Comparative Analyses of Copy-Number Variation in Autism Spectrum Disorder and Schizophrenia Reveal Etiological Overlap and Biological Insights
Open accessAbstract
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.
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Several microdeletions lead to loss of various lengths of the C-terminal portion of Dock4 protein, which is responsible for its Rac1-activating ability.
“For instance, several microdeletions lead to loss of various lengths of the C-terminal portion of Dock4 protein 19, 21, 26, which is responsible for its Rac1-activating ability 27.”
From Autism-like social deficit generated by Dock4 deficiency is rescued by restoration of Rac1 activity and NMDA receptor function. (2021) · cites this paper as [26]
Recent studies have identified DOCK4 variations associated with ASD, including single nucleotide variations and chromosome microdeletions or duplications.
“Recent studies have identified a number of DOCK4 variations associated with ASD, including both single nucleotide variations (SNVs) and chromosome microdeletions or duplications (Supplementary Table 1) 18–26.”
From Autism-like social deficit generated by Dock4 deficiency is rescued by restoration of Rac1 activity and NMDA receptor function. (2021) · cites this paper as [26]
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- Authors
- 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, Y.-I., Inagaki, M., Hashimoto, N., Kusumi, I., Son, S., Murai, T., Ikegame, T., Okada, N., Kasai, K., Kunimoto, S., Mori, D., Iwata, N., & Ozaki, N.
- Affiliations
- Nagoya University Institute for Advanced Research (JP)
- Nagoya University Hospital (JP)
- Nagoya University (JP)
- McLean Hospital (US)
- National Center of Neurology and Psychiatry (JP)
- Meijo University (JP)
- Institutes of Innovation for Future Society, Nagoya University (JP)
- Aichi Psychiatric Medical Center (JP)
- RIKEN Center for Brain Science (JP)
- Taisho University (JP)
- Fujita Health University (JP)
- The University of Osaka (JP)
- Niigata University (JP)
- Tokyo Metropolitan Institute of Medical Science (JP)
- University of Toyama (JP)
- Kohnodai Hospital, National Center for Global Health and Medicine (JP)
- The University of Tokyo (JP)
- Hamamatsu University (JP)
- Teikyo University (JP)
- Hamamatsu University School of Medicine (JP)
- Kanazawa University (JP)
- Kyoto University (JP)
- University of Fukui (JP)
- Tokushima University (JP)
- National Epilepsy Center (JP)
- Hokkaido University (JP)
- The University of Tokyo Institutes for Advanced Study (JP)
- Brain & Mind Research Center, Nagoya University (JP)
- Corresponding author
- Ozaki, Norio
- ORCID
- Kushima, Itaru
- Nakatochi, Masahiro
- Shimamura, Teppei
- Okada, Takashi
- Uno, Yota
- Ishizuka, Kanako
- Shiino, Tomoko
- Kimura, Hiroki
- Arioka, Yuko
- Yoshimi, Akira
- Nakamura, Yukako
- Yamamoto, Maeri
- Iidaka, Tetsuya
- Iritani, Shuji
- Inada, Toshiya
- Ogawa, Nanayo
- Shishido, Emiko
- Torii, Youta
- Kawano, Naoko
- Yamamoto, Toshimichi
- Ikeda, Masashi
- Hashimoto, Ryota
- Yamamori, Hidenaga
- Yasuda, Yuka
- Someya, Toshiyuki
- Watanabe, Yuichiro
- Egawa, Jun
- Itokawa, Masanari
- Arai, Makoto
- Miyashita, Mitsuhiro
- Suzuki, Michio
- Takahashi, Tsutomu
- Usami, Masahide
- Sasaki, Tsukasa
- Kuwabara, Hitoshi
- Tochigi, Mamoru
- Yamasue, Hidenori
- Eriguchi, Yosuke
- Benner, Seico
- Kojima, Masaki
- Yassin, Walid
- Yokoyama, Shigeru
- Kimura, Ryo
- Funabiki, Yasuko
- Kosaka, Hirotaka
- Ohmori, Tetsuro
- Numata, Shusuke
- Yoshikawa, Takeo
- Toyota, Tomoko
- Yamakawa, Kazuhiro
- Suzuki, Toshimitsu
- Inoue, Yushi
- Inagaki, Masumi
- Hashimoto, Naoki
- Kusumi, Ichiro
- Son, Shuraku
- Murai, Toshiya
- Ikegame, Tempei
- Okada, Naohiro
- Kasai, Kiyoto
- Mori, Daisuke
- Iwata, Nakao
- Ozaki, Norio
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2018-09
- Volume
- 24
- Issue
- 11
- Pages
- 2838-2856
- ISSN
- 2211-1247 (ISSN-L)
- OpenAlex
- W2890839967
- Cited by
- 251
- References
- 46
- Citations by year
- 2026: 14 · 2025: 16 · 2024: 24 · 2023: 29 · 2022: 39 · 2021: 64 · 2020: 34 · 2019: 28 · 2018: 2 · 2014: 1
- FWCI
- 19.63
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Japan Society for the Promotion of Science
- Ministry of Education, Culture, Sports, Science and Technology
- Ministry of Health, Labour and Welfare
- SENSHIN Medical Research Foundation
- Uehara Memorial Foundation
- Japan Agency for Medical Research and Development (JP16H06277, JP18dk0307075, JP18dk0307081, JP18dm0107083, JP18dm0107087, JP18dm0107088, JP18dm0107089, JP18dm0107092, JP18dm0107097, JP18dm0207004, JP18dm0207005, JP18dm0207006)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
- Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Keywords
- copy number variation, autism spectrum disorder, schizophrenia, intellectual disability, oxidative stress response, lipid metabolism, genome stability, 22q11.2, Japanese population
- MeSH terms
- Autism Spectrum Disorder, Adolescent, Adult, Child, Female, Genotype, Humans, Male, Middle Aged, Schizophrenia, Oxidative Stress, Genetic Predisposition to Disease, Genome-Wide Association Study, Young Adult, DNA Copy Number Variations
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