Faculty Profiles - ALEKSIC Branko

Papers - ALEKSIC Branko

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Clinical characterization of patients with schizophrenia and 16p13.11 duplication: A case series. International journal

Hiroki Kimura, Itaru Kushima, Masahiro Banno, Toshiya Inada, Akira Yoshimi, Branko Aleksic, Norio Ozaki

Neuropsychopharmacology reports Vol. 43 ( 2 ) page： 267 - 271 2023.6

Language：English

BACKGROUND: Chromosome 16p13.11 duplication is a well-known genetic risk factor for schizophrenia (SCZ) (odds ratio = 1.84). However, no case reports focusing on patients with SCZ and 16p13.11 duplication have been published. Therefore, here, we report the detailed clinical cases of four patients with SCZ and 16p13.11 duplication who were identified in our previous whole-genome copy number variant (CNV) study. CASE PRESENTATION: In the four patients with SCZ and 16p13.11 duplication detected by array comparative genomic hybridization, one patient was found to have treatment-resistant SCZ and an additional pathogenic rare CNV. Two of the four patients in this study had environmental risk factors that may have been involved in the development of SCZ. CONCLUSIONS: The results of this case series suggest that a genetic cohort study would be useful for evaluating which genetic and environmental risk factors could better explain the variable expressivity of 16p13.11 duplication. Furthermore, this work could be useful for elucidating the pathophysiology of SCZ.

DOI： 10.1002/npr2.12334

The genetic architecture of schizophrenia: review of large-scale genetic studies

Hidekazu Kato, Hiroki Kimura, Itaru Kushima, Nagahide Takahashi, Branko Aleksic, Norio Ozaki

Journal of Human Genetics Vol. 68 ( 3 ) page： 175 - 182 2023.3

Analysis of human neuronal cells carrying ASTN2 deletion: A cross-disorder risk variant of schizophrenia, autism spectrum disorder, and bipolar disorder

Yuko Arioka, Yu Hayashi, Hiroki Okumura, Itaru Kushima, Daisuke Mori, Tzuyao Lo, Gantsooj Otgonbayar, Hidekazu Kato, Yoshihiro Nawa, Hiroki Kimura, Branko Aleksic, Norio Ozaki

2023.2

Clinical manifestations of schizophrenia in four patients with variants in voltage-gated calcium channel-encoding genes: a case series. International journal

Tzuyao Lo, Itaru Kushima, Branko Aleksic, Akira Yoshimi, Toshiyuki Someya, Yuichiro Watanabe, Norio Ozaki

Psychiatry and clinical neurosciences Vol. 77 ( 1 ) page： 57 - 59 2023.1

X chromosome aneuploidies and schizophrenia: association analysis and phenotypic characterization

Itaru Kushima, Branko Aleksic, Hiroki Kimura, Masahiro Nakatochi, Tzuyao Lo, Masashi Ikeda, Makoto Arai, Ryota Hashimoto, Shusuke Numata, Yasunobu Okamura, Taku Obara, Toshiya Inada, Norio Ozaki

Psychiatry and Clinical Neurosciences Vol. 76 ( 12 ) page： 667 - 673 2022.12

Cross-disorder analysis of genic and regulatory copy number variations in bipolar disorder, schizophrenia, and autism spectrum disorder

Itaru Kushima, Masahiro Nakatochi, Branko Aleksic, Takashi Okada, Hiroki Kimura, Hidekazu Kato, Mako Morikawa, Toshiya Inada, Kanako Ishizuka, Youta Torii, Yukako Nakamura, Satoshi Tanaka, Miho Imaeda, Nagahide Takahashi, Maeri Yamamoto, Kunihiro Iwamoto, Yoshihiro Nawa, Nanayo Ogawa, Shuji Iritani, Yu Hayashi, Tzuyao Lo, Gantsooj Otgonbayar, Sho Furuta, Nakao Iwata, Masashi Ikeda, Takeo Saito, Kohei Ninomiya, Tomo Okochi, Ryota Hashimoto, Hidenaga Yamamori, Yuka Yasuda, Michiko Fujimoto, Kenichiro Miura, Masanari Itokawa, Makoto Arai, Mitsuhiro Miyashita, Kazuya Toriumi, Kazutaka Ohi, Toshiki Shioiri, Kiyoyuki Kitaichi, Toshiyuki Someya, Yuichiro Watanabe, Jun Egawa, Tsutomu Takahashi, Michio Suzuki, Tsukasa Sasaki, Mamoru Tochigi, Fumichika Nishimura, Hidenori Yamasue, Hitoshi Kuwabara, Tomoyasu Wakuda, Takahiro A. Kato, Shigenobu Kanba, Hideki Horikawa, Masahide Usami, Masaki Kodaira, Kyota Watanabe, Takeo Yoshikawa, Tomoko Toyota, Shigeru Yokoyama, Toshio Munesue, Ryo Kimura, Yasuko Funabiki, Hirotaka Kosaka, Minyoung Jung, Kiyoto Kasai, Tempei Ikegame, Seiichiro Jinde, Shusuke Numata, Makoto Kinoshita, Tadafumi Kato, Chihiro Kakiuchi, Kazuhiro Yamakawa, Toshimitsu Suzuki, Naoki Hashimoto, Shuhei Ishikawa, Bun Yamagata, Shintaro Nio, Toshiya Murai, Shuraku Son, Yasuto Kunii, Hirooki Yabe, Masumi Inagaki, Yu-ichi Goto, Yuto Okumura, Tomoya Ito, Yuko Arioka, Daisuke Mori, Norio Ozaki

Biological Psychiatry Vol. 92 ( 5 ) page： 362 - 374 2022.9

Contribution of copy number variations to the risk of severe eating disorders

Itaru Kushima, Miho Imaeda, Satoshi Tanaka, Hidekazu Kato, Tomoko Oya‐Ito, Masahiro Nakatochi, Branko Aleksic, Norio Ozaki

Psychiatry and Clinical Neurosciences Vol. 76 ( 9 ) page： 423 - 428 2022.9

Exome sequencing analysis of Japanese autism spectrum disorder case-control sample supports an increased burden of synaptic function-related genes

Hiroki Kimura, Masahiro Nakatochi, Branko Aleksic, James Guevara, Miho Toyama, Yu Hayashi, Hidekazu Kato, Itaru Kushima, Mako Morikawa, Kanako Ishizuka, Takashi Okada, Yoshinori Tsurusaki, Atsushi Fujita, Noriko Miyake, Tomoo Ogi, Atsushi Takata, Naomichi Matsumoto, Joseph Buxbaum, Norio Ozaki, Jonathan Sebat

Translational Psychiatry Vol. 12 ( 1 ) page： 265 2022.7

Language：English Publishing type：Research paper (scientific journal) Publisher：Springer Science and Business Media LLC

Abstract

Autism spectrum disorder (ASD) is a highly heritable, complex disorder in which rare variants contribute significantly to disease risk. Although many genes have been associated with ASD, there have been few genetic studies of ASD in the Japanese population. In whole exomes from a Japanese ASD sample of 309 cases and 299 controls, rare variants were associated with ASD within specific neurodevelopmental gene sets, including highly constrained genes, fragile X mental retardation protein target genes, and genes involved in synaptic function, with the strongest enrichment in trans-synaptic signaling (p = 4.4 × 10<sup>−4</sup>, Q-value = 0.06). In particular, we strengthen the evidence regarding the role of ABCA13, a synaptic function-related gene, in Japanese ASD. The overall results of this case-control exome study showed that rare variants related to synaptic function are associated with ASD susceptibility in the Japanese population.

DOI： 10.1038/s41398-022-02033-6

Other Link： https://www.nature.com/articles/s41398-022-02033-6

Treatment-resistant schizophrenia in patients with 3q29 deletion: A case series of four patients. International journal

Yoshihiro Nawa, Itaru Kushima, Branko Aleksic, Maeri Yamamoto, Hiroyuki Kimura, Masahiro Banno, Ryota Hashimoto, Norio Ozaki

Psychiatry and clinical neurosciences Vol. 76 ( 7 ) page： 338 - 339 2022.7

Psychiatric patients with a de novo 17q12 deletion: two case reports. International journal

Itaru Kushima, Mariko Uematsu, Kanako Ishizuka, Branko Aleksic, Norio Ozaki

Psychiatry and clinical neurosciences Vol. 76 ( 7 ) page： 345 - 347 2022.7

Exome sequencing of Japanese schizophrenia multiplex families supports the involvement of calcium ion channels

Miho Toyama, Yuto Takasaki, Aleksic Branko, Hiroki Kimura, Hidekazu Kato, Yoshihiro Nawa, Itaru Kushima, Kanako Ishizuka, Teppei Shimamura, Tomoo Ogi, Norio Ozaki

PLOS ONE Vol. 17 ( 5 ) page： e0268321 - e0268321 2022.5

Language：English Publishing type：Research paper (scientific journal) Publisher：Public Library of Science (PLoS)

Background

Most sequencing studies of schizophrenia (SCZ) have focused on de novo genetic variants due to interpretability. However, investigating shared rare variants among patients in the same multiplex family is also important. Relatively large-scale analyses of SCZ multiplex families have been done in Caucasian populations, but whether detected variants are also pathogenic in the Japanese population is unclear because of ethnic differences in rare variants.

Materials and methods

We performed whole-exome sequencing (WES) of 14 Japanese SCZ multiplex families. After quality control and filtering, we identified rare variants shared among affected persons within the same family. A gene ontology (GO) analysis was performed to identify gene categories possibly affected by these candidate variants.

Results

We found 530 variants in 486 genes as potential candidate variants from the 14 SCZ multiplex families examined. The GO analysis demonstrated significant enrichment in calcium channel activity.

Conclusion

This study provides supporting evidence that calcium ion channel activity is involved in SCZ. WES of multiplex families is a potential means of identifying disease-associated rare variants for SCZ.

DOI： 10.1371/journal.pone.0268321

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Investigation of OLIG2 as a candidate gene for schizophrenia and autism spectrum disorder.

Sho Furuta, Branko Aleksic, Yoshihiro Nawa, Hiroki Kimura, Itaru Kushima, Kanako Ishizuka, Hidekazu Kato, Miho Toyama, Yuko Arioka, Daisuke Mori, Mako Morikawa, Toshiya Inada, Norio Ozaki

Nagoya journal of medical science Vol. 84 ( 2 ) page： 260 - 268 2022.5

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

A number of genomic mutations that are thought to be strongly involved in the development of schizophrenia (SCZ) and autism spectrum disorder (ASD) have been identified. Abnormalities involving oligodendrocytes have been reported in SCZ, and as a related gene, oligodendrocyte lineage transcription factor 2 (OLIG2) has been reported to be strongly associated with SCZ. In this study, based on the common disease-rare variant hypothesis, target sequencing of candidate genes was performed to identify rare mutations with a high effect size and the possibility that the identified mutations may increase the risks of SCZ and ASD in the Japanese population. In this study, the exon region of OLIG2 was targeted; 370 patients with SCZ and 192 with ASD were subjected to next-generation sequencing. As a result, one rare missense mutation (A33T) was detected. We used the Sanger method to validate this missense mutation with a low frequency (<1%), and then carried out a genetic association analysis involving 3299 unrelated individuals (1447 with SCZ, 380 with ASD, and 1472 healthy controls) to clarify whether A33T was associated with SCZ or ASD. A33T was not found in either case group, and in only one control. We did not find evidence that p.A33T is involved in the onset of ASD or SCZ; however, associations with this variant need to be evaluated in larger samples to confirm our results.

DOI： 10.18999/nagjms.84.2.260

Case report of a female with bipolar disorder and <scp> <i>MBD5</i> </scp> deletion

Itaru Kushima, Tzuyao Lo, Branko Aleksic, Norio Ozaki

Psychiatry and Clinical Neurosciences Vol. 76 ( 4 ) page： 127 - 128 2022.4

Variable psychiatric manifestations in patients with 16p11.2 duplication: a case series of 4 patients

Yu Hayashi, Itaru Kushima, Branko Aleksic, Tetsu Senaha, Norio Ozaki

Psychiatry and Clinical Neurosciences Vol. 76 ( 3 ) page： 86 - 88 2022.3

Identification of ultra-rare disruptive variants in voltage-gated calcium channel-encoding genes in Japanese samples of schizophrenia and autism spectrum disorder. International journal

Chenyao Wang, Shin-Ichiro Horigane, Minoru Wakamori, Shuhei Ueda, Takeshi Kawabata, Hajime Fujii, Itaru Kushima, Hiroki Kimura, Kanako Ishizuka, Yukako Nakamura, Yoshimi Iwayama, Masashi Ikeda, Nakao Iwata, Takashi Okada, Branko Aleksic, Daisuke Mori, Takashi Yoshida, Haruhiko Bito, Takeo Yoshikawa, Sayaka Takemoto-Kimura, Norio Ozaki

Translational psychiatry Vol. 12 ( 1 ) page： 84 - 84 2022.2

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

Several large-scale whole-exome sequencing studies in patients with schizophrenia (SCZ) and autism spectrum disorder (ASD) have identified rare variants with modest or strong effect size as genetic risk factors. Dysregulation of cellular calcium homeostasis might be involved in SCZ/ASD pathogenesis, and genes encoding L-type voltage-gated calcium channel (VGCC) subunits Cav1.1 (CACNA1S), Cav1.2 (CACNA1C), Cav1.3 (CACNA1D), and T-type VGCC subunit Cav3.3 (CACNA1I) recently were identified as risk loci for psychiatric disorders. We performed a screening study, using the Ion Torrent Personal Genome Machine (PGM), of exon regions of these four candidate genes (CACNA1C, CACNA1D, CACNA1S, CACNA1I) in 370 Japanese patients with SCZ and 192 with ASD. Variant filtering was applied to identify biologically relevant mutations that were not registered in the dbSNP database or that have a minor allele frequency of less than 1% in East-Asian samples from databases; and are potentially disruptive, including nonsense, frameshift, canonical splicing site single nucleotide variants (SNVs), and non-synonymous SNVs predicted as damaging by five different in silico analyses. Each of these filtered mutations were confirmed by Sanger sequencing. If parental samples were available, segregation analysis was employed for measuring the inheritance pattern. Using our filter, we discovered one nonsense SNV (p.C1451* in CACNA1D), one de novo SNV (p.A36V in CACNA1C), one rare short deletion (p.E1675del in CACNA1D), and 14 NSstrict SNVs (non-synonymous SNV predicted as damaging by all of five in silico analyses). Neither p.A36V in CACNA1C nor p.C1451* in CACNA1D were found in 1871 SCZ cases, 380 ASD cases, or 1916 healthy controls in the independent sample set, suggesting that these SNVs might be ultra-rare SNVs in the Japanese population. The neuronal splicing isoform of Cav1.2 with the p.A36V mutation, discovered in the present study, showed reduced Ca2+-dependent inhibition, resulting in excessive Ca2+ entry through the mutant channel. These results suggested that this de novo SNV in CACNA1C might predispose to SCZ by affecting Ca2+ homeostasis. Thus, our analysis successfully identified several ultra-rare and potentially disruptive gene variants, lending partial support to the hypothesis that VGCC-encoding genes may contribute to the risk of SCZ/ASD.

DOI： 10.1038/s41398-022-01851-y

Sequencing of selected chromatin remodelling genes reveals increased burden of rare missense variants in ASD patients from the Japanese population

Tzuyao Lo, Itaru Kushima, Branko Aleksic, Hidekazu Kato, Yoshihiro Nawa, Yu Hayashi, Gantsooj Otgonbayar, Hiroki Kimura, Yuko Arioka, Daisuke Mori, Norio Ozaki

International Review of Psychiatry Vol. 34 ( 2 ) page： 154 - 167 2022.2

Autism Spectrum Disorder Comorbid with Obsessive Compulsive Disorder and Eating Disorder in a Woman with NBEA Deletion

Hidekazu Kato, Itaru Kuhisma, Akira Yoshimi, Kanako Ishizuka, Hiroki Kimura, Branko Aleksic, Nagahide Takahashi, Takashi Okada, Norio Ozaki

Psychiatry and Clinical Neurosciences Vol. 76 ( 1 ) page： 36 - 38 2022.1

Elucidation of molecular pathogenesis and drug development for psychiatric disorders from rare disease-susceptibility variants

Hiroki Kimura, Daisuke Mori, Branko Aleksic, Norio Ozaki

Neuroscience Research Vol. 170 page： 24 - 31 2021.9

Problem-Based Learning in Child and Adolescent Psychiatry: A Perspective from Japan

Junko Iwatsuki, Takeshi Kondo, Noriyuki Takahashi, Hideki Takami, Hiroshi Nishigori, Itzel Bustos-Villalobos, Branko Aleksic, Hideki Kasuya, Nobutaro Ban, Tetsuya Yagi, Norbert Skokauskas

Advances in Medical Education and Practice Vol. 12 page： 1329 - 1335 2021

Rare genetic variants in the gene encoding histone lysine demethylase 4C (KDM4C) and their contributions to susceptibility to schizophrenia and autism spectrum disorder

Hidekazu Kato, Itaru Kushima, Daisuke Mori, Akira Yoshimi, Branko Aleksic, Yoshihiro Nawa, Miho Toyama, Sho Furuta, Yanjie Yu, Kanako Ishizuka, Hiroki Kimura, Yuko Arioka, Keita Tsujimura, Mako Morikawa, Takashi Okada, Toshiya Inada, Masahiro Nakatochi, Keiko Shinjo, Yutaka Kondo, Kozo Kaibuchi, Yasuko Funabiki, Ryo Kimura, Toshimitsu Suzuki, Kazuhiro Yamakawa, Masashi Ikeda, Nakao Iwata, Tsutomu Takahashi, Michio Suzuki, Yuko Okahisa, Manabu Takaki, Jun Egawa, Toshiyuki Someya, Norio Ozaki

Translational Psychiatry Vol. 10 ( 1 ) page： 421 2020.12

Language：English Publishing type：Research paper (scientific journal) Publisher：Springer Science and Business Media LLC

<title>Abstract</title>Dysregulation of epigenetic processes involving histone methylation induces neurodevelopmental impairments and has been implicated in schizophrenia (SCZ) and autism spectrum disorder (ASD). Variants in the gene encoding lysine demethylase 4C (<italic>KDM4C</italic>) have been suggested to confer a risk for such disorders. However, rare genetic variants in <italic>KDM4C</italic> have not been fully evaluated, and the functional impact of the variants has not been studied using patient-derived cells. In this study, we conducted copy number variant (CNV) analysis in a Japanese sample set (2605 SCZ and 1141 ASD cases, and 2310 controls). We found evidence for significant associations between CNVs in <italic>KDM4C</italic> and SCZ (<italic>p</italic> = 0.003) and ASD (<italic>p</italic> = 0.04). We also observed a significant association between deletions in <italic>KDM4C</italic> and SCZ (corrected <italic>p</italic> = 0.04). Next, to explore the contribution of single nucleotide variants in <italic>KDM4C</italic>, we sequenced the coding exons in a second sample set (370 SCZ and 192 ASD cases) and detected 18 rare missense variants, including p.D160N within the JmjC domain of KDM4C. We, then, performed association analysis for p.D160N in a third sample set (1751 SCZ and 377 ASD cases, and 2276 controls), but did not find a statistical association with these disorders. Immunoblotting analysis using lymphoblastoid cell lines from a case with <italic>KDM4C</italic> deletion revealed reduced KDM4C protein expression and altered histone methylation patterns. In conclusion, this study strengthens the evidence for associations between <italic>KDM4C</italic> CNVs and these two disorders and for their potential functional effect on histone methylation patterns.

DOI： 10.1038/s41398-020-01107-7

Other Link： http://www.nature.com/articles/s41398-020-01107-7

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Papers - ALEKSIC Branko