Comparative Analyses of Copy-Number Variation in Autism Spectrum Disorder and Schizophrenia Reveal Etiological Overlap and Biological Insights

Itaru Kushima; Branko Aleksic; Masahiro Nakatochi; Teppei Shimamura; Takashi Okada; Yota Uno; Mako Morikawa; Kanako Ishizuka; Tomoko Shiino; Hiroki Kimura; Yuko Arioka; Akira Yoshimi; Yuto Takasaki; Yanjie Yu; Yukako Nakamura; Maeri Yamamoto; Tetsuya Iidaka; Shuji Iritani; Toshiya Inada; Nanayo Ogawa; Emiko Shishido; Youta Torii; Naoko Kawano; Yutaka Omura; Toru Yoshikawa; Tokio Uchiyama; Toshimichi Yamamoto; Masashi Ikeda; Ryota Hashimoto; Hidenaga Yamamori; Yuka Yasuda; Toshiyuki Someya; Yuichiro Watanabe; Jun Egawa; Ayako Nunokawa; Masanari Itokawa; Makoto Arai; Mitsuhiro Miyashita; Akiko Kobori; Michio Suzuki; Tsutomu Takahashi; Masahide Usami; Masaki Kodaira; Kyota Watanabe; Tsukasa Sasaki; Hitoshi Kuwabara; Mamoru Tochigi; Fumichika Nishimura; Hidenori Yamasue; Yosuke Eriguchi; Seico Benner; Masaki Kojima; Walid Yassin; Toshio Munesue; Shigeru Yokoyama; Ryo Kimura; Yasuko Funabiki; Hirotaka Kosaka; Makoto Ishitobi; Tetsuro Ohmori; Shusuke Numata; Takeo Yoshikawa; Tomoko Toyota; Kazuhiro Yamakawa; Toshimitsu Suzuki; Yushi Inoue; Kentaro Nakaoka; Yu ichi Goto; Masumi Inagaki; Naoki Hashimoto; Ichiro Kusumi; Shuraku Son; Toshiya Murai; Tempei Ikegame; Naohiro Okada; Kiyoto Kasai; Shohko Kunimoto; Daisuke Mori; Nakao Iwata; Norio Ozaki

doi:10.1016/j.celrep.2018.08.022

Comparative Analyses of Copy-Number Variation in Autism Spectrum Disorder and Schizophrenia Reveal Etiological Overlap and Biological Insights

Itaru Kushima, Branko Aleksic, Masahiro Nakatochi, Teppei Shimamura, Takashi Okada, Yota Uno, Mako Morikawa, Kanako Ishizuka, Tomoko Shiino, Hiroki Kimura, Yuko Arioka, Akira Yoshimi, Yuto Takasaki, Yanjie Yu, Yukako Nakamura, Maeri Yamamoto, Tetsuya Iidaka, Shuji Iritani, Toshiya Inada, Nanayo OgawaEmiko Shishido, Youta Torii, Naoko Kawano, Yutaka Omura, Toru Yoshikawa, Tokio Uchiyama, Toshimichi Yamamoto, Masashi Ikeda, Ryota Hashimoto, Hidenaga Yamamori, Yuka Yasuda, Toshiyuki Someya, Yuichiro Watanabe, Jun Egawa, Ayako Nunokawa, Masanari Itokawa, Makoto Arai, Mitsuhiro Miyashita, Akiko Kobori, Michio Suzuki, Tsutomu Takahashi, Masahide Usami, Masaki Kodaira, Kyota Watanabe, Tsukasa Sasaki, Hitoshi Kuwabara, Mamoru Tochigi, Fumichika Nishimura, Hidenori Yamasue, Yosuke Eriguchi, Seico Benner, Masaki Kojima, Walid Yassin, Toshio Munesue, Shigeru Yokoyama, Ryo Kimura, Yasuko Funabiki, Hirotaka Kosaka, Makoto Ishitobi, Tetsuro Ohmori, Shusuke Numata, Takeo Yoshikawa, Tomoko Toyota, Kazuhiro Yamakawa, Toshimitsu Suzuki, Yushi Inoue, Kentaro Nakaoka, Yu ichi Goto, Masumi Inagaki, Naoki Hashimoto, Ichiro Kusumi, Shuraku Son, Toshiya Murai, Tempei Ikegame, Naohiro Okada, Kiyoto Kasai, Shohko Kunimoto, Daisuke Mori, Nakao Iwata, Norio Ozaki

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Abstract

Compelling evidence in Caucasian populations suggests a role for copy-number variations (CNVs) in autism spectrum disorder (ASD) and schizophrenia (SCZ). We analyzed 1,108 ASD cases, 2,458 SCZ cases, and 2,095 controls in a Japanese population and confirmed an increased burden of rare exonic CNVs in both disorders. Clinically significant (or pathogenic) CNVs, including those at 29 loci common to both disorders, were found in about 8% of ASD and SCZ cases, which was significantly higher than in controls. Phenotypic analysis revealed an association between clinically significant CNVs and intellectual disability. Gene set analysis showed significant overlap of biological pathways in both disorders including oxidative stress response, lipid metabolism/modification, and genomic integrity. Finally, based on bioinformatics analysis, we identified multiple disease-relevant genes in eight well-known ASD/SCZ-associated CNV loci (e.g., 22q11.2, 3q29). Our findings suggest an etiological overlap of ASD and SCZ and provide biological insights into these disorders. Kushima et al. perform comparative analyses of CNVs in ASD and SCZ in a Japanese population. They identify pathogenic CNVs and biological pathways in each disorder with significant overlap. Patients with pathogenic CNVs have a higher prevalence of intellectual disability. Disease-relevant genes are detected in eight well-known ASD/SCZ-associated CNV loci.

Original language	English
Pages (from-to)	2838-2856
Number of pages	19
Journal	Cell Reports
Volume	24
Issue number	11
DOIs	https://doi.org/10.1016/j.celrep.2018.08.022
Publication status	Published - 11-09-2018

All Science Journal Classification (ASJC) codes

General Biochemistry,Genetics and Molecular Biology

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10.1016/j.celrep.2018.08.022

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Kushima, I., Aleksic, B., Nakatochi, M., Shimamura, T., Okada, T., Uno, Y., Morikawa, M., Ishizuka, K., Shiino, T., Kimura, H., Arioka, Y., Yoshimi, A., Takasaki, Y., Yu, Y., Nakamura, Y., Yamamoto, M., Iidaka, T., Iritani, S., Inada, T., ... Ozaki, N. (2018). Comparative Analyses of Copy-Number Variation in Autism Spectrum Disorder and Schizophrenia Reveal Etiological Overlap and Biological Insights. Cell Reports, 24(11), 2838-2856. https://doi.org/10.1016/j.celrep.2018.08.022

@article{5751719bd43a4932842c57416cceee8a,

title = "Comparative Analyses of Copy-Number Variation in Autism Spectrum Disorder and Schizophrenia Reveal Etiological Overlap and Biological Insights",

abstract = "Compelling evidence in Caucasian populations suggests a role for copy-number variations (CNVs) in autism spectrum disorder (ASD) and schizophrenia (SCZ). We analyzed 1,108 ASD cases, 2,458 SCZ cases, and 2,095 controls in a Japanese population and confirmed an increased burden of rare exonic CNVs in both disorders. Clinically significant (or pathogenic) CNVs, including those at 29 loci common to both disorders, were found in about 8% of ASD and SCZ cases, which was significantly higher than in controls. Phenotypic analysis revealed an association between clinically significant CNVs and intellectual disability. Gene set analysis showed significant overlap of biological pathways in both disorders including oxidative stress response, lipid metabolism/modification, and genomic integrity. Finally, based on bioinformatics analysis, we identified multiple disease-relevant genes in eight well-known ASD/SCZ-associated CNV loci (e.g., 22q11.2, 3q29). Our findings suggest an etiological overlap of ASD and SCZ and provide biological insights into these disorders. Kushima et al. perform comparative analyses of CNVs in ASD and SCZ in a Japanese population. They identify pathogenic CNVs and biological pathways in each disorder with significant overlap. Patients with pathogenic CNVs have a higher prevalence of intellectual disability. Disease-relevant genes are detected in eight well-known ASD/SCZ-associated CNV loci.",

keywords = "Japanese population, array comparative genomic hybridization, autism spectrum disorder, copy-number variation, gene ontology, genetic overlap, genome integrity, lipid metabolism, oxidative stress response, schizophrenia",

author = "Itaru Kushima and Branko Aleksic and Masahiro Nakatochi and Teppei Shimamura and Takashi Okada and Yota Uno and Mako Morikawa and Kanako Ishizuka and Tomoko Shiino and Hiroki Kimura and Yuko Arioka and Akira Yoshimi and Yuto Takasaki and Yanjie Yu and Yukako Nakamura and Maeri Yamamoto and Tetsuya Iidaka and Shuji Iritani and Toshiya Inada and Nanayo Ogawa and Emiko Shishido and Youta Torii and Naoko Kawano and Yutaka Omura and Toru Yoshikawa and Tokio Uchiyama and Toshimichi Yamamoto and Masashi Ikeda and Ryota Hashimoto and Hidenaga Yamamori and Yuka Yasuda and Toshiyuki Someya and Yuichiro Watanabe and Jun Egawa and Ayako Nunokawa and Masanari Itokawa and Makoto Arai and Mitsuhiro Miyashita and Akiko Kobori and Michio Suzuki and Tsutomu Takahashi and Masahide Usami and Masaki Kodaira and Kyota Watanabe and Tsukasa Sasaki and Hitoshi Kuwabara and Mamoru Tochigi and Fumichika Nishimura and Hidenori Yamasue and Yosuke Eriguchi and Seico Benner and Masaki Kojima and Walid Yassin and Toshio Munesue and Shigeru Yokoyama and Ryo Kimura and Yasuko Funabiki and Hirotaka Kosaka and Makoto Ishitobi and Tetsuro Ohmori and Shusuke Numata and Takeo Yoshikawa and Tomoko Toyota and Kazuhiro Yamakawa and Toshimitsu Suzuki and Yushi Inoue and Kentaro Nakaoka and Goto, {Yu ichi} and Masumi Inagaki and Naoki Hashimoto and Ichiro Kusumi and Shuraku Son and Toshiya Murai and Tempei Ikegame and Naohiro Okada and Kiyoto Kasai and Shohko Kunimoto and Daisuke Mori and Nakao Iwata and Norio Ozaki",

note = "Publisher Copyright: {\textcopyright} 2018 The Authors",

year = "2018",

month = sep,

day = "11",

doi = "10.1016/j.celrep.2018.08.022",

language = "English",

volume = "24",

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journal = "Cell Reports",

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Kushima, I, Aleksic, B, Nakatochi, M, Shimamura, T, Okada, T, Uno, Y, Morikawa, M, Ishizuka, K, Shiino, T, Kimura, H, Arioka, Y, Yoshimi, A, Takasaki, Y, Yu, Y, Nakamura, Y, Yamamoto, M, Iidaka, T, Iritani, S, Inada, T, Ogawa, N, Shishido, E, Torii, Y, Kawano, N, Omura, Y, Yoshikawa, T, Uchiyama, T, Yamamoto, T, Ikeda, M, Hashimoto, R, Yamamori, H, Yasuda, Y, Someya, T, Watanabe, Y, Egawa, J, Nunokawa, A, Itokawa, M, Arai, M, Miyashita, M, Kobori, A, Suzuki, M, Takahashi, T, Usami, M, Kodaira, M, Watanabe, K, Sasaki, T, Kuwabara, H, Tochigi, M, Nishimura, F, Yamasue, H, Eriguchi, Y, Benner, S, Kojima, M, Yassin, W, Munesue, T, Yokoyama, S, Kimura, R, Funabiki, Y, Kosaka, H, Ishitobi, M, Ohmori, T, Numata, S, Yoshikawa, T, Toyota, T, Yamakawa, K, Suzuki, T, Inoue, Y, Nakaoka, K, Goto, YI, Inagaki, M, Hashimoto, N, Kusumi, I, Son, S, Murai, T, Ikegame, T, Okada, N, Kasai, K, Kunimoto, S, Mori, D, Iwata, N & Ozaki, N 2018, 'Comparative Analyses of Copy-Number Variation in Autism Spectrum Disorder and Schizophrenia Reveal Etiological Overlap and Biological Insights', Cell Reports, vol. 24, no. 11, pp. 2838-2856. https://doi.org/10.1016/j.celrep.2018.08.022

TY - JOUR

T1 - Comparative Analyses of Copy-Number Variation in Autism Spectrum Disorder and Schizophrenia Reveal Etiological Overlap and Biological Insights

AU - Kushima, Itaru

AU - Aleksic, Branko

AU - Nakatochi, Masahiro

AU - Shimamura, Teppei

AU - Okada, Takashi

AU - Uno, Yota

AU - Morikawa, Mako

AU - Ishizuka, Kanako

AU - Shiino, Tomoko

AU - Kimura, Hiroki

AU - Arioka, Yuko

AU - Yoshimi, Akira

AU - Takasaki, Yuto

AU - Yu, Yanjie

AU - Nakamura, Yukako

AU - Yamamoto, Maeri

AU - Iidaka, Tetsuya

AU - Iritani, Shuji

AU - Inada, Toshiya

AU - Ogawa, Nanayo

AU - Shishido, Emiko

AU - Torii, Youta

AU - Kawano, Naoko

AU - Omura, Yutaka

AU - Yoshikawa, Toru

AU - Uchiyama, Tokio

AU - Yamamoto, Toshimichi

AU - Ikeda, Masashi

AU - Hashimoto, Ryota

AU - Yamamori, Hidenaga

AU - Yasuda, Yuka

AU - Someya, Toshiyuki

AU - Watanabe, Yuichiro

AU - Egawa, Jun

AU - Nunokawa, Ayako

AU - Itokawa, Masanari

AU - Arai, Makoto

AU - Miyashita, Mitsuhiro

AU - Kobori, Akiko

AU - Suzuki, Michio

AU - Takahashi, Tsutomu

AU - Usami, Masahide

AU - Kodaira, Masaki

AU - Watanabe, Kyota

AU - Sasaki, Tsukasa

AU - Kuwabara, Hitoshi

AU - Tochigi, Mamoru

AU - Nishimura, Fumichika

AU - Yamasue, Hidenori

AU - Eriguchi, Yosuke

AU - Benner, Seico

AU - Kojima, Masaki

AU - Yassin, Walid

AU - Munesue, Toshio

AU - Yokoyama, Shigeru

AU - Kimura, Ryo

AU - Funabiki, Yasuko

AU - Kosaka, Hirotaka

AU - Ishitobi, Makoto

AU - Ohmori, Tetsuro

AU - Numata, Shusuke

AU - Yoshikawa, Takeo

AU - Toyota, Tomoko

AU - Yamakawa, Kazuhiro

AU - Suzuki, Toshimitsu

AU - Inoue, Yushi

AU - Nakaoka, Kentaro

AU - Goto, Yu ichi

AU - Inagaki, Masumi

AU - Hashimoto, Naoki

AU - Kusumi, Ichiro

AU - Son, Shuraku

AU - Murai, Toshiya

AU - Ikegame, Tempei

AU - Okada, Naohiro

AU - Kasai, Kiyoto

AU - Kunimoto, Shohko

AU - Mori, Daisuke

AU - Iwata, Nakao

AU - Ozaki, Norio

PY - 2018/9/11

Y1 - 2018/9/11

N2 - Compelling evidence in Caucasian populations suggests a role for copy-number variations (CNVs) in autism spectrum disorder (ASD) and schizophrenia (SCZ). We analyzed 1,108 ASD cases, 2,458 SCZ cases, and 2,095 controls in a Japanese population and confirmed an increased burden of rare exonic CNVs in both disorders. Clinically significant (or pathogenic) CNVs, including those at 29 loci common to both disorders, were found in about 8% of ASD and SCZ cases, which was significantly higher than in controls. Phenotypic analysis revealed an association between clinically significant CNVs and intellectual disability. Gene set analysis showed significant overlap of biological pathways in both disorders including oxidative stress response, lipid metabolism/modification, and genomic integrity. Finally, based on bioinformatics analysis, we identified multiple disease-relevant genes in eight well-known ASD/SCZ-associated CNV loci (e.g., 22q11.2, 3q29). Our findings suggest an etiological overlap of ASD and SCZ and provide biological insights into these disorders. Kushima et al. perform comparative analyses of CNVs in ASD and SCZ in a Japanese population. They identify pathogenic CNVs and biological pathways in each disorder with significant overlap. Patients with pathogenic CNVs have a higher prevalence of intellectual disability. Disease-relevant genes are detected in eight well-known ASD/SCZ-associated CNV loci.

AB - Compelling evidence in Caucasian populations suggests a role for copy-number variations (CNVs) in autism spectrum disorder (ASD) and schizophrenia (SCZ). We analyzed 1,108 ASD cases, 2,458 SCZ cases, and 2,095 controls in a Japanese population and confirmed an increased burden of rare exonic CNVs in both disorders. Clinically significant (or pathogenic) CNVs, including those at 29 loci common to both disorders, were found in about 8% of ASD and SCZ cases, which was significantly higher than in controls. Phenotypic analysis revealed an association between clinically significant CNVs and intellectual disability. Gene set analysis showed significant overlap of biological pathways in both disorders including oxidative stress response, lipid metabolism/modification, and genomic integrity. Finally, based on bioinformatics analysis, we identified multiple disease-relevant genes in eight well-known ASD/SCZ-associated CNV loci (e.g., 22q11.2, 3q29). Our findings suggest an etiological overlap of ASD and SCZ and provide biological insights into these disorders. Kushima et al. perform comparative analyses of CNVs in ASD and SCZ in a Japanese population. They identify pathogenic CNVs and biological pathways in each disorder with significant overlap. Patients with pathogenic CNVs have a higher prevalence of intellectual disability. Disease-relevant genes are detected in eight well-known ASD/SCZ-associated CNV loci.

KW - Japanese population

KW - array comparative genomic hybridization

KW - autism spectrum disorder

KW - copy-number variation

KW - gene ontology

KW - genetic overlap

KW - genome integrity

KW - lipid metabolism

KW - oxidative stress response

KW - schizophrenia

UR - http://www.scopus.com/inward/record.url?scp=85052872475&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85052872475&partnerID=8YFLogxK

U2 - 10.1016/j.celrep.2018.08.022

DO - 10.1016/j.celrep.2018.08.022

M3 - Article

C2 - 30208311

AN - SCOPUS:85052872475

SN - 2211-1247

VL - 24

SP - 2838

EP - 2856

JO - Cell Reports

JF - Cell Reports

IS - 11

ER -

Comparative Analyses of Copy-Number Variation in Autism Spectrum Disorder and Schizophrenia Reveal Etiological Overlap and Biological Insights

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