Faculty Profiles - ALEKSIC Branko

Papers - ALEKSIC Branko

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Rare loss of function mutations in N-methyl-D-aspartate glutamate receptors and their contributions to schizophrenia susceptibility. Reviewed International journal

Yanjie Yu, Yingni Lin, Yuto Takasaki, Chenyao Wang, Hiroki Kimura, Jingrui Xing, Kanako Ishizuka, Miho Toyama, Itaru Kushima, Daisuke Mori, Yuko Arioka, Yota Uno, Tomoko Shiino, Yukako Nakamura, Takashi Okada, Mako Morikawa, Masashi Ikeda, Nakao Iwata, Yuko Okahisa, Manabu Takaki, Shinji Sakamoto, Toshiyuki Someya, Jun Egawa, Masahide Usami, Masaki Kodaira, Akira Yoshimi, Tomoko Oya-Ito, Branko Aleksic, Kinji Ohno, Norio Ozaki

Translational psychiatry Vol. 8 ( 1 ) page： 12 - 12 2018.1

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

In schizophrenia (SCZ) and autism spectrum disorder (ASD), the dysregulation of glutamate transmission through N-methyl-D-aspartate receptors (NMDARs) has been implicated as a potential etiological mechanism. Previous studies have accumulated evidence supporting NMDAR-encoding genes' role in etiology of SCZ and ASD. We performed a screening study for exonic regions of GRIN1, GRIN2A, GRIN2C, GRIN2D, GRIN3A, and GRIN3B, which encode NMDAR subunits, in 562 participates (370 SCZ and 192 ASD). Forty rare variants were identified including 38 missense, 1 frameshift mutation in GRIN2C and 1 splice site mutation in GRIN2D. We conducted in silico analysis for all variants and detected seven missense variants with deleterious prediction. De novo analysis was conducted if pedigree samples were available. The splice site mutation in GRIN2D is predicted to result in intron retention by minigene assay. Furthermore, the frameshift mutation in GRIN2C and splice site mutation in GRIN2D were genotyped in an independent sample set comprising 1877 SCZ cases, 382 ASD cases, and 2040 controls. Both of them were revealed to be singleton. Our study gives evidence in support of the view that ultra-rare variants with loss of function (frameshift, nonsense or splice site) in NMDARs genes may contribute to possible risk of SCZ.

DOI： 10.1038/s41398-017-0061-y

Genetics in pediatric consultation-liaison psychiatry and multidisciplinary management of complex conditions Reviewed International journal

Aleksic B.

Pediatric Consultation-Liaison Psychiatry: A Global, Healthcare Systems-Focused, and Problem-Based Approach page： 251 - 264 2018.1

CLINICALLY RELEVANT GENETIC VARIANTS: MODELS FOR UNDERSTANDING SCHIZOPHRENIA AND OTHER NEUROPSYCHIATRIC DISORDERS DUPLICATIONS AT 15Q11-Q13 IN SCHIZOPHRENIA AND NEURODEVELOPMENTAL DISORDERS Reviewed International journal

George Kirov, Anthony Isles, Andres Ingason, Chelsea Lowther, James Walters, Anne Bassett, Gregory Costain, Douglas Levinson, Micha Gawlick, Franziska Degenhardt, Branko Aleksic, JooWook Ahn, Caroline Ogilvie, Kari Stefansson, Michael Owen

EUROPEAN NEUROPSYCHOPHARMACOLOGY Vol. 27 page： S277 - S277 2017.10

IDENTIFICATION OF RARE DISRUPTIVE VARIANTS IN VOLTAGE-GATED CHANNEL GENES (CACNA1C, CACNA1D, CACNA1S, CACNA1I) IN JAPANESE SAMPLES OF SCHIZOPHRENIA AND AUTISM SPECTRUM DISORDER USING ION TORRENT PGM PLATFORM Reviewed International journal

Chenyao Wang, Hiroki Kimura, Jingrui Xing, Kanoko Ishizuka, Itaru Kushima, Yuko Arioka, Akira Yoshimi, Yukako Nakamura, Yomoko Shiino, Yuko Oya, Yuto Takasaki, Branko Aleksic, Daisuke Mori, Norio Ozaki

EUROPEAN NEUROPSYCHOPHARMACOLOGY Vol. 27 page： S341 - S342 2017.10

Relationship between maternal depression and bonding failure: A prospective cohort study of pregnant women International journal

Masako Ohara, Takashi Okada, Chika Kubota, Yukako Nakamura, Tomoko Shiino, Branko Aleksic, Mako Morikawa, Aya Yamauchi, Yota Uno, Satomi Murase, Setsuko Goto, Atsuko Kanai, Tomoko Masuda, Masahiko Ando, Norio Ozaki

PSYCHIATRY AND CLINICAL NEUROSCIENCES Vol. 71 ( 10 ) page： 733 - 741 2017.10

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

Aim: Although the association between maternal depression and bonding failure during pregnancy and after delivery has been investigated, the causal relationships remain unclear.
Methods: A total of 751 women (mean [SD] age, 32.1 [4.4] years) completed the Mother-Infant Bonding Questionnaire and the Edinburgh Postnatal Depression Scale during early pregnancy before week 25 (T1), during late pregnancy around week 36 (T2), and at 5 days after delivery (T3). We created a structural regression model to clarify the relationships between depressive mood and bonding failure during pregnancy and at 5 days after delivery. The model was tested with structural equation modeling.
Results: Our non-recursive model fit the data well, and we found that: (i) during T2, bonding failure predicted depressive mood (P < 0.01, r = 0.23); (ii) at T3, bonding failure predicted depressive mood (P < 0.05, r = 0.31); (iii) during T1, depressive mood was correlated with bonding failure (P < 0.01, r = 0.45); (iv) depressive mood during T1 predicted depressive mood during T2 (P < 0.01, r = 0.58); (v) depressive mood during T2 predicted depressive mood at T3 (P < 0.01, r = 0.45); (vi) bonding failure during T1 predicted bonding failure during T2 (P < 0.01, r = 0.84); and (vii) bonding failure during T2 predicted bonding failure at T3 (P < 0.01, r = 0.44). The determinant coefficients of depressive mood and bonding failure at T3 were 0.41 and 0.28, respectively.
Conclusion: Our large-scale cohort study indicates that bonding failure predicts depressive mood during pregnancy and 5 days after delivery. These findings suggest that protection and support for pregnant women with depressive mood and bonding failure may prevent both issues during pregnancy and the early stage after delivery.

DOI： 10.1111/pcn.12541

MUTATION SCREENING OF THE PCDH15 GENE IN PATIENTS SUFFERING FROM AUTISM SPECTRUM DISORDERS AND SCHIZOPHRENIA Reviewed International journal

Kanako Ishizuka, Chenyao Wang, Hiroki Kimura, Jingrui Xing, Itaru Kushima, Yuko Arioka, Akira Yoshimi, Yukako Nakamura, Tomoko Oya-Ito, Yuto Takasaki, Yota Uno, Takashi Okada, Daisuke Mori, Branko Aleksic, Norio Ozaki

EUROPEAN NEUROPSYCHOPHARMACOLOGY Vol. 27 page： S162 - S163 2017.10

Rates, distribution and implications of postzygotic mosaic mutations in autism spectrum disorder Reviewed International journal

Elaine T. Lim, Mohammed Uddin, Silvia De Rubeis, Yingleong Chan, Anne S. Kamumbu, Xiaochang Zhang, Alissa M. D'Gama, Sonia N. Kim, Robert Sean Hill, Arthur P. Goldberg, Christopher Poultney, Nancy J. Minshew, Itaru Kushima, Branko Aleksic, Norio Ozaki, Mara Parellada, Celso Arango, Maria J. Penzol, Angel Carracedo, Alexander Kolevzon, Christina M. Hultman, Lauren A. Weiss, Menachem Fromer, Andreas G. Chiocchetti, Christine M. Freitag, George M. Church, Stephen W. Scherer, Joseph D. Buxbaum, Christopher A. Walsh

NATURE NEUROSCIENCE Vol. 20 ( 9 ) page： 1217 - + 2017.9

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

We systematically analyzed postzygotic mutations (PZMs) in whole-exome sequences from the largest collection of trios (5,947) with autism spectrum disorder (ASD) available, including 282 unpublished trios, and performed resequencing using multiple independent technologies. We identified 7.5% of de novo mutations as PZMs, 83.3% of which were not described in previous studies. Damaging, nonsynonymous PZMs within critical exons of prenatally expressed genes were more common in ASD probands than controls (P < 1 x 10(-6)), and genes carrying these PZMs were enriched for expression in the amygdala (P = 5.4 x 10(-3)). Two genes (KLF16 and MSANTD2) were significantly enriched for PZMs genome-wide, and other PZMs involved genes (SCN2A, HNRNPU and SMARCA4) whose mutation is known to cause ASD or other neurodevelopmental disorders. PZMs constitute a significant proportion of de novo mutations and contribute importantly to ASD risk.

DOI： 10.1038/nn.4598

Social support helps protect against perinatal bonding failure and depression among mothers: a prospective cohort study Reviewed International journal

Masako Ohara, Takashi Okada, Branko Aleksic, Mako Morikawa, Chika Kubota, Yukako Nakamura, Tomoko Shiino, Aya Yamauchi, Yota Uno, Satomi Murase, Setsuko Goto, Atsuko Kanai, Tomoko Masuda, Masahiro Nakatochi, Masahiko Ando, Norio Ozaki

SCIENTIFIC REPORTS Vol. 7 ( 1 ) page： 9546 2017.8

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

Causal relationships between perinatal bonding failure, depression, and social support among mothers remain unclear. A total of 494 women (mean age 32.4 +/- 4.5 years) completed the Mother-Infant Bonding Questionnaire (MIBQ), the Edinburgh Postnatal Depression Scale (EPDS), and the Japanese version of the Social Support Questionnaire in early pregnancy before week 25 (T1) and 1 month after delivery (T2). Our model of recursive structured equation modeling (SEM) showed acceptable fit (CMIN/df = 2.2, CFI = 0.97, and RMSEA = 0.05). It was revealed that: (1) a lower number of supportive persons at T1 significantly predicted both MIBQ and EPDS scores at T1 and T2; (2) at T1, poorer satisfaction with the social support received significantly predicted EPDS scores; (3) both MIBQ and EPDS scores at T1 significantly predicted their respective scores at T2. Out cohort study indicates that the number of individuals who are available to provide social support and the degree of satisfaction with the level of social support received during pregnancy have a great influence on bonding failure and depression in the postpartum period. These findings suggest that psychosocial interventions that focus on these two aspects of social support during pregnancy are effective in preventing bonding failure and depression in the postpartum period.

DOI： 10.1038/s41598-017-08768-3

A novel rare variant R292H in RTN4R affects growth cone formation and possibly contributes to schizophrenia susceptibility

H. Kimura, Y. Fujita, T. Kawabata, K. Ishizuka, C. Wang, Y. Iwayama, Y. Okahisa, I. Kushima, M. Morikawa, Y. Uno, T. Okada, M. Ikeda, T. Inada, A. Branko, D. Mori, T. Yoshikawa, N. Iwata, H. Nakamura, T. Yamashita, N. Ozaki

TRANSLATIONAL PSYCHIATRY Vol. 7 page： in print 2017.8

Language：English Publisher：NATURE PUBLISHING GROUP

Reticulon 4 receptor (RTN4R) plays an essential role in regulating axonal regeneration and plasticity in the central nervous system through the activation of rho kinase, and is located within chromosome 22q11.2, a region that is known to be a hotspot for schizophrenia (SCZ) and autism spectrum disorder (ASD). Recently, rare variants such as copy-number variants and single-nucleotide variants have been a focus of research because of their large effect size associated with increased susceptibility to SCZ and ASD and the possibility of elucidating the pathophysiology of mental disorder through functional analysis of the discovered rare variants. To discover rare variants with large effect size and to evaluate their role in the etiopathophysiology of SCZ and ASD, we sequenced the RTN4R coding exons with a sample comprising 370 SCZ and 192 ASD patients, and association analysis using a large number of unrelated individuals (1716 SCZ, 382 ASD and 4009 controls). Through this mutation screening, we discovered four rare (minor allele frequency <1%) missense mutations (R68H, D259N, R292H and V363M) of RTN4R. Among these discovered rare mutations, R292H was found to be significantly associated with SCZ (P = 0.048). Furthermore, in vitro functional assays showed that the R292H mutation affected the formation of growth cones. This study strengthens the evidence for association between rare variants within RTN4R and SCZ, and may shed light on the molecular mechanisms underlying the neurodevelopmental disorder.

DOI： 10.1038/tp.2017.170

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Drug-induced Extrapyramidal Symptoms Scale (DIEPSS) Serbian Language version: Inter-rater and Test-retest Reliability Reviewed

Ami Peljto, Ljubica Zamurovic, Milica Pejovic Milovancevic, Branko Aleksic, Dusica Lecic Tosevski, Toshiya Inada

SCIENTIFIC REPORTS Vol. 7 ( 1 ) page： 8105 2017.8

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

Drug-induced Extrapyramidal Symptoms Scale (DIEPSS) is developed in the era of second-generation antipsychotics and is suitable for evaluation of the low incidence of extrapyramidal symptoms occurring in the treatment of atypical antipsychotics, as well as the relationship between personal and social functioning. The study was carried out at the Institute of Mental Health in Serbia in 2015 Study used the 127 DIEPSS video clips material, recorded from 1987 till 2015. Four raters performed the assessment simultaneously, individually rating one assigned item immediately after seeing the video clip. For the purpose of evaluating test-retest reliability the second assessment of the same material was performed nine months after the first assessment. Inter-rater reliability was high for each individual item, with ICCs ranging from 0.769 to 0.949. The inter-rater reliability was highest for akathisia item and lowest for dyskinesia. The test-retest reliability was high for each individual item, with ICCs ranging from 0.713 to 0.935. The test-retest reliability was highest for bradykinesia item and lowest for dystonia. The Serbian version of DIEPSS has high level of inter-rater and test-retest reliability. High values of concordance rates (ICC > 0.7) for each evaluated individual item suggest that items of DIEPSS are well defined.

DOI： 10.1038/s41598-017-08706-3

Rare genetic variants in CX3CR1 and their contribution to the increased risk of schizophrenia and autism spectrum disorders

Kanako Ishizuka, Yuki Fujita, Takeshi Kawabata, Hiroki Kimura, Yoshimi Iwayama, Toshiya Inada, Yuko Okahisa, Jun Egawa, Masahide Usami, Itaru Kushima, Yota Uno, Takashi Okada, Masashi Ikeda, Aleksic Branko, Daisuke Mori, Takeo Yoshikawa, Nakao Iwata, Haruki Nakamura, Toshihide Yamashita, Norio Ozaki

Translational Psychiatry Vol. 7 ( 8 ) page： in print - e1184 2017.8

Genomic signature of the natural oncolytic herpes simplex virus HF10 and its therapeutic role in preclinical and clinical trials Reviewed International journal

Ibrahim Ragab Eissa, Yoshinori Naoe, Itzel Bustos-Villalobos, Toru Ichinose, Maki Tanaka, Wu Zhiwen, Nobuaki Mukoyama, Taishi Morimoto, Noriyuki Miyajima, Hasegawa Hitoki, Seiji Sumigama, Branko Aleksic, Yasuhiro Kodera, Hideki Kasuya

Frontiers in Oncology Vol. 7 ( JUL ) page： 149 2017.7

Language：English Publishing type：Research paper (scientific journal) Publisher：Frontiers Media S.A.

Oncolytic viruses (OVs) are opening new possibilities in cancer therapy with their unique mechanism of selective replication within tumor cells and triggering of antitumor immune responses. HF10 is an oncolytic herpes simplex virus-1 with a unique genomic structure that has non-engineered deletions and insertions accompanied by frame-shift mutations, in contrast to the majority of engineered OVs. At the genetic level, HF10 naturally lacks the expression of UL43, UL49.5, UL55, UL56, and latency-associated transcripts, and overexpresses UL53 and UL54. In preclinical studies, HF10 replicated efficiently within tumor cells with extensive cytolytic effects and induced increased numbers of activated CD4+ and CD8+ T cells and natural killer cells within the tumor, leading to a significant reduction in tumor growth and prolonged survival rates. Investigator-initiated clinical studies of HF10 have been completed in recurrent breast carcinoma, head and neck cancer, and unresectable pancreatic cancer in Japan. Phase I trials were subsequently completed in refractory superficial cancers and melanoma in the United States. HF10 has been demonstrated to have a high safety margin with low frequency of adverse effects in all treated patients. Interestingly, HF10 antigens were detected in pancreatic carcinoma over 300 days after treatment with infiltration of CD4+ and CD8+ T cells, which enhanced the immune response. To date, preliminary results from a Phase II trial have indicated that HF10 in combination with ipilimumab (anti-CTLA-4) is safe and well tolerated, with high antitumor efficacy. Improvement of the effect of ipilimumab was observed in patients with stage IIIb, IIIc, or IV unresectable or metastatic melanoma. This review provides a concise description of the genomic functional organization of HF10 compared with talimogene laherparepvec. Furthermore, this review focuses on HF10 in cancer treatment as monotherapy as well as in combination therapy through a concise description of all preclinical and clinical data. In addition, we will address approaches for future directions in HF10 studies as cancer therapy.

DOI： 10.3389/fonc.2017.00149

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Effect of Adjunctive Aripiprazole on Sexual Dysfunction in Schizophrenia: A Preliminary Open-Label Study Reviewed International journal

Junko Fujioi, Kunihiro Iwamoto, Masahiro Banno, Tsutomu Kikuchi, Branko Aleksic, Norio Ozaki

PHARMACOPSYCHIATRY Vol. 50 ( 2 ) page： 74 - 78 2017.3

Language：English Publishing type：Research paper (scientific journal) Publisher：GEORG THIEME VERLAG KG

Introduction Although adjunctive aripiprazole improves hyperprolactinemia, sufficient evidence for its effects on sexual dysfunction has not been obtained. We assessed the usefulness of adjunctive aripiprazole for schizophrenia with sexual dysfunction.
Methods 22 Japanese schizophrenia patients with antipsychotic-induced hyperprolactinemia and sexual dysfunction were enrolled, and 19 of them completed the study. Aripiprazole was administrated in a flexible titration schedule to participants according to the judgment of each doctor, and patients were followed for 24 weeks. Serum prolactin, Clinical Global Impression Scales-Severity (CGI-S), and Nagoya Sexual Function Questionnaire (NSFQ) were measured at baseline and at 4, 8, 12, and 24 weeks.
Results Prolactin at week 4 and later was significantly lower than that at baseline. Compared to baseline, we observed a significant improvement in total sexual dysfunction as measured by NSFQ at week 8 and later. In males, erectile dysfunction was significantly reduced at week 24. In females, menstrual irregularity and galactorrhea were significantly reduced at week 24. CGI-S did not significantly change.
Discussion Although the small sample size is a limitation in this study, adjunctive aripiprazole may be useful treatment for sexual dysfunction including hyperprolactinemia in schizophrenia.

DOI： 10.1055/s-0042-116323

Other Link： http://orcid.org/0000-0002-2539-1031

High-resolution copy number variation analysis of schizophrenia in Japan

I. Kushima, B. Aleksic, M. Nakatochi, T. Shimamura, T. Shiino, A. Yoshimi, H. Kimura, Y. Takasaki, C. Wang, J. Xing, K. Ishizuka, T. Oya-Ito, Y. Nakamura, Y. Arioka, T. Maeda, M. Yamamoto, M. Yoshida, H. Noma, S. Hamada, M. Morikawa, Y. Uno, T. Okada, T. Iidaka, S. Iritani, T. Yamamoto, M. Miyashita, A. Kobori, M. Arai, M. Itokawa, M-C Cheng, Y-A Chuang, C-H Chen, M. Suzuki, T. Takahashi, R. Hashimoto, H. Yamamori, Y. Yasuda, Y. Watanabe, A. Nunokawa, T. Someya, M. Ikeda, T. Toyota, T. Yoshikawa, S. Numata, T. Ohmori, S. Kunimoto, D. Mori, N. Iwata, N. Ozaki

MOLECULAR PSYCHIATRY Vol. 22 ( 3 ) page： 430 - 440 2017.3

Language：English Publisher：NATURE PUBLISHING GROUP

Recent schizophrenia (SCZ) studies have reported an increased burden of de novo copy number variants (CNVs) and identified specific high-risk CNVs, although with variable phenotype expressivity. However, the pathogenesis of SCZ has not been fully elucidated. Using array comparative genomic hybridization, we performed a high-resolution genome-wide CNV analysis on a mainly (92%) Japanese population (1699 SCZ cases and 824 controls) and identified 7066 rare CNVs, 70.0% of which were small (< 100 kb). Clinically significant CNVs were significantly more frequent in cases than in controls (odds ratio = 3.04, P = 9.3 x 10 (-9), 9.0% of cases). We confirmed a significant association of X-chromosome aneuploidies with SCZ and identified 11 de novo CNVs (e. g., MBD5 deletion) in cases. In patients with clinically significant CNVs, 41.7% had a history of congenital/developmental phenotypes, and the rate of treatment resistance was significantly higher (odds ratio = 2.79, P = 0.0036). We found more severe clinical manifestations in patients with two clinically significant CNVs. Gene set analysis replicated previous findings (e. g., synapse, calcium signaling) and identified novel biological pathways including oxidative stress response, genomic integrity, kinase and small GTPase signaling. Furthermore, involvement of multiple SCZ candidate genes and biological pathways in the pathogenesis of SCZ was suggested in established SCZ-associated CNV loci. Our study shows the high genetic heterogeneity of SCZ and its clinical features and raises the possibility that genomic instability is involved in its pathogenesis, which may be related to the increased burden of de novo CNVs and variable expressivity of CNVs.

DOI： 10.1038/mp.2016.88

Serbian Language version of the Modified Checklist for Autism in Toddlers, Revised, with Follow-Up: Cross-Cultural Adaptation and Assessment of Reliability Reviewed International journal

Mia Carakovac, Jelena Jovanovic, Marko Kalanj, Nenad Rudic, Olivera Aleksic-Hil, Branko Aleksic, Itzel Bustos Villalobos, Hideki Kasuya, Norio Ozaki, Dusica Lecic-Tosevski, Milica Pejovic-Milovancevic

SCIENTIFIC REPORTS Vol. 6 page： 38222 2016.12

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

Early detection of Autism Spectrum Disorder (ASD) has proven to be of high significance, however there is a limited availability of ASD screening tools in Serbian language. In this study we aim to translate, assess reliability and, in part, test the applicability of Modified Checklist for Autism in Toddlers, Revised, with Follow-Up (M-CHAT R/F) in Serbian Healthcare environment. We screened 128 children in three primary healthcare centres and 20 children in a tertiary psychiatric center, using M-CHAT R/F translated into Serbian language, between December 2014 and October 2015. At the end of the screening process 80% of participants in the risk group screened positive for ASD, while in the control group 4 (3.1%) participants screened positive, with a mean total scores of 8.25 and 0.66 respectively. The Cronbach's a coefficient was 0.91 and Guttman's.6 was 0.93. Test-retest reliability was deemed as acceptable, and no significant correlation was found between M-CHAT-R/F scores and Epworth Sleepiness Scale for children scores. The Serbian version of the M-CHAT-R/F has shown satisfactory reliability. We can therefore assert that it is a reliable tool for identifying ASD and it can be used in clinical practice to improve early detection, assessment and treatment.

DOI： 10.1038/srep38222

Identification of a rare variant in CHD8 that contributes to schizophrenia and autism spectrum disorder susceptibility Reviewed

Hiroki Kimura, Chenyao Wang, Kanako Ishizuka, Jingrui Xing, Yuto Takasaki, Itaru Kushima, Branko Aleksic, Yota Uno, Takashi Okada, Masashi Ikeda, Daisuke Mori, Toshiya Inada, Nakao Iwata, Norio Ozaki

SCHIZOPHRENIA RESEARCH Vol. 178 ( 1-3 ) page： 104 - 106 2016.12

Investigation of single-nucleotide variants in MBD5 associated with autism spectrum disorders and schizophrenia phenotypes. Reviewed

Kanako Ishizuka, Hiroki Kimura, Akira Yoshimi, Masahiro Banno, Itaru Kushima, Yota Uno, Takashi Okada, Daisuke Mori, Branko Aleksic, Norio Ozaki

Nagoya journal of medical science Vol. 78 ( 4 ) page： 465 - 474 2016.11

Language：English Publishing type：Research paper (scientific journal) Publisher：NAGOYA UNIV, SCH MED

MBD5 (Methyl-CpG-binding domain 5) is a critical gene for normal development. While deletion or duplication of MBD5 may contribute to a genetic predisposition to autism spectrum disorders (ASD), intellectual disability, or epilepsy, the impact of rare MBD5 single nucleotide variants (SNVs) on neurodevelopmental features, particularly features with late onset, has not been fully explored. In this study, we conducted exon-targeted resequencing of MBD5 with next-generation sequencing technology in 562 Japanese patients (192 with idiopathic ASD and 370 with schizophrenia (SCZ)) and detected 16 MBD5 SNVs with allele frequencies of ≤1%. We then performed phenotype analyses with 12 novel variants of these 16 SNVs. SCZ patients with these variants exhibited mainly within normal development ranges until the first psychosis and ASD patients with SNVs did not precisely overlap with the core characteristics described in previous literature as being associated with MBD5 SNVs. Our results suggested that MBD5 variants might contribute to a broad spectrum of neurodevelopmental pathophysiology. Further research and assessment of clinical diagnostic screening are necessary for understanding the burden of rare MBD5 SNVs for these neurodevelopmental disorders.

DOI： 10.18999/nagjms.78.4.465

Mutation screening of GRIN2B in schizophrenia and autism spectrum disorder in a Japanese population. Reviewed International journal

Yuto Takasaki, Takayoshi Koide, Chenyao Wang, Hiroki Kimura, Jingrui Xing, Itaru Kushima, Kanako Ishizuka, Daisuke Mori, Mariko Sekiguchi, Masashi Ikeda, Miki Aizawa, Naoko Tsurumaru, Yoshimi Iwayama, Akira Yoshimi, Yuko Arioka, Mami Yoshida, Hiromi Noma, Tomoko Oya-Ito, Yukako Nakamura, Shohko Kunimoto, Branko Aleksic, Yota Uno, Takashi Okada, Hiroshi Ujike, Jun Egawa, Hitoshi Kuwabara, Toshiyuki Someya, Takeo Yoshikawa, Nakao Iwata, Norio Ozaki

Scientific reports Vol. 6 page： 33311 - 33311 2016.9

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

N-methyl-d-aspartate receptors (NMDARs) play a critical role in excitatory synaptic transmission and plasticity in the central nervous systems. Recent genetics studies in schizophrenia (SCZ) show that SCZ is susceptible to NMDARs and the NMDAR signaling complex. In autism spectrum disorder (ASD), several studies report dysregulation of NMDARs as a risk factor for ASD. To further examine the association between NMDARs and SCZ/ASD development, we conducted a mutation screening study of GRIN2B which encodes NR2B subunit of NMDARs, to identify rare mutations that potentially cause diseases, in SCZ and ASD patients (n = 574 and 152, respectively). This was followed by an association study in a large sample set of SCZ, ASD, and normal healthy controls (n = 4145, 381, and 4432, respectively). We identified five rare missense mutations through the mutation screening of GRIN2B. Although no statistically significant association between any single mutation and SCZ or ASD was found, one of its variant, K1292R, is found only in the patient group. To further examine the association between mutations in GRIN2B and SCZ/ASD development, a larger sample size and functional experiments are needed.

DOI： 10.1038/srep33311

Current viewpoints on DSM-5 in Japan

Toshihide Kuroki, Makoto Ishitobi, Yoko Kamio, Genichi Sugihara, Toshiya Murai, Keisuke Motomura, Kazuyoshi Ogasawara, Hiroyuki Kimura, Branko Aleksic, Norio Ozaki, Tomohiro Nakao, Kazuo Yamada, Kazuhiro Yoshiuchi, Nobuo Kiriike, Toshio Ishikawa, Chiharu Kubo, Chiaki Matsunaga, Hisatsugu Miyata, Takashi Asada, Shigenobu Kanba

PSYCHIATRY AND CLINICAL NEUROSCIENCES Vol. 70 ( 9 ) page： 371 - 393 2016.9

Language：English Publishing type：Research paper (bulletin of university, research institution) Publisher：WILEY

The fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) was published in 2013, and its official Japanese version was published in 2014. The Japanese Government uses classifications from the 10th revision of the InternationalClassification ofDiseases (ICD-10) to categorize disorders and determine treatment fees. However, since the publication of the DSM-III, the use of the DSM system has become prevalent in research and educational settings in Japan. In addition to traditional psychiatry, both the ICD and the DSM are taught by many Japanese medical schools, and virtually all clinical research and trials refer to the DSM to define targeted disorders. Amid the current backdrop in which the reputation of the DSM-5 is being established, the editorial board of Psychiatry andClinicalNeurosciences has asked Japanese experts across 12 specialties to examine the structure of the DSM-5, including the following categories: Neurodevelopmental Disorders, Schizophrenia Spectrum Disorders, Major Depression, Bipolar Disorders, Obsessive-Compulsive Disorders, Somatic Symptom Disorder, Eating Disorders, Substance-Related and Addictive Disorders, Gender Dysphoria, and Neurocognitive Disorders. Although opinions were only obtained from these selected experts, we believe that we have succeeded, to a certain extent, in presenting views that are representative of each specialty.

DOI： 10.1111/pcn.12421

Validation and factor analysis of mother-infant bonding questionnaire in pregnant and postpartum women in Japan Reviewed

Masako Ohara, Takashi Okada, Chika Kubota, Yukako Nakamura, Tomoko Shiino, Branko Aleksic, Mako Morikawa, Aya Yamauchi, Yota Uno, Satomi Murase, Setsuko Goto, Atsuko Kanai, Tomoko Masuda, Norio Ozaki

BMC PSYCHIATRY Vol. 16 ( 1 ) page： 212 2016.7

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

Background: The Mother-Infant Bonding Questionnaire (MIBQ) has been widely used to assess maternal emotional involvement with infants. Although the reliability and validity of the MIBQ in the postpartum period has been confirmed, it remains unclear whether the MIBQ is appropriate to assess maternal bonding in both pregnancy and the postpartum period over time. Our study were aimed to 1) examine the reliability and validity of the MIBQ for clinical use among pregnant and postpartum women; and 2) examine the factor structure of the items, create subscales, and confirm the stability of the MIBQ in the pregnancy and postpartum periods.
Methods: Participants (n = 751, mean age 32.1 +/- 4.4 years) completed the MIBQ and the Edinburgh Postnatal Depression Scale (EPDS) in early pregnancy (before week 25), in late pregnancy (around week 36), 5 days after delivery, and 1 month after delivery. We randomly divided participants into two sample sets. We conducted an exploratory factor analysis of the nine MIBQ items using data from one group of mothers (Group 1; n = 376) in all four periods. The factor structure derived from the exploratory factor analysis was confirmed by a confirmatory factor analysis in the second group (Group 2; n = 375) of mothers in all four periods.
Results: Exploratory factor analysis yielded two factors: Lack of Affection (LA) and Anger and Rejection (AR). Confirmatory factor analysis demonstrated that LA and AR factors existed for the MIBQ in all periods. Cronbach's alpha coefficients were 0.879 and 0.584, respectively. The scores for LA and AR were significantly correlated over the four time periods. Mothers with higher AR scores on the MIBQ at any of the four periods had higher scores on the EPDS.
Conclusions: The MIBQ has two subscales regardless of the timing of the assessment. The MIBQ is appropriate for pregnant as well as postpartum women to assess maternal bonding toward the fetus and infant.

DOI： 10.1186/s12888-016-0933-3

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