Integrative Analyses of De Novo Mutations Provide Deeper Biological Insights into Autism Spectrum Disorder

doi:10.1016/j.celrep.2017.12.074

. 2018 Jan 16;22(3):734-747.

doi: 10.1016/j.celrep.2017.12.074.

Integrative Analyses of De Novo Mutations Provide Deeper Biological Insights into Autism Spectrum Disorder

Atsushi Takata¹, Noriko Miyake¹, Yoshinori Tsurusaki², Ryoko Fukai³, Satoko Miyatake⁴, Eriko Koshimizu¹, Itaru Kushima⁵, Takashi Okada⁵, Mako Morikawa⁵, Yota Uno⁵, Kanako Ishizuka⁵, Kazuhiko Nakamura⁶, Masatsugu Tsujii⁷, Takeo Yoshikawa⁸, Tomoko Toyota⁸, Nobuhiko Okamoto⁹, Yoko Hiraki¹⁰, Ryota Hashimoto¹¹, Yuka Yasuda¹², Shinji Saitoh¹³, Kei Ohashi¹³, Yasunari Sakai¹⁴, Shouichi Ohga¹⁴, Toshiro Hara¹⁵, Mitsuhiro Kato¹⁶, Kazuyuki Nakamura¹⁷, Aiko Ito¹⁸, Chizuru Seiwa¹⁸, Emi Shirahata¹⁸, Hitoshi Osaka¹⁹, Ayumi Matsumoto¹⁹, Saoko Takeshita²⁰, Jun Tohyama²¹, Tomoko Saikusa²², Toyojiro Matsuishi²², Takumi Nakamura²³, Takashi Tsuboi²⁴, Tadafumi Kato²⁵, Toshifumi Suzuki²⁶, Hirotomo Saitsu¹, Mitsuko Nakashima¹, Takeshi Mizuguchi¹, Fumiaki Tanaka²⁷, Norio Mori²⁸, Norio Ozaki⁵, Naomichi Matsumoto²⁹

Affiliations

¹ Department of Human Genetics, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan.
² Department of Human Genetics, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan; Clinical Research Institute, Kanagawa Children's Medical Center, 2-138-4 Mutsukawa, Minami-ku, Yokohama 232-8555, Japan.
³ Department of Human Genetics, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan; Department of Neurology and Stroke Medicine, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan.
⁴ Department of Human Genetics, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan; Clinical Genetics Department, Yokohama City University Hospital, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan.
⁵ Department of Psychiatry, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan.
⁶ Department of Neuropsychiatry, Hirosaki University Graduate School of Medicine, 5 Zaif-cho, Hirosaki 036-8562, Japan; Department of Psychiatry, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu 431-3192, Japan.
⁷ Faculty of Sociology, Chukyo University, 101 Tokodachi, Kaizu-cho, Toyota 470-0393, Japan.
⁸ Laboratory for Molecular Psychiatry, RIKEN Brain Science Institute, 2-1 Hirosawa, Wako 351-0198, Japan.
⁹ Department of Medical Genetics, Osaka Medical Center and Research Institute for Maternal and Child Health, 840 Murodo-cho, Izumi 594-1101, Japan.
¹⁰ Hiroshima Municipal Center for Child Health and Development, 2-15-55 Hikarimachi, Higashi-ku, Hiroshima 732-0052, Japan.
¹¹ Molecular Research Center for Children's Mental Development, United Graduate School of Child Development, Osaka University, D3, 2-2 Yamadaoka, Suita 565-0871, Japan; Department of Psychiatry, Osaka University Graduate School of Medicine, D3, 2-2 Yamadaoka, Suita 565-0871, Japan.
¹² Department of Psychiatry, Osaka University Graduate School of Medicine, D3, 2-2 Yamadaoka, Suita 565-0871, Japan.
¹³ Department of Pediatrics and Neonatology, Nagoya City University Graduate School of Medical Sciences, Kawasumi 1, Mizuho-cho, Mizuho-ku, Nagoya 467-8601, Japan.
¹⁴ Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
¹⁵ Fukuoka Children's Hospital, 5-1-1 Kashiiteriha, Higashi-ku, Fukuoka 813-0017, Japan.
¹⁶ Department of Pediatrics, Showa University School of Medicine, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8666, Japan.
¹⁷ Department of Pediatrics, Yamagata University Faculty of Medicine, 2-2-2 Iida-nishi, Yamagata 990-9585, Japan.
¹⁸ Department of Pediatrics, Yamagata Prefectural Rehabilitation Center for Children with Disabilities, 3-7-1 Kawasaki, Kaminoyama, Yamagata 999-3145, Japan.
¹⁹ Department of Pediatrics, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke 329-0498, Japan.
²⁰ Department of Pediatrics, Yokohama City University Medical Center, 4-57 Urafune, Minami-ku, Yokohama 232-0024, Japan.
²¹ Department of Pediatrics, Nishi-Niigata Chuo National Hospital, 1-14-1 Masago, Nishi-ku, Niigata 950-2085, Japan.
²² Departments of Pediatrics and Child Health, Kurume University School of Medicine, 67 Asahi-machi, Kurume 830-0011, Japan; Department of Pediatrics, St. Mary's Hospital, 422 Tsubukuhonmach, Kurume 830-8543, Japan.
²³ Laboratory for Molecular Dynamics of Mental Disorders, RIKEN Brain Science Institute, 2-1 Hirosawa, Wako-shi, Saitama 351-0198, Japan; Department of Life Sciences, Graduate School of Arts and Sciences, University of Tokyo, Tokyo 153-8902, Japan.
²⁴ Department of Life Sciences, Graduate School of Arts and Sciences, University of Tokyo, Tokyo 153-8902, Japan.
²⁵ Laboratory for Molecular Dynamics of Mental Disorders, RIKEN Brain Science Institute, 2-1 Hirosawa, Wako-shi, Saitama 351-0198, Japan.
²⁶ Department of Human Genetics, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan; Department of Obstetrics and Gynecology, Juntendo University Faculty of Medicine, Tokyo 113-8421, Japan.
²⁷ Department of Neurology and Stroke Medicine, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan.
²⁸ Department of Psychiatry, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu 431-3192, Japan.
²⁹ Department of Human Genetics, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan. Electronic address: naomat@yokohama-cu.ac.jp.

PMID: 29346770
DOI: 10.1016/j.celrep.2017.12.074

Free article

Integrative Analyses of De Novo Mutations Provide Deeper Biological Insights into Autism Spectrum Disorder

Atsushi Takata et al. Cell Rep. 2018.

Free article

. 2018 Jan 16;22(3):734-747.

doi: 10.1016/j.celrep.2017.12.074.

Authors

Affiliations

¹ Department of Human Genetics, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan.
² Department of Human Genetics, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan; Clinical Research Institute, Kanagawa Children's Medical Center, 2-138-4 Mutsukawa, Minami-ku, Yokohama 232-8555, Japan.
³ Department of Human Genetics, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan; Department of Neurology and Stroke Medicine, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan.
⁴ Department of Human Genetics, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan; Clinical Genetics Department, Yokohama City University Hospital, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan.
⁵ Department of Psychiatry, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan.
⁶ Department of Neuropsychiatry, Hirosaki University Graduate School of Medicine, 5 Zaif-cho, Hirosaki 036-8562, Japan; Department of Psychiatry, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu 431-3192, Japan.
⁷ Faculty of Sociology, Chukyo University, 101 Tokodachi, Kaizu-cho, Toyota 470-0393, Japan.
⁸ Laboratory for Molecular Psychiatry, RIKEN Brain Science Institute, 2-1 Hirosawa, Wako 351-0198, Japan.
⁹ Department of Medical Genetics, Osaka Medical Center and Research Institute for Maternal and Child Health, 840 Murodo-cho, Izumi 594-1101, Japan.
¹⁰ Hiroshima Municipal Center for Child Health and Development, 2-15-55 Hikarimachi, Higashi-ku, Hiroshima 732-0052, Japan.
¹¹ Molecular Research Center for Children's Mental Development, United Graduate School of Child Development, Osaka University, D3, 2-2 Yamadaoka, Suita 565-0871, Japan; Department of Psychiatry, Osaka University Graduate School of Medicine, D3, 2-2 Yamadaoka, Suita 565-0871, Japan.
¹² Department of Psychiatry, Osaka University Graduate School of Medicine, D3, 2-2 Yamadaoka, Suita 565-0871, Japan.
¹³ Department of Pediatrics and Neonatology, Nagoya City University Graduate School of Medical Sciences, Kawasumi 1, Mizuho-cho, Mizuho-ku, Nagoya 467-8601, Japan.
¹⁴ Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
¹⁵ Fukuoka Children's Hospital, 5-1-1 Kashiiteriha, Higashi-ku, Fukuoka 813-0017, Japan.
¹⁶ Department of Pediatrics, Showa University School of Medicine, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8666, Japan.
¹⁷ Department of Pediatrics, Yamagata University Faculty of Medicine, 2-2-2 Iida-nishi, Yamagata 990-9585, Japan.
¹⁸ Department of Pediatrics, Yamagata Prefectural Rehabilitation Center for Children with Disabilities, 3-7-1 Kawasaki, Kaminoyama, Yamagata 999-3145, Japan.
¹⁹ Department of Pediatrics, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke 329-0498, Japan.
²⁰ Department of Pediatrics, Yokohama City University Medical Center, 4-57 Urafune, Minami-ku, Yokohama 232-0024, Japan.
²¹ Department of Pediatrics, Nishi-Niigata Chuo National Hospital, 1-14-1 Masago, Nishi-ku, Niigata 950-2085, Japan.
²² Departments of Pediatrics and Child Health, Kurume University School of Medicine, 67 Asahi-machi, Kurume 830-0011, Japan; Department of Pediatrics, St. Mary's Hospital, 422 Tsubukuhonmach, Kurume 830-8543, Japan.
²³ Laboratory for Molecular Dynamics of Mental Disorders, RIKEN Brain Science Institute, 2-1 Hirosawa, Wako-shi, Saitama 351-0198, Japan; Department of Life Sciences, Graduate School of Arts and Sciences, University of Tokyo, Tokyo 153-8902, Japan.
²⁴ Department of Life Sciences, Graduate School of Arts and Sciences, University of Tokyo, Tokyo 153-8902, Japan.
²⁵ Laboratory for Molecular Dynamics of Mental Disorders, RIKEN Brain Science Institute, 2-1 Hirosawa, Wako-shi, Saitama 351-0198, Japan.
²⁶ Department of Human Genetics, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan; Department of Obstetrics and Gynecology, Juntendo University Faculty of Medicine, Tokyo 113-8421, Japan.
²⁷ Department of Neurology and Stroke Medicine, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan.
²⁸ Department of Psychiatry, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu 431-3192, Japan.
²⁹ Department of Human Genetics, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan. Electronic address: naomat@yokohama-cu.ac.jp.

PMID: 29346770
DOI: 10.1016/j.celrep.2017.12.074

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: AGO1; ASD; ATP1A3; ATP2B2; GGNBP2; MCM6; cardiac glycosides; cerebellum; de novo mutations; striatum.

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Integrative Analyses of De Novo Mutations Provide Deeper Biological Insights into Autism Spectrum Disorder

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Integrative Analyses of De Novo Mutations Provide Deeper Biological Insights into Autism Spectrum Disorder

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