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

Author

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, and Norio Ozaki

Subjects
Biology (General), QH301-705.5
Abstract

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

Published
2018
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2. Integrative Analyses of De Novo Mutations Provide Deeper Biological Insights into Autism Spectrum Disorder

Author

Atsushi Takata, Noriko Miyake, Yoshinori Tsurusaki, Ryoko Fukai, Satoko Miyatake, Eriko Koshimizu, Itaru Kushima, Takashi Okada, Mako Morikawa, Yota Uno, Kanako Ishizuka, Kazuhiko Nakamura, Masatsugu Tsujii, Takeo Yoshikawa, Tomoko Toyota, Nobuhiko Okamoto, Yoko Hiraki, Ryota Hashimoto, Yuka Yasuda, Shinji Saitoh, Kei Ohashi, Yasunari Sakai, Shouichi Ohga, Toshiro Hara, Mitsuhiro Kato, Kazuyuki Nakamura, Aiko Ito, Chizuru Seiwa, Emi Shirahata, Hitoshi Osaka, Ayumi Matsumoto, Saoko Takeshita, Jun Tohyama, Tomoko Saikusa, Toyojiro Matsuishi, Takumi Nakamura, Takashi Tsuboi, Tadafumi Kato, Toshifumi Suzuki, Hirotomo Saitsu, Mitsuko Nakashima, Takeshi Mizuguchi, Fumiaki Tanaka, Norio Mori, Norio Ozaki, and Naomichi Matsumoto

Subjects
ASD, de novo mutations, cerebellum, striatum, ATP2B2, GGNBP2, MCM6, AGO1, ATP1A3, cardiac glycosides, Biology (General), QH301-705.5
Abstract

Recent studies have established important roles of de novo mutations (DNMs) in autism spectrum disorders (ASDs). Here, we analyze DNMs in 262 ASD probands of Japanese origin and confirm the “de novo paradigm” of ASDs across ethnicities. Based on this consistency, we combine the lists of damaging DNMs in our and published ASD cohorts (total number of trios, 4,244) and perform integrative bioinformatics analyses. Besides replicating the findings of previous studies, our analyses highlight ATP-binding genes and fetal cerebellar/striatal circuits. Analysis of individual genes identified 61 genes enriched for damaging DNMs, including ten genes for which our dataset now contributes to statistical significance. Screening of compounds altering the expression of genes hit by damaging DNMs reveals a global downregulating effect of valproic acid, a known risk factor for ASDs, whereas cardiac glycosides upregulate these genes. Collectively, our integrative approach provides deeper biological and potential medical insights into ASDs.

Published
2018
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3. Comparative Analyses of Copy-Number Variation in Autism Spectrum Disorder and Schizophrenia Reveal Etiological Overlap and Biological Insights

Author

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

Subjects
Adult, Male, 0301 basic medicine, Adolescent, DNA Copy Number Variations, Genotype, Bioinformatics analysis, Autism Spectrum Disorder, Biology, General Biochemistry, Genetics and Molecular Biology, Young Adult, 03 medical and health sciences, 0302 clinical medicine, mental disorders, Intellectual disability, medicine, Gene set analysis, Humans, Genetic Predisposition to Disease, Copy-number variation, Child, lcsh:QH301-705.5, Genetics, Middle Aged, Japanese population, medicine.disease, Oxidative Stress, 030104 developmental biology, lcsh:Biology (General), Autism spectrum disorder, Schizophrenia, Etiology, Female, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

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

Published
2018
Full Text
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4. Integrative Analyses of De Novo Mutations Provide Deeper Biological Insights into Autism Spectrum Disorder

Author

Ayumi Matsumoto, Takashi Tsuboi, Takeo Yoshikawa, Ryoko Fukai, Nobuhiko Okamoto, Yasunari Sakai, Takeshi Mizuguchi, Shouichi Ohga, Hitoshi Osaka, Naomichi Matsumoto, Chizuru Seiwa, Kei Ohashi, Saoko Takeshita, Mako Morikawa, Masatsugu Tsujii, Norio Mori, Kazuyuki Nakamura, Mitsuhiro Kato, Shinji Saitoh, Takashi Okada, Eriko Koshimizu, Aiko Ito, Yota Uno, Toshiro Hara, Kanako Ishizuka, Yoko Hiraki, Noriko Miyake, Toshifumi Suzuki, Tomoko Toyota, Kazuhiko Nakamura, Itaru Kushima, Ryota Hashimoto, Toyojiro Matsuishi, Jun Tohyama, Fumiaki Tanaka, Norio Ozaki, Atsushi Takata, Tomoko Saikusa, Takumi Nakamura, Satoko Miyatake, Tadafumi Kato, Emi Shirahata, Yuka Yasuda, Hirotomo Saitsu, Yoshinori Tsurusaki, and Mitsuko Nakashima

Subjects
0301 basic medicine, Proband, AGO1, cerebellum, Autism Spectrum Disorder, striatum, de novo mutations, ATP2B2, Computational biology, Biology, behavioral disciplines and activities, ASD, General Biochemistry, Genetics and Molecular Biology, cardiac glycosides, 03 medical and health sciences, mental disorders, medicine, Humans, Genetic Predisposition to Disease, Gene, lcsh:QH301-705.5, De novo mutations, MCM6, Integrative bioinformatics, ATP1A3, medicine.disease, 030104 developmental biology, GGNBP2, lcsh:Biology (General), Autism spectrum disorder, Mutation, Autism
Abstract

Recent studies have established important roles of de novo mutations (DNMs) in autism spectrum disorders (ASDs). Here, we analyze DNMs in 262 ASD probands of Japanese origin and confirm the "de novo paradigm" of ASDs across ethnicities. Based on this consistency, we combine the lists of damaging DNMs in our and published ASD cohorts (total number of trios, 4,244) and perform integrative bioinformatics analyses. Besides replicating the findings of previous studies, our analyses highlight ATP-binding genes and fetal cerebellar/striatal circuits. Analysis of individual genes identified 61 genes enriched for damaging DNMs, including ten genes for which our dataset now contributes to statistical significance. Screening of compounds altering the expression of genes hit by damaging DNMs reveals a global downregulating effect of valproic acid, a known risk factor for ASDs, whereas cardiac glycosides upregulate these genes. Collectively, our integrative approach provides deeper biological and potential medical insights into ASDs.

Published
2018

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