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

doi:10.1016/j.biopsych.2022.04.003

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 HayashiTzuyao 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

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Abstract

Background: We aimed to determine the similarities and differences in the roles of genic and regulatory copy number variations (CNVs) in bipolar disorder (BD), schizophrenia (SCZ), and autism spectrum disorder (ASD). Methods: Based on high-resolution CNV data from 8708 Japanese samples, we performed to our knowledge the largest cross-disorder analysis of genic and regulatory CNVs in BD, SCZ, and ASD. Results: In genic CNVs, we found an increased burden of smaller (<100 kb) exonic deletions in BD, which contrasted with the highest burden of larger (>500 kb) exonic CNVs in SCZ/ASD. Pathogenic CNVs linked to neurodevelopmental disorders were significantly associated with the risk for each disorder, but BD and SCZ/ASD differed in terms of the effect size (smaller in BD) and subtype distribution of CNVs linked to neurodevelopmental disorders. We identified 3 synaptic genes (DLG2, PCDH15, and ASTN2) as risk factors for BD. Whereas gene set analysis showed that BD-associated pathways were restricted to chromatin biology, SCZ and ASD involved more extensive and similar pathways. Nevertheless, a correlation analysis of gene set results indicated weak but significant pathway similarities between BD and SCZ or ASD (r = 0.25–0.31). In SCZ and ASD, but not BD, CNVs were significantly enriched in enhancers and promoters in brain tissue. Conclusions: BD and SCZ/ASD differ in terms of CNV burden, characteristics of CNVs linked to neurodevelopmental disorders, and regulatory CNVs. On the other hand, they have shared molecular mechanisms, including chromatin biology. The BD risk genes identified here could provide insight into the pathogenesis of BD.

Original language	English
Pages (from-to)	362-374
Number of pages	13
Journal	Biological Psychiatry
Volume	92
Issue number	5
DOIs	https://doi.org/10.1016/j.biopsych.2022.04.003
Publication status	Published - 01-09-2022

All Science Journal Classification (ASJC) codes

Biological Psychiatry

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10.1016/j.biopsych.2022.04.003

Cite this

Kushima, I., Nakatochi, M., Aleksic, B., Okada, T., Kimura, H., Kato, H., Morikawa, M., Inada, T., Ishizuka, K., Torii, Y., Nakamura, Y., Tanaka, S., Imaeda, M., Takahashi, N., Yamamoto, M., Iwamoto, K., Nawa, Y., Ogawa, N., Iritani, S., ... Ozaki, N. (2022). Cross-Disorder Analysis of Genic and Regulatory Copy Number Variations in Bipolar Disorder, Schizophrenia, and Autism Spectrum Disorder. Biological Psychiatry, 92(5), 362-374. https://doi.org/10.1016/j.biopsych.2022.04.003

@article{acde184ca17540a385f972846bb08b73,

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

abstract = "Background: We aimed to determine the similarities and differences in the roles of genic and regulatory copy number variations (CNVs) in bipolar disorder (BD), schizophrenia (SCZ), and autism spectrum disorder (ASD). Methods: Based on high-resolution CNV data from 8708 Japanese samples, we performed to our knowledge the largest cross-disorder analysis of genic and regulatory CNVs in BD, SCZ, and ASD. Results: In genic CNVs, we found an increased burden of smaller (<100 kb) exonic deletions in BD, which contrasted with the highest burden of larger (>500 kb) exonic CNVs in SCZ/ASD. Pathogenic CNVs linked to neurodevelopmental disorders were significantly associated with the risk for each disorder, but BD and SCZ/ASD differed in terms of the effect size (smaller in BD) and subtype distribution of CNVs linked to neurodevelopmental disorders. We identified 3 synaptic genes (DLG2, PCDH15, and ASTN2) as risk factors for BD. Whereas gene set analysis showed that BD-associated pathways were restricted to chromatin biology, SCZ and ASD involved more extensive and similar pathways. Nevertheless, a correlation analysis of gene set results indicated weak but significant pathway similarities between BD and SCZ or ASD (r = 0.25–0.31). In SCZ and ASD, but not BD, CNVs were significantly enriched in enhancers and promoters in brain tissue. Conclusions: BD and SCZ/ASD differ in terms of CNV burden, characteristics of CNVs linked to neurodevelopmental disorders, and regulatory CNVs. On the other hand, they have shared molecular mechanisms, including chromatin biology. The BD risk genes identified here could provide insight into the pathogenesis of BD.",

keywords = "Autism spectrum disorder, Bipolar disorder, Chromatin biology, Copy number variation, Cross-disorder analysis, Schizophrenia",

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

note = "Publisher Copyright: {\textcopyright} 2022 Society of Biological Psychiatry",

year = "2022",

month = sep,

day = "1",

doi = "10.1016/j.biopsych.2022.04.003",

language = "English",

volume = "92",

pages = "362--374",

journal = "Biological Psychiatry",

issn = "0006-3223",

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number = "5",

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Kushima, I, Nakatochi, M, Aleksic, B, Okada, T, Kimura, H, Kato, H, Morikawa, M, Inada, T, Ishizuka, K, Torii, Y, Nakamura, Y, Tanaka, S, Imaeda, M, Takahashi, N, Yamamoto, M, Iwamoto, K, Nawa, Y, Ogawa, N, Iritani, S, Hayashi, Y, Lo, T, Otgonbayar, G, Furuta, S, Iwata, N, Ikeda, M, Saito, T, Ninomiya, K, Okochi, T, Hashimoto, R, Yamamori, H, Yasuda, Y, Fujimoto, M, Miura, K, Itokawa, M, Arai, M, Miyashita, M, Toriumi, K, Ohi, K, Shioiri, T, Kitaichi, K, Someya, T, Watanabe, Y, Egawa, J, Takahashi, T, Suzuki, M, Sasaki, T, Tochigi, M, Nishimura, F, Yamasue, H, Kuwabara, H, Wakuda, T, Kato, TA, Kanba, S, Horikawa, H, Usami, M, Kodaira, M, Watanabe, K, Yoshikawa, T, Toyota, T, Yokoyama, S, Munesue, T, Kimura, R, Funabiki, Y, Kosaka, H, Jung, M, Kasai, K, Ikegame, T, Jinde, S, Numata, S, Kinoshita, M, Kato, T, Kakiuchi, C, Yamakawa, K, Suzuki, T, Hashimoto, N, Ishikawa, S, Yamagata, B, Nio, S, Murai, T, Son, S, Kunii, Y, Yabe, H, Inagaki, M, Goto, YI, Okumura, Y, Ito, T, Arioka, Y, Mori, D & Ozaki, N 2022, 'Cross-Disorder Analysis of Genic and Regulatory Copy Number Variations in Bipolar Disorder, Schizophrenia, and Autism Spectrum Disorder', Biological Psychiatry, vol. 92, no. 5, pp. 362-374. https://doi.org/10.1016/j.biopsych.2022.04.003

TY - JOUR

T1 - Cross-Disorder Analysis of Genic and Regulatory Copy Number Variations in Bipolar Disorder, Schizophrenia, and Autism Spectrum Disorder

AU - Kushima, Itaru

AU - Nakatochi, Masahiro

AU - Aleksic, Branko

AU - Okada, Takashi

AU - Kimura, Hiroki

AU - Kato, Hidekazu

AU - Morikawa, Mako

AU - Inada, Toshiya

AU - Ishizuka, Kanako

AU - Torii, Youta

AU - Nakamura, Yukako

AU - Tanaka, Satoshi

AU - Imaeda, Miho

AU - Takahashi, Nagahide

AU - Yamamoto, Maeri

AU - Iwamoto, Kunihiro

AU - Nawa, Yoshihiro

AU - Ogawa, Nanayo

AU - Iritani, Shuji

AU - Hayashi, Yu

AU - Lo, Tzuyao

AU - Otgonbayar, Gantsooj

AU - Furuta, Sho

AU - Iwata, Nakao

AU - Ikeda, Masashi

AU - Saito, Takeo

AU - Ninomiya, Kohei

AU - Okochi, Tomo

AU - Hashimoto, Ryota

AU - Yamamori, Hidenaga

AU - Yasuda, Yuka

AU - Fujimoto, Michiko

AU - Miura, Kenichiro

AU - Itokawa, Masanari

AU - Arai, Makoto

AU - Miyashita, Mitsuhiro

AU - Toriumi, Kazuya

AU - Ohi, Kazutaka

AU - Shioiri, Toshiki

AU - Kitaichi, Kiyoyuki

AU - Someya, Toshiyuki

AU - Watanabe, Yuichiro

AU - Egawa, Jun

AU - Takahashi, Tsutomu

AU - Suzuki, Michio

AU - Sasaki, Tsukasa

AU - Tochigi, Mamoru

AU - Nishimura, Fumichika

AU - Yamasue, Hidenori

AU - Kuwabara, Hitoshi

AU - Wakuda, Tomoyasu

AU - Kato, Takahiro A.

AU - Kanba, Shigenobu

AU - Horikawa, Hideki

AU - Usami, Masahide

AU - Kodaira, Masaki

AU - Watanabe, Kyota

AU - Yoshikawa, Takeo

AU - Toyota, Tomoko

AU - Yokoyama, Shigeru

AU - Munesue, Toshio

AU - Kimura, Ryo

AU - Funabiki, Yasuko

AU - Kosaka, Hirotaka

AU - Jung, Minyoung

AU - Kasai, Kiyoto

AU - Ikegame, Tempei

AU - Jinde, Seiichiro

AU - Numata, Shusuke

AU - Kinoshita, Makoto

AU - Kato, Tadafumi

AU - Kakiuchi, Chihiro

AU - Yamakawa, Kazuhiro

AU - Suzuki, Toshimitsu

AU - Hashimoto, Naoki

AU - Ishikawa, Shuhei

AU - Yamagata, Bun

AU - Nio, Shintaro

AU - Murai, Toshiya

AU - Son, Shuraku

AU - Kunii, Yasuto

AU - Yabe, Hirooki

AU - Inagaki, Masumi

AU - Goto, Yu ichi

AU - Okumura, Yuto

AU - Ito, Tomoya

AU - Arioka, Yuko

AU - Mori, Daisuke

AU - Ozaki, Norio

PY - 2022/9/1

Y1 - 2022/9/1

N2 - Background: We aimed to determine the similarities and differences in the roles of genic and regulatory copy number variations (CNVs) in bipolar disorder (BD), schizophrenia (SCZ), and autism spectrum disorder (ASD). Methods: Based on high-resolution CNV data from 8708 Japanese samples, we performed to our knowledge the largest cross-disorder analysis of genic and regulatory CNVs in BD, SCZ, and ASD. Results: In genic CNVs, we found an increased burden of smaller (<100 kb) exonic deletions in BD, which contrasted with the highest burden of larger (>500 kb) exonic CNVs in SCZ/ASD. Pathogenic CNVs linked to neurodevelopmental disorders were significantly associated with the risk for each disorder, but BD and SCZ/ASD differed in terms of the effect size (smaller in BD) and subtype distribution of CNVs linked to neurodevelopmental disorders. We identified 3 synaptic genes (DLG2, PCDH15, and ASTN2) as risk factors for BD. Whereas gene set analysis showed that BD-associated pathways were restricted to chromatin biology, SCZ and ASD involved more extensive and similar pathways. Nevertheless, a correlation analysis of gene set results indicated weak but significant pathway similarities between BD and SCZ or ASD (r = 0.25–0.31). In SCZ and ASD, but not BD, CNVs were significantly enriched in enhancers and promoters in brain tissue. Conclusions: BD and SCZ/ASD differ in terms of CNV burden, characteristics of CNVs linked to neurodevelopmental disorders, and regulatory CNVs. On the other hand, they have shared molecular mechanisms, including chromatin biology. The BD risk genes identified here could provide insight into the pathogenesis of BD.

AB - Background: We aimed to determine the similarities and differences in the roles of genic and regulatory copy number variations (CNVs) in bipolar disorder (BD), schizophrenia (SCZ), and autism spectrum disorder (ASD). Methods: Based on high-resolution CNV data from 8708 Japanese samples, we performed to our knowledge the largest cross-disorder analysis of genic and regulatory CNVs in BD, SCZ, and ASD. Results: In genic CNVs, we found an increased burden of smaller (<100 kb) exonic deletions in BD, which contrasted with the highest burden of larger (>500 kb) exonic CNVs in SCZ/ASD. Pathogenic CNVs linked to neurodevelopmental disorders were significantly associated with the risk for each disorder, but BD and SCZ/ASD differed in terms of the effect size (smaller in BD) and subtype distribution of CNVs linked to neurodevelopmental disorders. We identified 3 synaptic genes (DLG2, PCDH15, and ASTN2) as risk factors for BD. Whereas gene set analysis showed that BD-associated pathways were restricted to chromatin biology, SCZ and ASD involved more extensive and similar pathways. Nevertheless, a correlation analysis of gene set results indicated weak but significant pathway similarities between BD and SCZ or ASD (r = 0.25–0.31). In SCZ and ASD, but not BD, CNVs were significantly enriched in enhancers and promoters in brain tissue. Conclusions: BD and SCZ/ASD differ in terms of CNV burden, characteristics of CNVs linked to neurodevelopmental disorders, and regulatory CNVs. On the other hand, they have shared molecular mechanisms, including chromatin biology. The BD risk genes identified here could provide insight into the pathogenesis of BD.

KW - Autism spectrum disorder

KW - Bipolar disorder

KW - Chromatin biology

KW - Copy number variation

KW - Cross-disorder analysis

KW - Schizophrenia

UR - http://www.scopus.com/inward/record.url?scp=85132578719&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85132578719&partnerID=8YFLogxK

U2 - 10.1016/j.biopsych.2022.04.003

DO - 10.1016/j.biopsych.2022.04.003

M3 - Article

C2 - 35667888

AN - SCOPUS:85132578719

SN - 0006-3223

VL - 92

SP - 362

EP - 374

JO - Biological Psychiatry

JF - Biological Psychiatry

IS - 5

ER -

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

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