Kanai, Tomoko Masuda, Branko Aleksic, Hinako Usui, Norio Ozaki

JOURNAL OF PSYCHOSOMATIC RESEARCH Vol. 71 ( 4 ) page： 264 - 269 2011.10

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

Background: The primary objective of this study was to analyze the pattern of depressive moods related to pregnancy and postpartum in a dataset collected prospectively. A secondary objective was to assess the association between (1) low moods during pregnancy and postpartum depressive symptoms, and (2) maternity blues and postpartum depressive symptom.
Method: Three hundred eighty-seven women completed self-administered questionnaires. The participants were asked to respond to Stein's Maternity Blues Scale (Stein's Scale) on five consecutive days after delivery and to the Edinburgh Postnatal Depression Scale (EPDS) during both pregnancy and postpartum.
Results: 32.0% of the women were identified as having a score of more than 9 on EPDS during pregnancy and postpartum. 21.6% of the women scored above the Stein's Scale cut-off point for at least 1 day during the 5-day period following delivery. The odds ratio (95% CI) for postpartum low mood if the women experienced low mood during pregnancy was 4.46 (2.48-8.04), while the odds ratio for postpartum depressive symptoms if the women experienced symptoms of maternity blues was 5.48 (2.74-10.98). In logistic regression analysis, the number of days in which women scored over the cut-off point by Stein's Scale proved to be the more significant predictor of scoring over the EPDS cutoff (8/9) [OR (95% CI)=2.74 (1.89-3.96)].
Conclusion: The rate of maternity blues in our findings was similar to the rates previously reported in Japan, but lower than the rates observed in Western countries. Furthermore, our longitudinal study confirms the likelihood of subsequent postpartum depressive symptoms if low moods during pregnancy and/or maternity blues are present. (C) 2011 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.jpsychores.2011.02.001

Association analysis of the GDNF gene with methamphetamine use disorder in a Japanese population Reviewed

Tomoko Yoshimura, Hinako Usui, Nagahide Takahashi, Akira Yoshimi, Shinichi Saito, Branko Aleksic, Hiroshi Ujike, Toshiya Inada, Mitsuhiko Yamada, Naohisa Uchimura, Nakao Iwata, Ichiro Sora, Masaomi Iyo, Norio Ozaki

PROGRESS IN NEURO-PSYCHOPHARMACOLOGY & BIOLOGICAL PSYCHIATRY Vol. 35 ( 5 ) page： 1268 - 1272 2011.7

Language：English Publisher：PERGAMON-ELSEVIER SCIENCE LTD

Methamphetamine (MAP) dependence is a highly heritable and aberrant dopaminergic signaling that has been implicated in the disease. Glial cell line-derived neurotrophic factor (GDNF), which plays an important role in the survival of dopaminergic neurons, may be involved in this disorder. In this study, we examined the association between GDNF and MAP dependence using a Japanese population-based sample.
We selected eight single nucleotide polymorphisms (SNPs) in the GDNF locus for the association analysis. When patients with MAP dependence were divided into two subgroups consisting of multi-substance and MAP-only users, we detected a significant association between these two groups and the tagging SNP, rs2910704 (after Bonferroni's correction; allele P = 0.034). Thus, GDNF is likely to be related to the severity of MAP use in the Japanese population. (C) 2011 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.pnpbp.2011.04.003

Reliability and validity of a new sexual function questionnaire (Nagoya Sexual Function Questionnaire) for schizophrenic patients taking antipsychotics

Tsutomu Kikuchi, Kunihiro Iwamoto, Kazumi Sasada, Branko Aleksic, Keizo Yoshida, Norio Ozaki

HUMAN PSYCHOPHARMACOLOGY-CLINICAL AND EXPERIMENTAL Vol. 26 ( 4-5 ) page： 300 - 306 2011.6

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

Objective This study aims to validate a new user-friendly sexual function questionnaire (Nagoya Sexual Function Questionnaire [NSFQ]) for schizophrenic patients taking antipsychotics.
Methods Schizophrenic outpatients (men = 30, women = 30) were asked to fill out the NSFQ at initial entry into the research program (Time(1)) and again 1 to 2 weeks later (Time(2)). To assess the convergent validity of the NSFQ, at Time(1), subjects were asked to fill out the Japanese version of the Udvalg for Kliniske Undersogekser Side Effect Rating Scale (UKU). To assess the discriminant validity of the NSFQ, at Time(1), subjects were also asked to fill out the Japanese version of Epworth Sleepiness Scale.
Results Results from Cronbach's alpha analysis indicated that the NSFQ demonstrated excellent internal consistency and scale reliability. The NSFQ also demonstrated strong test-retest reliability. The NSFQ total score was highly correlated with the UKU total score. The NSFQ was shown to have good convergent validity with the UKU. The NSFQ total score was not correlated with the Japanese version of Epworth Sleepiness Scale total score.
Conclusions This study revealed the internal consistency, test-retest reliability, and convergent and discriminant validities of the NSFQ. Copyright (C) 2011 John Wiley & Sons, Ltd.

DOI： 10.1002/hup.1205

Genome-Wide Association Study of Schizophrenia in a Japanese Population Reviewed

Masashi Ikeda, Branko Aleksic, Yoko Kinoshita, Tomo Okochi, Kunihiro Kawashima, Itaru Kushima, Yoshihito Ito, Yukako Nakamura, Taro Kishi, Takenori Okumura, Yasuhisa Fukuo, Hywel J. Williams, Marian L. Hamshere, Dobril Ivanov, Toshiya Inada, Michio Suzuki, Ryota Hashimoto, Hiroshi Ujike, Masatoshi Takeda, Nick Craddock, Kozo Kaibuchi, Michael J. Owen, Norio Ozaki, Michael C. O'Donovan, Nakao Iwata

BIOLOGICAL PSYCHIATRY Vol. 69 ( 5 ) page： 472 - 478 2011.3

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER SCIENCE INC

Background: Genome-wide association studies have detected a small number of weak but strongly supported schizophrenia risk alleles. Moreover, a substantial polygenic component to the disorder consisting of a large number of such alleles has been reported by the International Schizophrenia Consortium.
Method: We report a Japanese genome-wide association study of schizophrenia comprising 575 cases and 564 controls. We attempted to replicate 97 markers, representing a nonredundant panel of markers derived mainly from the top 150 findings, in up to three data sets totaling 1990 cases and 5389 controls. We then attempted to replicate the observation of a polygenic component to the disorder in the Japanese and to determine whether this overlaps that seen in UK populations.
Results: Single-locus analysis did not reveal genome-wide support for any locus in the genome-wide association study sample (best p = 6.2 x 10(-6)) or in the complete data set in which the best supported locus was SULT6B1 (rs11895771: p = 3.7 x 10(-5) in the meta-analysis). Of loci previously supported by genome-wide association studies, we obtained in the Japanese support for NOTCH4 (rs2071287: p(meta) = 5.1 x 10(-5)). Using the approach reported by the International Schizophrenia Consortium, we replicated the observation of a polygenic component to schizophrenia within the Japanese population (p = .005). Our trans Japan-UK analysis of schizophrenia also revealed a significant correlation (best p = 7.0 x 10(-5)) in the polygenic component across populations.
Conclusions: These results indicate a shared polygenic risk of schizophrenia between Japanese and Caucasian samples, although we did not detect unequivocal evidence for a novel susceptibility gene for schizophrenia.

DOI： 10.1016/j.biopsych.2010.07.010

Depression associated with alcohol intake and younger age in Japanese office workers: A case-control and a cohort study Reviewed

Kazuyoshi Ogasawara, Yukako Nakamura, Branko Aleksic, Keizo Yoshida, Katsuhisa Ando, Nakao Iwata, Yuhei Kayukawa, Norio Ozaki

JOURNAL OF AFFECTIVE DISORDERS Vol. 128 ( 1-2 ) page： 33 - 40 2011.1

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER SCIENCE BV

Background: Depression influences a worker's productivity and health substantially. Recently, the Japanese society and government reported that working overtime is one of the primary causes of depression and suicide in workers. However, only a few studies have investigated the relation between overtime hours and mental health status, and conclusions vary. In addition, prior findings are inconsistent in terms of the relation between depression and lifestyle factors, including alcohol intake and smoking. Additional studies are required to clarify the relation between possible risk factors and depression in Japanese workers.
Methods: We performed a case-control and a cohort study. Subjects were office workers in four Japanese companies. Diagnosis of depression was made by two psychiatrists who conducted independent clinical interviews using DSM-IV-TR criteria.
Results: There was no significant association between working overtime and the onset of depression. The frequency of alcohol intake was significantly related to the onset of depression. We also found a significant relation between younger age and depression onset. Body mass index and physical illness, including diabetes mellitus, had no significant association with depression onset. Limitations: Data were self-reported and the number of included female workers was small.
Conclusions: Reducing working hours alone is unlikely to be effective in preventing workers' depression. Additional countermeasures are needed, including a reduction in alcohol intake and work stress. Considerations for younger workers are also needed. (C) 2010 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.jad.2010.06.015

Necessity for ethical consideration of research in the aftermath of disaster Reviewed

Yoshihiko Iijima, Branko Aleksic, Norio Ozaki

PSYCHIATRY AND CLINICAL NEUROSCIENCES Vol. 65 ( 5 ) page： 535 - 536 2011

Efficacy of donepezil for the treatment of visual and multiple sensory hallucinations in dementia with Lewy bodies

Ukai Katsuyuki, Aleksic Branko, Ishihara Ryoko, Shibayama Hiroto, Iritani Shuji, Ozaki Norio

CNPT Vol. 2 page： 56 - 58 2011

Language：English Publisher：The Japanese Society of Clinical Neuropsychopharmacology

In this manuscript, we present a case report of a patient suffering from dementia with Lewy bodies who experienced not only visual but also four other sensory hallucinations, which were interdependent and may have influenced the patient's behavior. To the best of our knowledge, based on our search of the literature, this is the first such reported case of dementia with Lewy bodies.In this paper, we review the literature related to drug therapy for dementia with Lewy bodies, and propose, based on our clinical observations, that cholinesterase inhibitors, including donepezil, should be used as first-line drugs for the treatment and management of psychotic symptoms, including all five sensory hallucinations, in dementia with Lewy bodies.

DOI： 10.5234/cnpt.2.56

Other Link： http://search.jamas.or.jp/link/ui/2013137088

Gene-wide association study between the methylenetetrahydrofolate reductase gene (MTHFR) and schizophrenia in the Japanese population, with an updated meta-analysis on currently available data. Reviewed International journal

Akira Yoshimi, Branko Aleksic, Yukiko Kawamura, Nagahide Takahashi, Shinnosuke Yamada, Hinako Usui, Shinichi Saito, Yoshihito Ito, Nakao Iwata, Toshiya Inada, Yukihiro Noda, Kiyofumi Yamada, Norio Ozaki

Schizophrenia research Vol. 124 ( 1-3 ) page： 216 - 222 2010.12

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

Methylenetetrahydrofolate reductase (MTHFR) is a critical molecule for single-carbon transfer reactions. Recent evidence suggests that polymorphisms of MTHFR are related to neural tube deficits and the pathogenesis of schizophrenia. While several studies have demonstrated associations between the gene encoding the MTHFR (MTHFR) polymorphisms and schizophrenia, these studies lack consistency. Therefore, we conducted a gene-wide association study (patients with schizophrenia = 696, control subjects = 747) and performed imputation analysis. Additionally, we performed meta-analysis on currently available data from 18 studies for two common functional polymorphisms (rs1801131 and rs1801133). There were no significant associations with schizophrenia in the single marker analysis for the seven tagging SNPs of MTHFR. In the haplotypic analysis, a nominally significant association was observed between the haplotypes, which included four SNPs (rs1801133, rs17421511, rs17037396, and rs9651118) and the schizophrenic patients. Additionally, the imputation analysis demonstrated there were several associated markers on the MTHFR chromosomal region. However, confirmatory analyses of three tagging SNPs (rs1801133, rs17037396, and rs9651118) and the top SNP (rs17421511) for the imputation results (patients with schizophrenia = 797, control subjects = 1025) failed to replicate the haplotypic analysis and the imputation results. These findings suggest that MTHFR polymorphisms are unlikely to be related to the development of schizophrenia in the Japanese population. However, since our meta-analysis results demonstrated strong support for association of rs1801133 with schizophrenia, further replication studies based on a gene-wide approach need to be considered.

DOI： 10.1016/j.schres.2010.07.011

Influence of HTR2A polymorphisms and parental rearing on personality traits in healthy Japanese subjects Reviewed

Yukako Nakamura, Yoshihito Ito, Branko Aleksic, Itaru Kushima, Norio Yasui-Furukori, Toshiya Inada, Yutaka Ono, Norio Ozaki

JOURNAL OF HUMAN GENETICS Vol. 55 ( 12 ) page： 838 - 841 2010.12

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

Genetic factors and environmental influences contribute to the determination of human personality traits. This study examined the influence of serotonin receptor 2A polymorphisms and parental rearing on temperament. Subjects included 1245 Japanese volunteers (592 males and 653 females). Three single-nucleotide polymorphisms (SNPs) (rs6311, rs6313 and rs643627) were selected for genotyping. All subjects completed the 125-item Japanese short version of the temperament and character inventory, and 572 completed the Japanese version of the Parental Bonding Instrument. All SNPs were in Hardy-Weinberg equilibrium. A significant association (P=0.0026) was observed between rs643627 and novelty seeking in females. On the other hand, significant effects of maternal overprotection to harm avoidance (HA) were seen for rs6311 (P=0.0005), rs6313 (P=0.0004) and rs643627 (P=0.0003) in males only. In terms of the interaction of genotype and maternal overprotection with HA, interaction was observed in rs6311 (P=0.0290) and rs6313 (P=0.0230) in females only. Our results indicate a relationship between the rs643627 polymorphism and novelty seeking in females. In terms of serotonin receptor 2A gene polymorphisms and maternal overprotection, our findings suggest the existence of a gene-environmental interaction that influences HA. Journal of Human Genetics (2010) 55, 838-841; doi:10.1038/jhg.2010.110; published online 9 September 2010

DOI： 10.1038/jhg.2010.110

A two-stage case-control association study of the dihydropyrimidinase-like 2 gene (DPYSL2) with schizophrenia in Japanese subjects. Reviewed International journal

Takayoshi Koide, Branko Aleksic, Yoshihito Ito, Hinako Usui, Akira Yoshimi, Toshiya Inada, Michio Suzuki, Ryota Hashimoto, Masatoshi Takeda, Nakao Iwata, Norio Ozaki

Journal of human genetics Vol. 55 ( 7 ) page： 469 - 472 2010.7

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

We examined the association of schizophrenia (SCZ) and dihydropyrimidinase-like 2 (DPYSL2), also known as collapsin response mediator protein 2, which regulates axonal growth and branching. We genotyped 20 tag single nucleotide polymorphisms (SNPs) in 1464 patients and 1310 controls. There were two potential associations in a screening population of 384 patients and 384 controls (rs2585458: P=0.046, rs4733048: P=0.014). However, we could not replicate these associations in a confirmatory population of 1080 patients and 926 controls (rs2585458: P=0.39, rs4733048: P=0.70) or a joint analysis (rs2585458: P=0.72, rs4733048: P=0.10). We conclude that DPYSL2 does not have a major function in SCZ in Japanese subjects.

DOI： 10.1038/jhg.2010.38

Genetic association study of KREMEN1 and DKK1 and schizophrenia in a Japanese population Reviewed

Branko Aleksic, Itaru Kushima, Yoshihito Ito, Yukako Nakamura, Hiroshi Ujike, Michio Suzuki, Toshiya Inada, Ryota Hashimoto, Masatoshi Takeda, Nakao Iwata, Norio Ozaki

SCHIZOPHRENIA RESEARCH Vol. 118 ( 1-3 ) page： 113 - 117 2010.5

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER SCIENCE BV

The aim of the current study was to examine the association of KREMEN1 and DKK1, two wnt pathway-related genes with schizophrenia in Japanese subjects. We genotyped 16 common genetic variants within the aforementioned genes and examined their associations with schizophrenia. Results demonstrated that a common variant in the promoter region of KREMEN1 might modulate the risk of schizophrenia in the Japanese. However, further replication will be needed for conclusive interpretation of the effect of this locus on the pathogenesis of schizophrenia. (C) 2010 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.schres.2010.01.014

Association Study of Bromodomain-Containing 1 Gene With Schizophrenia in Japanese Population Reviewed

Itaru Kushima, Branko Aleksic, Masashi Ikeda, Yoshio Yamanouchi, Yoko Kinoshita, Yoshihito Ito, Yukako Nakamura, Toshiya Inada, Nakao Iwata, Norio Ozaki

AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS Vol. 153B ( 3 ) page： 786 - 791 2010.4

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

Chromosome 22q13 region has been implicated in schizophrenia in several linkage studies. Genes within this locus are therefore promising genetic and biologic candidate genes for schizophrenia if they are expressed in the brain or predicted to have some role in brain development. A recent study reported that bromodomain-containing 1 gene (BRD1), located in 22q13, showed an association with schizophrenia in a Scottish population. Except for being a putative regulator of transcription, the precise function of BRD1 is not clear; however, expression analysis of BRD1 mRNA revealed widespread expression in mammalian brains. In our study, we explored the association of BRD1 with schizophrenia in a Japanese population (626 cases and 770 controls). In this association analysis, we first examined 10 directly genotyped single-nucleotide polymorphisms (SNPs) and 20 imputed SNPs. Second, we compared the BRD1 mRNA levels between cases and controls using lymphoblastoid cell lines (LCLs) derived from 29 cases and 30 controls. Although the SNP (rs138880) that previously has been associated with schizophrenia showed the same trend in the Japanese population, no significant association was detected between BRD1 and schizophrenia in our study. Similarly, no significant differences in BRD1 mRNA levels in LCLs were detected. Taken together, we could not strongly show that common SNPs in the BRD1 gene account for a substantial proportion of the genetic risk for schizophrenia in the Japanese population. (C) 2009 Wiley-Liss, Inc.

DOI： 10.1002/ajmg.b.31048

Association study of ubiquitin-specific peptidase 46 (USP46) with bipolar disorder and schizophrenia in a Japanese population Reviewed

Itaru Kushima, Branko Aleksic, Yoshihito Ito, Yukako Nakamura, Kazuhiko Nakamura, Norio Mori, Mitsuru Kikuchi, Toshiya Inada, Hiroshi Kunugi, Shinichiro Nanko, Tadafumi Kato, Takeo Yoshikawa, Hiroshi Ujike, Michio Suzuki, Nakao Iwata, Norio Ozaki

JOURNAL OF HUMAN GENETICS Vol. 55 ( 3 ) page： 133 - 136 2010.3

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

Recently, ubiquitin-specific peptidase 46 (Usp46) has been identified as a quantitative trait gene responsible for immobility in the tail suspension test and forced swimming test in mice. Mice with 3-bp deletion in Usp46 exhibited loss of 'behavioral despair' under inescapable stresses in addition to abnormalities in circadian behavioral rhythms and the GABAergic system. Considering the face and construct validity as an animal model for bipolar disorder, we explored an association of USP46 and bipolar disorder in a Japanese population. We also examined an association of USP46 and schizophrenia. We found nominal evidence for an association of rs12646800 and schizophrenia. This association was not significant after correction for multiple testing. No significant association was detected for bipolar disorder. In conclusion, our data argue against the presence of any strong genetic susceptibility factors for bipolar disorder or schizophrenia in the region USP46. Journal of Human Genetics (2010) 55, 133-136; doi: 10.1038/jhg.2009.139; published online 29 January 2010

DOI： 10.1038/jhg.2009.139

Copy Number Variation in Schizophrenia in the Japanese Population Reviewed

Masashi Ikeda, Branko Aleksic, George Kirov, Yoko Kinoshita, Yoshio Yamanouchi, Tsuyoshi Kitajima, Kunihiro Kawashima, Tomo Okochi, Taro Kishi, Irina Zaharieva, Michael J. Owen, Michael C. O'Donovan, Norio Ozaki, Nakao Iwata

BIOLOGICAL PSYCHIATRY Vol. 67 ( 3 ) page： 283 - 286 2010.2

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER SCIENCE INC

Background: Copy number variants (CNVs) have been shown to increase the risk to develop schizophrenia. The best supported findings are at 1q21.1, 15q11.2, 15q13.3, and 22q11.2 and deletions at the gene neurexin 1 (NRXN1).
Methods: In this study, we used Affymetrix 5.0 arrays to investigate the role of rare CNVs in 575 patients with schizophrenia and 564 control subjects from Japan.
Results: There was a nonsignificant trend for excess of rare CNVs in schizophrenia (p = .087); however, we did not confirm the previously implicated association for very large CNVs (>500 kilobase [kb]) in this population. We provide support for three previous findings in schizophrenia, as we identified one deletion in a case at 1q21.1, one deletion within NRXN1, and four duplications in cases and one in a control subject at 16p13.1, a locus first implicated in autism and later in schizophrenia.
Conclusions: In this population, we support some of the previous findings in schizophrenia but could not find an increased burden of very large (>500 kb) CNVs, which was proposed recently. However, we provide support for the role of CNVs at 16p13.1, 1q21.1, and NRXN1.

DOI： 10.1016/j.biopsych.2009.08.034

Comparison of pharmacological profiles of serotonin norepinephrine reuptake inhibitors

Adachi Yasunori, Aleksic Branko, Ozaki Norio

CNPT Vol. 1 page： 10 - 15 2010

Language：English Publisher：The Japanese Society of Clinical Neuropsychopharmacology

Serotonin norepinephrine reuptake inhibitors (SNRIs) work by inhibiting the reuptake of the neurotransmitters serotonin and norepinephrine. This results in an increase in the extracellular concentrations of serotonin and norepinephrine and therefore an increase in neurotransmission. The three SNRIs milnacipran, duloxetine, and venlafaxine have different affinity and selectivity profiles. Milnacipran and duloxetine inhibit the reuptake of serotonin and norepinephrine at all doses. In contrast, venlafaxine selectively inhibits the reuptake of serotonin at low doses, but this serotonin transporter specificity disappears as the dose increases (i.e., it acts as an SNRI). In addition, the SNRIs, as well as the SSRIs, have few significant side effects because they interact only infrequently with other neurotransmitter receptors. Milnacipran and duloxetine seem to have fewer side effects and essentially show no cardiovascular toxicity. However, venlafaxine appears the least well-tolerated because of a high incidence of serotonergic adverse events (nausea, sexual dysfunction, withdrawal problems) and dose-dependent hypertension. SNRIs have increased efficacy and good tolerability and are used for the treatment of anxiety disorders and chronic pain. Our results suggest that SNRIs may have more advantages than other kinds of antidepressants and that the differences in the pharmacological profiles of each should be understood when using them.

DOI： 10.5234/cnpt.1.10

Other Link： http://search.jamas.or.jp/link/ui/2012047008

BDNF is not associated with schizophrenia: Data from a Japanese population study and meta-analysis Reviewed

Kunihiro Kawashima, Masashi Ikeda, Taro Kishi, Tsuyoshi Kitajima, Yoshio Yamanouchi, Yoko Kinoshita, Tomo Okochi, Branko Aleksic, Makoto Tomita, Takeya Okada, Hiroshi Kunugi, Toshiya Inada, Norio Ozaki, Nakao Iwata

SCHIZOPHRENIA RESEARCH Vol. 112 ( 1-3 ) page： 72 - 79 2009.7

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER SCIENCE BV

A variety of evidence suggests brain-derived neurotrophic factor (BDNF) as a candidate gene for schizophrenia, and several genetic studies have shown a significant association between the disease and certain SNPs within BDNF (specifically, Val66Met and C270T). According to a recent study, the functional microsatellite marker BDNF-LCPR (BDNF-linked complex polymorphic region), which affects the expression level of BDNF, is associated with bipolar disorder. The goals of our current study were to 1) evaluate the quality of HapMap-based linkage disequilibrium (LD) tagging of BDNF-LCPR, 2) examine whether these tagging SNPs are associated with schizophrenia in a Japanese population, and 3) conduct a meta-analysis of the two most extensively studied polymorphisms: Val66Met and C270T. We genotyped eight tagging SNPs, including Val66Met and C270T. Our LID evaluation showed that BDNF-LCPR could be represented by these tagging SNPs in controls (with 73.5% allelic coverage). However, the functional A1 allele was not captured due to its low minor allele frequency (2.2%). In a case-control study (1117 schizophrenics and 1102 controls), no association was found in single-marker or multimarker analysis. Moreover, in a meta-analysis, the Val66Met polymorphism was not associated with schizophrenia, whereas C270T showed a trend for association in a fixed model (p = 0.036), but not in a random model (p = 0.053). From these findings, we conclude that if BDNF is indeed associated with schizophrenia, the A1 allele in BDNF-LCPR would be the most promising candidate. Further LD evaluation, as well as an association study in which BDNF-LCPR is genotyped directly, would be required for a more conclusive result. (C) 2009 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.schres.2009.03.040

Dense association mapping of dihydropyrimidinase-like 2 (DPYSL2) gene in susceptibility to schizophrenia in a Japanese population Reviewed

Yoshihito Ito, Takayoshi Koide, Branko Aleksic, Toshiya Inada, Nakao Iwata, Norio Ozaki

NEUROSCIENCE RESEARCH Vol. 65 page： S253 - S253 2009

No association between the oligodendrocyte-related gene PLP1 and schizophrenia in the Japanese population Reviewed

Branko Aleksic, Masashi Ikeda, Ryoko Ishihara, Shinichi Saito, Toshiya Inada, Nakao Iwata, Norio Ozaki

JOURNAL OF HUMAN GENETICS Vol. 53 ( 9 ) page： 863 - 866 2008.9

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

PLP1 is one of the major myelin-related genes. A large body of expression-based studies showed significantly lower levels of the PLP1 messenger ribonucleic acid (mRNA) transcripts in schizophrenia. Moreover, one family-based study identified a weak association signal in a male subset using 487 Chinese family trios. We carried out a population-based association study between PLP1 and schizophrenia in 1,640 subjects. Our data does not support genetic variation in close vicinity or within PLP1 locus as a susceptibility factor.

DOI： 10.1007/s10038-008-0318-7

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