Cell Reports (Jan 2018)
Integrative Analyses of De Novo Mutations Provide Deeper Biological Insights into Autism Spectrum Disorder
- 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,
- Naomichi Matsumoto
Affiliations
- Atsushi Takata
- Department of Human Genetics, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan
- Noriko Miyake
- Department of Human Genetics, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan
- Yoshinori Tsurusaki
- Department of Human Genetics, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan
- Ryoko Fukai
- Department of Human Genetics, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan
- Satoko Miyatake
- Department of Human Genetics, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan
- Eriko Koshimizu
- Department of Human Genetics, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan
- Itaru Kushima
- Department of Psychiatry, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan
- Takashi Okada
- Department of Psychiatry, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan
- Mako Morikawa
- Department of Psychiatry, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan
- Yota Uno
- Department of Psychiatry, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan
- Kanako Ishizuka
- Department of Psychiatry, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan
- Kazuhiko Nakamura
- Department of Neuropsychiatry, Hirosaki University Graduate School of Medicine, 5 Zaif-cho, Hirosaki 036-8562, Japan
- Masatsugu Tsujii
- Faculty of Sociology, Chukyo University, 101 Tokodachi, Kaizu-cho, Toyota 470-0393, Japan
- Takeo Yoshikawa
- Laboratory for Molecular Psychiatry, RIKEN Brain Science Institute, 2-1 Hirosawa, Wako 351-0198, Japan
- Tomoko Toyota
- Laboratory for Molecular Psychiatry, RIKEN Brain Science Institute, 2-1 Hirosawa, Wako 351-0198, Japan
- Nobuhiko Okamoto
- Department of Medical Genetics, Osaka Medical Center and Research Institute for Maternal and Child Health, 840 Murodo-cho, Izumi 594-1101, Japan
- Yoko Hiraki
- Hiroshima Municipal Center for Child Health and Development, 2-15-55 Hikarimachi, Higashi-ku, Hiroshima 732-0052, Japan
- Ryota Hashimoto
- Molecular Research Center for Children’s Mental Development, United Graduate School of Child Development, Osaka University, D3, 2-2 Yamadaoka, Suita 565-0871, Japan
- Yuka Yasuda
- Department of Psychiatry, Osaka University Graduate School of Medicine, D3, 2-2 Yamadaoka, Suita 565-0871, Japan
- Shinji Saitoh
- Department of Pediatrics and Neonatology, Nagoya City University Graduate School of Medical Sciences, Kawasumi 1, Mizuho-cho, Mizuho-ku, Nagoya 467-8601, Japan
- Kei Ohashi
- Department of Pediatrics and Neonatology, Nagoya City University Graduate School of Medical Sciences, Kawasumi 1, Mizuho-cho, Mizuho-ku, Nagoya 467-8601, Japan
- Yasunari Sakai
- Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan
- Shouichi Ohga
- Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan
- Toshiro Hara
- Fukuoka Children’s Hospital, 5-1-1 Kashiiteriha, Higashi-ku, Fukuoka 813-0017, Japan
- Mitsuhiro Kato
- Department of Pediatrics, Showa University School of Medicine, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8666, Japan
- Kazuyuki Nakamura
- Department of Pediatrics, Yamagata University Faculty of Medicine, 2-2-2 Iida-nishi, Yamagata 990-9585, Japan
- Aiko Ito
- Department of Pediatrics, Yamagata Prefectural Rehabilitation Center for Children with Disabilities, 3-7-1 Kawasaki, Kaminoyama, Yamagata 999-3145, Japan
- Chizuru Seiwa
- Department of Pediatrics, Yamagata Prefectural Rehabilitation Center for Children with Disabilities, 3-7-1 Kawasaki, Kaminoyama, Yamagata 999-3145, Japan
- Emi Shirahata
- Department of Pediatrics, Yamagata Prefectural Rehabilitation Center for Children with Disabilities, 3-7-1 Kawasaki, Kaminoyama, Yamagata 999-3145, Japan
- Hitoshi Osaka
- Department of Pediatrics, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke 329-0498, Japan
- Ayumi Matsumoto
- Department of Pediatrics, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke 329-0498, Japan
- Saoko Takeshita
- Department of Pediatrics, Yokohama City University Medical Center, 4-57 Urafune, Minami-ku, Yokohama 232-0024, Japan
- Jun Tohyama
- Department of Pediatrics, Nishi-Niigata Chuo National Hospital, 1-14-1 Masago, Nishi-ku, Niigata 950-2085, Japan
- Tomoko Saikusa
- Departments of Pediatrics and Child Health, Kurume University School of Medicine, 67 Asahi-machi, Kurume 830-0011, Japan
- Toyojiro Matsuishi
- Departments of Pediatrics and Child Health, Kurume University School of Medicine, 67 Asahi-machi, Kurume 830-0011, Japan
- Takumi Nakamura
- Laboratory for Molecular Dynamics of Mental Disorders, RIKEN Brain Science Institute, 2-1 Hirosawa, Wako-shi, Saitama 351-0198, Japan
- Takashi Tsuboi
- Department of Life Sciences, Graduate School of Arts and Sciences, University of Tokyo, Tokyo 153-8902, Japan
- Tadafumi Kato
- Laboratory for Molecular Dynamics of Mental Disorders, RIKEN Brain Science Institute, 2-1 Hirosawa, Wako-shi, Saitama 351-0198, Japan
- Toshifumi Suzuki
- Department of Human Genetics, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan
- Hirotomo Saitsu
- Department of Human Genetics, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan
- Mitsuko Nakashima
- Department of Human Genetics, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan
- Takeshi Mizuguchi
- Department of Human Genetics, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan
- Fumiaki Tanaka
- Department of Neurology and Stroke Medicine, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan
- Norio Mori
- Department of Psychiatry, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu 431-3192, Japan
- Norio Ozaki
- Department of Psychiatry, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan
- Naomichi Matsumoto
- Department of Human Genetics, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan
- DOI
- https://doi.org/10.1016/j.celrep.2017.12.074
- Journal volume & issue
-
Vol. 22,
no. 3
pp. 734 – 747
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.
Keywords
