Cross-Disorder Analysis of Genic and Regulatory Copy Number Variations in Bipolar Disorder, Schizophrenia, and Autism Spectrum Disorder

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

doi:10.1016/j.biopsych.2022.04.003

Cited by 30 publications

(32 citation statements)

References 73 publications

(76 reference statements)

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“…Detailed phenotyping will allow identifying more homogeneous groups of patients with the hope that similarities in phenotypes are a reflection of similar pathogenic mechanisms involved. Likewise, more attention should be given to rare, high impact genetic variants associated with BD, such as single nucleotide substitutions, indels, or copy number variants ( 24 , 25 ), with the hope that studying their biological consequences is relatively straightforward (compared to common variants), which will speed up downstream discoveries. The complex biology of BD, despite creating obvious challenges for researches, could on the other hand allow exploring different possible targeted treatment options for the patients.…”

Section: Discussionmentioning

confidence: 99%

“…From the standpoint of both clinical manifestations and molecular biology, BD is a part of a spectrum where it forms a continuum with unipolar depression and schizophrenia (i.e., depression → BD type 2 → BD type 1 → schizophrenia) ( 19 – 23 ). Both common ( 22 ) and rare ( 24 , 25 ) genetic variants contribute to the pathogenesis of BD: the first category explains ∼20% of the phenotypic variance, while the contribution of the second category is yet to be determined. The majority of the associated common variants are found in non-coding sequences of the genome and the reported rare variants change amino acid sequences of proteins.…”

Section: Epigenetic Consequences Of Genetic Variants Associated With Bdmentioning

confidence: 99%

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Genomic regulatory sequences in the pathogenesis of bipolar disorder

Levchenko

Плотнікова²

2023

Front. Psychiatry

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The lifetime prevalence of bipolar disorder is estimated to be about 2%. Epigenetics defines regulatory mechanisms that determine relatively stable patterns of gene expression by controlling all key steps, from DNA to messenger RNA to protein. This Mini Review highlights recent discoveries of modified epigenetic control resulting from genetic variants associated with bipolar disorder in genome-wide association studies. The revealed epigenetic abnormalities implicate gene transcription and post-transcriptional regulation. In the light of these discoveries, the Mini Review focuses on the genes PACS1, MCHR1, DCLK3, HAPLN4, LMAN2L, TMEM258, GNL3, LRRC57, CACNA1C, CACNA1D, and NOVA2 and their potential biological role in the pathogenesis of bipolar disorder. Molecular mechanisms under control of these genes do not translate into a unified picture and substantially more research is needed to fill the gaps in knowledge and to solve current limitations in prognosis and treatment of bipolar disorder. In conclusion, the genetic and functional studies confirm the complex nature of bipolar disorder and indicate future research directions to explore possible targeted treatment options, eventually working toward a personalized approach.

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Section: Discussionmentioning

confidence: 99%

Section: Epigenetic Consequences Of Genetic Variants Associated With Bdmentioning

confidence: 99%

Genomic regulatory sequences in the pathogenesis of bipolar disorder

Levchenko

Плотнікова²

2023

Front. Psychiatry

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“…Age was matched in patients with 47, XXY/47, XXX and patients without pathogenic CNVs. Pathogenic CNVs were defined as reported in our previous study 23 …”

Section: Methodsmentioning

confidence: 99%

X chromosome aneuploidies and schizophrenia: association analysis and phenotypic characterization

Kushima

Aleksić

Kimura

et al. 2022

Psychiatry Clin Neurosci

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The aims of the present study were: (i) to examine the association between schizophrenia (SCZ) and 47, XXY or 47, XXX in a large case-control sample; and (ii) to characterize the clinical features of patients with SCZ with these X chromosome aneuploidies.Methods: To identify 47, XXY and 47, XXX, array comparative genomic hybridization (aCGH) was performed in 3188 patients with SCZ and 3586 controls. We examined the association between 47, XXY and 47, XXX and SCZ in males and females separately using exact conditional tests to control for platform effects. Clinical data were retrospectively examined for patients with SCZ with X chromosome aneuploidies.Results: Of the analyzed samples, 3117 patients (97.8%) and 3519 controls (98.1%) passed our quality control. X chromosome aneuploidies were exclusively identified in patients: 47, XXY in seven patients (0.56%), 47, XXX in six patients (0.42%). Statistical analysis revealed a significant association between SCZ and 47, XXY (P = 0.028) and 47, XXX (P = 0.011). Phenotypic data were available from 12 patients. Treatment-resistance to antipsychotics and manic symptoms were observed in six patients each (four with 47, XXY and two with 47, XXX for both), respectively. Statistical analysis revealed that treatment-resistance to antipsychotics, mood stabilizer use, and manic symptoms were significantly more common in patients with 47, XXY than in male patients without pathogenic copy number variations. Conclusion:These findings indicate that both 47, XXY and 47, XXX are significantly associated with risk for SCZ. Patients with SCZ with 47, XXY may be characterized by treatment-resistance and manic symptoms.

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“…Lithium and GSK3 also appear to affect different cell signaling mechanisms that have been associated with the development of subtypes of autism spectrum disorders (ASD). This may not be that surprising since bipolar disorder associated risk genes such as SHANK2 and ANK3 are shared between these disorders ( Bi et al, 2012 ; Stahl et al, 2019 ; Zaslavsky et al, 2019 ; Kushima et al, 2022 ).…”

Section: Biological Functions Modulated By Gsk3 and Lithiummentioning

confidence: 99%

Inhibition of glycogen synthase kinase 3 by lithium, a mechanism in search of specificity

Chatterjee

Beaulieu

2022

Front. Mol. Neurosci.

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Inhibition of Glycogen synthase kinase 3 (GSK3) is a popular explanation for the effects of lithium ions on mood regulation in bipolar disorder and other mental illnesses, including major depression, cyclothymia, and schizophrenia. Contribution of GSK3 is supported by evidence obtained from animal and patient derived model systems. However, the two GSK3 enzymes, GSK3α and GSK3β, have more than 100 validated substrates. They are thus central hubs for major biological functions, such as dopamine-glutamate neurotransmission, synaptic plasticity (Hebbian and homeostatic), inflammation, circadian regulation, protein synthesis, metabolism, inflammation, and mitochondrial functions. The intricate contributions of GSK3 to several biological processes make it difficult to identify specific mechanisms of mood stabilization for therapeutic development. Identification of GSK3 substrates involved in lithium therapeutic action is thus critical. We provide an overview of GSK3 biological functions and substrates for which there is evidence for a contribution to lithium effects. A particular focus is given to four of these: the transcription factor cAMP response element-binding protein (CREB), the RNA-binding protein FXR1, kinesin subunits, and the cytoskeletal regulator CRMP2. An overview of how co-regulation of these substrates may result in shared outcomes is also presented. Better understanding of how inhibition of GSK3 contributes to the therapeutic effects of lithium should allow for identification of more specific targets for future drug development. It may also provide a framework for the understanding of how lithium effects overlap with those of other drugs such as ketamine and antipsychotics, which also inhibit brain GSK3.

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Cross-Disorder Analysis of Genic and Regulatory Copy Number Variations in Bipolar Disorder, Schizophrenia, and Autism Spectrum Disorder

Cited by 30 publications

References 73 publications

Genomic regulatory sequences in the pathogenesis of bipolar disorder

Genomic regulatory sequences in the pathogenesis of bipolar disorder

X chromosome aneuploidies and schizophrenia: association analysis and phenotypic characterization

Inhibition of glycogen synthase kinase 3 by lithium, a mechanism in search of specificity

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