Faculty Profiles - ALEKSIC Branko

Papers - ALEKSIC Branko

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22q11.2重複を有する神経発達症症例の1考察

石塚佳奈子, 久島周, アレクシッチ・ブランコ, 尾崎紀夫

日本神経精神薬理学会年会プログラム・抄録集 Vol. 46回 page： 164 - 164 2016.7

Resequencing and Association Analysis of Six PSD-95-Related Genes as Possible Susceptibility Genes for Schizophrenia and Autism Spectrum Disorders. Reviewed International journal

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

Scientific reports Vol. 6 page： 27491 - 27491 2016.6

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

PSD-95 associated PSD proteins play a critical role in regulating the density and activity of glutamate receptors. Numerous previous studies have shown an association between the genes that encode these proteins and schizophrenia (SZ) and autism spectrum disorders (ASD), which share a substantial portion of genetic risks. We sequenced the protein-encoding regions of DLG1, DLG2, DLG4, DLGAP1, DLGAP2, and SynGAP in 562 cases (370 SZ and 192 ASD patients) on the Ion PGM platform. We detected 26 rare (minor allele frequency <1%), non-synonymous mutations, and conducted silico functional analysis and pedigree analysis when possible. Three variants, G344R in DLG1, G241S in DLG4, and R604C in DLGAP2, were selected for association analysis in an independent sample set of 1315 SZ patients, 382 ASD patients, and 1793 healthy controls. Neither DLG4-G241S nor DLGAP2-R604C was detected in any samples in case or control sets, whereas one additional SZ patient was found that carried DLG1-G344R. Our results suggest that rare missense mutations in the candidate PSD genes may increase susceptibility to SZ and/or ASD. These findings may strengthen the theory that rare, non-synonymous variants confer substantial genetic risks for these disorders.

DOI： 10.1038/srep27491

Behavioral and neurochemical abnormalities in heterozygous Reelin Orleans mutant mouse model of schizophrenia Reviewed International journal

Kiyofumi Yamada, Akira Sobue, Yuki Aoyama, Shan Wei, Taku Nagai, Branko Aleksic, Itaru Kushima, Norio Ozaki

INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY Vol. 19 page： 185 - 185 2016.6

Parental Origin of Interstitial Duplications at 15q11.2-q13.3 in Schizophrenia and Neurodevelopmental Disorders Reviewed

Anthony R. Isles, Andres Ingason, Chelsea Lowther, James Walters, Micha Gawlick, Gerald Stoeber, Elliott Rees, Joanna Martin, Rosie B. Little, Harry Potter, Lyudmila Georgieva, Lucilla Pizzo, Norio Ozaki, Branko Aleksic, Itaru Kushima, Masashi Ikeda, Nakao Iwata, Douglas F. Levinson, Pablo V. Gejman, Jianxin Shi, Alan R. Sanders, Jubao Duan, Joseph Willis, Sanjay Sisodiya, Gregory Costain, Thomas M. Werge, Franziska Degenhardt, Ina Giegling, Dan Rujescu, Stefan J. Hreidarsson, Evald Saemundsen, Joo Wook Ahn, Caroline Ogilvie, Santhosh D. Girirajan, Hreinn Stefansson, Kari Stefansson, Michael C. O'Donovan, Michael J. Owen, Anne Bassett, George Kirov

PLOS GENETICS Vol. 12 ( 5 ) page： e1005993 2016.5

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

Duplications at 15q11.2-q13.3 overlapping the Prader-Willi/Angelman syndrome (PWS/AS) region have been associated with developmental delay (DD), autism spectrum disorder (ASD) and schizophrenia (SZ). Due to presence of imprinted genes within the region, the parental origin of these duplications may be key to the pathogenicity. Duplications of maternal origin are associated with disease, whereas the pathogenicity of paternal ones is unclear. To clarify the role of maternal and paternal duplications, we conducted the largest and most detailed study to date of parental origin of 15q11.2-q13.3 interstitial duplications in DD, ASD and SZ cohorts. We show, for the first time, that paternal duplications lead to an increased risk of developing DD/ASD/multiple congenital anomalies (MCA), but do not appear to increase risk for SZ. The importance of the epigenetic status of 15q11.2-q13.3 duplications was further underlined by analysis of a number of families, in which the duplication was paternally derived in the mother, who was unaffected, whereas her offspring, who inherited a maternally derived duplication, suffered from psychotic illness. Interestingly, the most consistent clinical characteristics of SZ patients with 15q11.2-q13.3 duplications were learning or developmental problems, found in 76% of carriers. Despite their lower pathogenicity, paternal duplications are less frequent in the general population with a general population prevalence of 0.0033% compared to 0.0069% for maternal duplications. This may be due to lower fecundity of male carriers and differential survival of embryos, something echoed in the findings that both types of duplications are de novo in just over 50% of cases. Isodicentric chromosome 15 (idic15) or interstitial triplications were not observed in SZ patients or in controls. Overall, this study refines the distinct roles of maternal and paternal interstitial duplications at 15q11.2-q13.3, underlining the critical importance of maternally expressed imprinted genes in the contribution of Copy Number Variants (CNVs) at this interval to the incidence of psychotic illness. This work will have tangible benefits for patients with 15q11.2-q13.3 duplications by aiding genetic counseling.

DOI： 10.1371/journal.pgen.1005993

PM338. Investigation of the association of rare single nucleotide variants in methyl-CpG-binding domain protein 5 (MBD5) with phenotypes of autism spectrum disorders and schizophrenia. Reviewed International journal

Ishizuka K, Aleksic B, Chenyao W, Kimura H, Kushima I, Okada T, Ozaki N, Uno Y

The international journal of neuropsychopharmacology Vol. 19 ( Suppl_1 ) page： 23 - 24 2016.5

Investigation of Rare Single-Nucleotide PCDH15 Variants in Schizophrenia and Autism Spectrum Disorders Reviewed

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

PLOS ONE Vol. 11 ( 4 ) page： e0153224 2016.4

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

Both schizophrenia (SCZ) and autism spectrum disorders (ASD) are neuropsychiatric disorders with overlapping genetic etiology. Protocadherin 15 (PCDH15), which encodes a member of the cadherin super family that contributes to neural development and function, has been cited as a risk gene for neuropsychiatric disorders. Recently, rare variants of large effect have been paid attention to understand the etiopathology of these complex disorders. Thus, we evaluated the impacts of rare, single-nucleotide variants (SNVs) in PCDH15 on SCZ or ASD. First, we conducted coding exon-targeted resequencing of PCDH15 with next-generation sequencing technology in 562 Japanese patients (370 SCZ and 192 ASD) and detected 16 heterozygous SNVs. We then performed association analyses on 2,096 cases (1,714 SCZ and 382 ASD) and 1,917 controls with six novel variants of these 16 SNVs. Of these six variants, four (p. R219K, p. T281A, p. D642N, c. 3010-1G> C) were ultra-rare variants (minor allele frequency < 0.0005) that may increase disease susceptibility. Finally, no statistically significant association between any of these rare, heterozygous PCDH15 point variants and SCZ or ASD was found. Our results suggest that a larger sample size of resequencing subjects is necessary to detect associations between rare PCDH15 variants and neuropsychiatric disorders.

DOI： 10.1371/journal.pone.0153224

Association of copy number polymorphisms at the promoter and translated region of COMT with Japanese patients with schizophrenia

Ryoko Higashiyama, Tohru Ohnuma, Yuto Takebayashi, Ryo Hanzawa, Nobuto Shibata, Hidenaga Yamamori, Yuka Yasuda, Itaru Kushima, Branko Aleksic, Kenji Kondo, Masashi Ikeda, Ryota Hashimoto, Nakao Iwata, Norio Ozaki, Heii Arai

AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS Vol. 171 ( 3 ) page： 447 - 457 2016.4

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

Chromosome 22q11.2 deletion syndrome and genetic variations including single-nucleotide polymorphism (SNP) and copy number variation (CNV) in catechol-O-methyltransferase (COMT) situated at 22q11.2 remains controversial. Here, the genetic relationship between COMT and Japanese patients with schizophrenia was investigated by examining whether the SNPs correlated with schizophrenia based on a common disease-common variant hypothesis. Additionally, 22q11.2DS were screened based on a common disease-rare variant hypothesis; low-frequency CNVs situated at two COMT promoters and exons were investigated based on the low-frequency variants with an intermediate effect; and positive findings from the first stage were reconfirmed using a second-stage replication study including a larger sample size. Eight SNPs and 10 CNVs were investigated using Taqman SNP and CNV quantitative real-time polymerase chain reaction method. For the first-stage analysis, 513 unrelated Japanese patients with schizophrenia and 705 healthy controls were examined. For the second-stage replication study, positive findings from the first stage were further investigated using a larger sample size, namely 1,854 patients with schizophrenia and 2,137 controls. The first-stage analysis showed significant associations among schizophrenia, intronic SNP rs165774, CNV6 situated at promoter 1, CNV8 at exon 6, and CNV9 at exon 7. The second-stage study showed that intronic SNP rs165774 ((2)=8.327, P=0.0039), CNV6 ((2)=19.66, P=0.00005), and CNV8 ((2)=16.57, P=0.00025) were significantly associated with schizophrenia. Large and rare CNVs as well as low-frequency CNVs and relatively small CNVs, namely <30kb in COMT, may be genetic risk factors for schizophrenia. (c) 2016 Wiley Periodicals, Inc.

DOI： 10.1002/ajmg.b.32426

Association of Beck Depression Inventory score and Temperament and Character Inventory-125 in patients with eating disorders and severe malnutrition Reviewed

Satoshi Tanaka, Keizo Yoshida, Hiroto Katayama, Kunihiro Kohmura, Naoko Kawano, Miho Imaeda, Saki Kato, Masahiko Ando, Branko Aleksic, Kazuo Nishioka, Norio Ozaki

Journal of Eating Disorders Vol. 3 ( 1 ) page： 36 2015.11

Language：English Publishing type：Research paper (bulletin of university, research institution) Publisher：BioMed Central Ltd.

The authors investigated the association between personality and physical/mental status in malnourished patients with eating disorders. A total of 45 patients with anorexia nervosa, avoidant/restrictive food intake disorder, and other specified feeding or eating disorders were included and compared with 39 healthy controls. Personality characteristics and severity of depression were assessed using the Temperament and Character Inventory-125 and Beck's Depression Inventory. Depression correlated with harm avoidance and self-directedness in both cases and controls. Body mass index did not correlate with personality in either group. These findings should be verified by longitudinal studies with higher weight/weight recovered patients.

DOI： 10.1186/s40337-015-0077-8

Association study of BCL9 gene polymorphism rs583583 with schizophrenia and negative symptoms in Japanese population. Reviewed International journal

Hiroki Kimura, Satoshi Tanaka, Itaru Kushima, Takayoshi Koide, Masahiro Banno, Tsutomu Kikuchi, Yukako Nakamura, Tomoko Shiino, Akira Yoshimi, Tomoko Oya-Ito, Jingrui Xing, Chenyao Wang, Yuto Takasaki, Branko Aleksic, Takashi Okada, Masashi Ikeda, Toshiya Inada, Tetsuya Iidaka, Nakao Iwata, Norio Ozaki

Scientific reports Vol. 5 page： 15705 - 15705 2015.10

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

B-cell CLL/lymphoma 9 (BCL9) is located within the schizophrenia (SCZ) suspected locus chr1q21.1. A recent study reported that a single nucleotide polyphormism (SNP) within BCL9 (rs583583) is associated with negative symptoms of Schizophrenia, as measured by the Positive and Negative Syndrome Scale (PANSS), in the Caucasian population. We therefore investigated genetic association of rs583583, and its effect on negative symptoms in the Japanese patients. For association analysis, we used a Japanese sample set comprising 1089 SCZ and 950 controls (CON). Analysis of the effect of rs586586 on negative symptoms as examined by PANSS was investigated using 280 SCZ. Furthermore, for analysis of cognitive performance, we investigated 90 SCZ and 51 CON using the Continuous Performance Test (CPT-IP) and the Wisconsin Card Sorting Test (WCST) Keio version. We did not detect association between rs583583 and SCZ. Furthermore, rs583583 was not associated with PANSS negative scores or with CPT-IT or WCST cognitive tests. Considering the results of our previous study, combined with the results of the current study of rs583583, we argue that BCL9 most likely does not harbor a common genetic variant that can increase the risk for SCZ in the Japanese population.

DOI： 10.1038/srep15705

White matter microstructure between the pre-SMA and the cingulum bundle is related to response conflict in healthy subjects

Maeri Yamamoto, Itaru Kushima, Hiroki Kimura, Akiko Hayashi, Naoko Kawano, Branko Aleksic, Tetsuya Iidaka, Norio Ozaki

BRAIN AND BEHAVIOR Vol. 5 ( 10 ) page： e00375 2015.10

Language：English Publishing type：Research paper (scientific journal) Publisher：JOHN WILEY & SONS INC

Introduction: Response conflict involves selectively attending to relevant information and suppressing distracting, irrelevant information. The medial frontal cortex (MFC) is considered to be involved in response conflict. However, it remains unclear which white matter connectivity is associated with response conflict. This study aimed to delineate the neural connectivity of response conflict in healthy subjects and investigate the association between white matter microstructure and performance of a response conflict task. Method: Twenty-eight healthy subjects underwent functional magnetic resonance imaging (fMRI) during the Flanker task and diffusion MRI. We identified the presupplementary motor area (pre-SMA) using fMRI. Furthermore, we delineated the white matter connectivity between the pre-SMA and the cingulum bundle (CB), which is located in the MFC, using probabilistic tractography. We calculated the mean diffusivity (MD), index of white matter microstructure, of this tract and evaluate the association between MD and performance of the Flanker task. Result: The mean MD of this tract was significantly and positively associated with performance of the Flanker task. Conclusion: The present study suggests the white matter connectivity between the pre-SMA and the CB is related to the response conflict in healthy subjects and finer white matter microstructure is associated with smaller response conflict.

DOI： 10.1002/brb3.375

Glia-related genes and their contribution to schizophrenia

Chenyao Wang, Branko Aleksic, Norio Ozaki

PSYCHIATRY AND CLINICAL NEUROSCIENCES Vol. 69 ( 8 ) page： 448 - 461 2015.8

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

Schizophrenia, a debilitating disease with 1% prevalence in the general population, is characterized by major neuropsychiatric symptoms, including delusions, hallucinations, and deficits in emotional and social behavior. Previous studies have directed their investigations on the mechanism of schizophrenia towards neuronal dysfunction and have defined schizophrenia as a neuron-centric' disorder. However, along with the development of genetics and systematic biology approaches in recent years, the crucial role of glial cells in the brain has also been shown to contribute to the etiopathology of schizophrenia. Here, we summarize comprehensive data that support the involvement of glial cells (including oligodendrocytes, astrocytes, and microglial cells) in schizophrenia and list several acknowledged glia-related genes or molecules associated with schizophrenia. Instead of purely an abnormality of neurons in schizophrenia, an additional glial perspective' provides us a novel and promising insight into the causal mechanisms and treatment for this disease.

DOI： 10.1111/pcn.12290

The effects of acute treatment with ramelteon, triazolam, and placebo on driving performance, cognitive function, and equilibrium function in healthy volunteers Reviewed

Akemi Miyata, Kunihiro Iwamoto, Naoko Kawano, Kunihiro Kohmura, Maeri Yamamoto, Branko Aleksic, Kazutoshi Ebe, Akiko Noda, Yukihiro Noda, Shuji Iritani, Norio Ozaki

PSYCHOPHARMACOLOGY Vol. 232 ( 12 ) page： 2127 - 2137 2015.6

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

Hypnotics are widely used to treat insomnia but adverse effects of different hypnotics, especially benzodiazepine receptor agonists, are getting more attention lately. The effects of novel hypnotics have not been fully examined.
This study aims to assess the effects of two hypnotics, ramelteon and triazolam, on driving performance, cognitive function, and equilibrium function.
In this double-blinded, three-way crossover trial, 17 healthy males received acute doses of 8 mg ramelteon, 0.125 mg triazolam, and placebo. The subjects were administered three driving tasks-road-tracking, car-following, and harsh-braking-using a driving simulator and three cognitive tasks-Continuous Performance Test, N-back Test, and Trail-Making Test-at baseline and at 1 and 4 h post-dosing. The Stanford Sleepiness Scale scores and computerized posturography were also assessed.
In the driving simulations, ramelteon and triazolam increased the number of subjects who slid off the road. Triazolam increased the standard deviation of lateral position compared to ramelteon and placebo at 1 h post-dosing. Ramelteon and triazolam significantly increased the time to complete of Trail-Making Test part A and the environmental area in posturography compared to placebo at 1 and 4 h post-dosing. Ramelteon and triazolam significantly increased subjective sleepiness compared to placebo at 1 h post-dosing.
Ramelteon may affect road-tracking performance, visual attention and/or psychomotor speed measured by Trail-Making Test part A, and body balance in acute dosing. Lower dose of triazolam also impaired performance worse than ramelteon. Physicians should consider risks and benefits when prescribing both drugs, especially in the initial period of administration.

DOI： 10.1007/s00213-014-3843-4

Relationship between social support during pregnancy and postpartum depressive state: a prospective cohort study Reviewed

Mako Morikawa, Takashi Okada, Masahiko Ando, Branko Aleksic, Shohko Kunimoto, Yukako Nakamura, Chika Kubota, Yota Uno, Ai Tamaji, Norika Hayakawa, Kaori Furumura, Tomoko Shiino, Tokiko Morita, Naoko Ishikawa, Harue Ohoka, Hinako Usui, Naomi Banno, Satomi Murase, Setsuko Goto, Atsuko Kanai, Tomoko Masuda, Norio Ozaki

SCIENTIFIC REPORTS Vol. 5 page： 10520 2015.5

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

Although the association between social support and postpartum depression has been previously investigated, its causal relationship remains unclear. Therefore, we examined prospectively whether social support during pregnancy affected postpartum depression. Social support and depressive symptoms were assessed by Japanese version of Social Support Questionnaire (J-SSQ) and Edinburgh Postnatal Depression Scale (EPDS), among 877 pregnant women in early pregnancy and at one month postpartum. First, J-SSQ was standardized among peripartum women. The J-SSQ was found to have a two-factor structure, with Number and Satisfaction subscales, by exploratory and confirmatory factor analyses. Analysis of covariance was performed to examine how EPDS and J-SSQ scores during pregnancy affected the EPDS score at postpartum. Significant associations were found between postpartum EPDS score and both EPDS and total scores on the Number subscales during pregnancy (beta = 0.488 and -0.054, ps < 0.001). Specifically, this negative correlation was stronger in depressive than non-depressive groups. Meanwhile, total score on Satisfaction subscales was not significantly associated with postpartum EPDS score. These results suggest that having a larger number of supportive persons during pregnancy helps protect against postpartum depression, and that this effect is greater in depressive than non-depressive pregnant women. This finding is expected to be vitally important in preventive interventions.

DOI： 10.1038/srep10520

Early exposure to the combined measles-mumps-rubella vaccine and thimerosal-containing vaccines and risk of autism spectrum disorder Reviewed

Yota Uno, Tokio Uchiyama, Michiko Kurosawa, Branko Aleksic, Norio Ozaki

VACCINE Vol. 33 ( 21 ) page： 2511 - 2516 2015.5

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER SCI LTD

Objective: This case-control study investigated the relationship between the risk of Autism Spectrum Disorder (ASD) onset, and early exposure to the combined Measles-Mumps-Rubella (MMR) vaccine and thimerosal consumption measured from vaccinations in the highly genetically homogenous Japanese population.
Methods: Vaccination histories at 1, 3, 6, 12, 18, 24, and 36 months from birth were investigated in ASD cases (189 samples), and controls (224 samples) matching age and sex in each case. Crude odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated to determine relationship between MMR vaccination and ASD. The differences in mean values of the thimerosal dosage between cases and controls were analyzed using an unpaired t-test. MMR vaccination and thimerosal dosage were also investigated using a conditional multiple-regression model.
Results: There were no significant differences in MMR vaccination and thimerosal dosage between cases and controls at any age. Furthermore, the ORs (95% CIs) of MMR vaccination and thimerosal dosage associated with ASD in the conditional multiple regression model were, respectively, 0.875(0.345-2.222) and 1.205(0.862-1.683) at age 18 months, 0.724(0.421-1.243) and 1.343(0.997-1.808) at 24 months, and 1.040(0.648-1.668) and 0.844(0.632-1.128) at 36 months. Thus, there were no significant differences.
Conclusions: No convincing evidence was found in this study that MMR vaccination and increasing thimerosal dose were associated with an increased risk of ASD onset. (C) 2014 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.vaccine.2014.12.036

Temperament and character profiles of patients with burning mouth syndrome Reviewed

Tatsuya Tokura, Hiroyuki Kimura, Mikiko Ito, Wataru Nagashima, Naohiro Sato, Yuki Kimura, Munetaka Arao, Branko Aleksic, Keizo Yoshida, Kenichi Kurita, Norio Ozaki

JOURNAL OF PSYCHOSOMATIC RESEARCH Vol. 78 ( 5 ) page： 495 - 498 2015.5

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

Objective: Burning mouth syndrome (BMS) is a chronic disease in which patients feel a burning sensation and pain in the oral cavity. Although personality traits have been suggested to influence the development and course of BMS, they have not yet been examined in detail. We therefore investigated the personality traits of BMS patients.
Methods: Sample consisted of 65 BMS patients presenting to the Aichi-Gakuin Dental School Hospital between May 2005 and April 2009. They were also diagnosed as having pain disorder by a psychiatrist. The control group consisted of 116 healthy subjects. The Temperament and Character Inventory (TCI) was used to evaluate personality traits, while the Beck Depression Inventory (BDI) was used to evaluate the depression rate in both groups.
Results: In TCI, we found that, in comparison to the control group, the novelty seeking score was significantly lower (p = 0.009), the harm avoidance score was significantly higher (p < 0.001), and the self-directedness score was significantly lower (p = 0.039) in the BMS group. To remove the influence of depression, we performed an analysis of covariance of each TCI item using the BDI score as a covariate. No significant differences were observed in harm avoidance or self-directedness, whereas the differences noted in novelty seeking were significant (p = 0.008).
Conclusion: The novelty seeking score was low in BMS patients in comparison to the control group. They also had high harm avoidance and low self-directedness tendencies, but these were attributed to the influence of depression. (C) 2015 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.jpsychores.2015.02.006

Identification of Rare, Single-Nucleotide Mutations in NDE1 and Their Contributions to Schizophrenia Susceptibility. Reviewed International journal

Hiroki Kimura, Daisuke Tsuboi, Chenyao Wang, Itaru Kushima, Takayoshi Koide, Masashi Ikeda, Yoshimi Iwayama, Tomoko Toyota, Noriko Yamamoto, Shohko Kunimoto, Yukako Nakamura, Akira Yoshimi, Masahiro Banno, Jingrui Xing, Yuto Takasaki, Mami Yoshida, Branko Aleksic, Yota Uno, Takashi Okada, Tetsuya Iidaka, Toshiya Inada, Michio Suzuki, Hiroshi Ujike, Hiroshi Kunugi, Tadafumi Kato, Takeo Yoshikawa, Nakao Iwata, Kozo Kaibuchi, Norio Ozaki

Schizophrenia bulletin Vol. 41 ( 3 ) page： 744 - 753 2015.5

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

BACKGROUND: Nuclear distribution E homolog 1 (NDE1), located within chromosome 16p13.11, plays an essential role in microtubule organization, mitosis, and neuronal migration and has been suggested by several studies of rare copy number variants to be a promising schizophrenia (SCZ) candidate gene. Recently, increasing attention has been paid to rare single-nucleotide variants (SNVs) discovered by deep sequencing of candidate genes, because such SNVs may have large effect sizes and their functional analysis may clarify etiopathology. METHODS AND RESULTS: We conducted mutation screening of NDE1 coding exons using 433 SCZ and 145 pervasive developmental disorders samples in order to identify rare single nucleotide variants with a minor allele frequency ≤5%. We then performed genetic association analysis using a large number of unrelated individuals (3554 SCZ, 1041 bipolar disorder [BD], and 4746 controls). Among the discovered novel rare variants, we detected significant associations between SCZ and S214F (P = .039), and between BD and R234C (P = .032). Furthermore, functional assays showed that S214F affected axonal outgrowth and the interaction between NDE1 and YWHAE (14-3-3 epsilon; a neurodevelopmental regulator). CONCLUSIONS: This study strengthens the evidence for association between rare variants within NDE1 and SCZ, and may shed light into the molecular mechanisms underlying this severe psychiatric disorder.

DOI： 10.1093/schbul/sbu147

【自閉症の生物学】自閉スペクトラム症の遺伝学研究の最近の進歩 Reviewed International journal

木村大樹, Aleksic Branko, 尾崎紀夫

細胞工学 Vol. 34 ( 5 ) page： 453 - 457 2015.4

The Disrupted-in-Schizophrenia-1 Ser704Cys polymorphism and brain neurodevelopmental markers in schizophrenia and healthy subjects Reviewed

Tsutomu Takahashi, Mihoko Nakamura, Yukako Nakamura, Branko Aleksic, Mikio Kido, Daiki Sasabayashi, Yoichiro Takayanagi, Atsushi Furuichi, Yumiko Nishikawa, Kyo Noguchi, Norio Ozaki, Michio Suzuki

PROGRESS IN NEURO-PSYCHOPHARMACOLOGY & BIOLOGICAL PSYCHIATRY Vol. 56 page： 11 - 17 2015.1

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

Increasing evidence has implicated the role of Disrupted-in-Schizophrenia-1 (DISC1), a potential susceptibility gene for schizophrenia, in early neurodevelopmental processes. However, the effect of its genotype variation on brain morphologic changes related to neurodevelopmental abnormalities in schizophrenia remains largely unknown. This magnetic resonance imaging study examined the association between DISC1 Ser704Cys polymorphism and a range of brain neurodevelopmental markers [cavum septi pellucidi (CSP), adhesio interthalamica (AI), olfactory sulcus depth, and sulcogyral pattern (Types I, II, III, and IV) in the orbitofrontal cortex (OFC)] in an all Japanese sample of 75 schizophrenia patients and 87 healthy controls. The Cys carriers had significantly larger CSP than the Ser homozygotes for both schizophrenia patients and healthy controls. The Cys carriers also exhibited a reduction in the Type I pattern of the right OFC in the healthy controls, but not in the schizophrenia patients. The DISC1 Ser704Cys polymorphism did not affect the AI and olfactory sulcus depth in either group. These results suggested a possible role of the DISC1 genotype in the early neurodevelopment of human brains, but failed to show its specific role in the neurodevelopmental pathology of schizophrenia. (C) 2014 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.pnpbp.2014.07.005

Resequencing and association analysis of PTPRA, a possible susceptibility gene for schizophrenia and autism spectrum disorders. Reviewed International journal

Jingrui Xing, Chenyao Wang, Hiroki Kimura, Yuto Takasaki, Shohko Kunimoto, Akira Yoshimi, Yukako Nakamura, Takayoshi Koide, Masahiro Banno, Itaru Kushima, Yota Uno, Takashi Okada, Branko Aleksic, Masashi Ikeda, Nakao Iwata, Norio Ozaki

PloS one Vol. 9 ( 11 ) page： e112531 2014.11

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

BACKGROUND: The PTPRA gene, which encodes the protein RPTP-α, is critical to neurodevelopment. Previous linkage studies, genome-wide association studies, controlled expression analyses and animal models support an association with both schizophrenia and autism spectrum disorders, both of which share a substantial portion of genetic risks. METHODS: We sequenced the protein-encoding areas of the PTPRA gene for single nucleotide polymorphisms or small insertions/deletions (InDel) in 382 schizophrenia patients. To validate their association with the disorders, rare (minor allele frequency <1%), missense mutations as well as one InDel in the 3'UTR region were then genotyped in another independent sample set comprising 944 schizophrenia patients, 336 autism spectrum disorders patients, and 912 healthy controls. RESULTS: Eight rare mutations, including 3 novel variants, were identified during the mutation-screening phase. In the following association analysis, L59P, one of the two missense mutations, was only observed among patients of schizophrenia. Additionally, a novel duplication in the 3'UTR region, 174620_174623dupTGAT, was predicted to be located within a Musashi Binding Element. MAJOR CONCLUSIONS: No evidence was seen for the association of rare, missense mutations in the PTPRA gene with schizophrenia or autism spectrum disorders; however, we did find some rare variants with possibly damaging effects that may increase the susceptibility of carriers to the disorders.

DOI： 10.1371/journal.pone.0112531

Synaptic, transcriptional and chromatin genes disrupted in autism Reviewed

Silvia De Rubeis, Xin He, Arthur P. Goldberg, Christopher S. Poultney, Kaitlin Samocha, A. Ercument Cicek, Yan Kou, Li Liu, Menachem Fromer, Susan Walker, Tarjinder Singh, Lambertus Klei, Jack Kosmicki, Shih-Chen Fu, Branko Aleksic, Monica Biscaldi, Patrick F. Bolton, Jessica M. Brownfeld, Jinlu Cai, Nicholas G. Campbell, Angel Carracedo, Maria H. Chahrour, Andreas G. Chiocchetti, Hilary Coon, Emily L. Crawford, Lucy Crooks, Sarah R. Curran, Geraldine Dawson, Eftichia Duketis, Bridget A. Fernandez, Louise Gallagher, Evan Geller, Stephen J. Guter, R. Sean Hill, Iuliana Ionita-Laza, Patricia Jimenez Gonzalez, Helena Kilpinen, Sabine M. Klauck, Alexander Kolevzon, Irene Lee, Jing Lei, Terho Lehtimaeki, Chiao-Feng Lin, Avi Ma'ayan, Christian R. Marshall, Alison L. McInnes, Benjamin Neale, Michael J. Owen, Norio Ozaki, Mara Parellada, Jeremy R. Parr, Shaun Purcell, Kaija Puura, Deepthi Rajagopalan, Karola Rehnstrom, Abraham Reichenberg, Aniko Sabo, Michael Sachse, Stephan J. Sanders, Chad Schafer, Martin Schulte-Ruether, David Skuse, Christine Stevens, Peter Szatmari, Kristiina Tammimies, Otto Valladares, Annette Voran, Li-San Wang, Lauren A. Weiss, A. Jeremy Willsey, Timothy W. Yu, Ryan K. C. Yuen, Edwin H. Cook, Christine M. Freitag, Michael Gill, Christina M. Hultman, Thomas Lehner, Aarno Palotie, Gerard D. Schellenberg, Pamela Skiar, Matthew W. State, James S. Sutcliffe, Christopher A. Walsh, Stephen W. Scherer, Michael E. Zwick, Jeffrey C. Barrett, David J. Cutler, Kathryn Roeder, Bernie Devlin, Mark J. Daly, Joseph D. Buxbaum

NATURE Vol. 515 ( 7526 ) page： 209 - + 2014.11

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

The genetic architecture of autism spectrum disorder involves the interplay of common and rare variants and their impact on hundreds of genes. Using exome sequencing, here we show that analysis of rare coding variation in 3,871 autism cases and 9,937 ancestry-matched or parental controls implicates 22 autosomal genes at a false discovery rate (FDR) < 0.05, plus a set of 107 autosomal genes strongly enriched for those likely to affect risk (FDR < 0.30). These 107 genes, which show unusual evolutionary constraint against mutations, incur de novo loss-of-function mutations in over 5% of autistic subjects. Many of the genes implicated encode proteins for synaptic formation, transcriptional regulation and chromatin-remodelling pathways. These include voltage-gated ion channels regulating the propagation of action potentials, pacemaking and excitability-transcription coupling, as well as histone-modifying enzymes and chromatin remodellers-most prominently those that mediate post-translational lysine methylation/demethylation modifications of histones.

DOI： 10.1038/nature13772

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