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. 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 Takata  1 , Noriko Miyake  1 , Yoshinori Tsurusaki  2 , Ryoko Fukai  3 , Satoko Miyatake  4 , Eriko Koshimizu  1 , Itaru Kushima  5 , Takashi Okada  5 , Mako Morikawa  5 , Yota Uno  5 , Kanako Ishizuka  5 , Kazuhiko Nakamura  6 , Masatsugu Tsujii  7 , Takeo Yoshikawa  8 , Tomoko Toyota  8 , Nobuhiko Okamoto  9 , Yoko Hiraki  10 , Ryota Hashimoto  11 , Yuka Yasuda  12 , Shinji Saitoh  13 , Kei Ohashi  13 , Yasunari Sakai  14 , Shouichi Ohga  14 , Toshiro Hara  15 , Mitsuhiro Kato  16 , Kazuyuki Nakamura  17 , Aiko Ito  18 , Chizuru Seiwa  18 , Emi Shirahata  18 , Hitoshi Osaka  19 , Ayumi Matsumoto  19 , Saoko Takeshita  20 , Jun Tohyama  21 , Tomoko Saikusa  22 , Toyojiro Matsuishi  22 , Takumi Nakamura  23 , Takashi Tsuboi  24 , Tadafumi Kato  25 , Toshifumi Suzuki  26 , Hirotomo Saitsu  1 , Mitsuko Nakashima  1 , Takeshi Mizuguchi  1 , Fumiaki Tanaka  27 , Norio Mori  28 , Norio Ozaki  5 , Naomichi Matsumoto  29
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Free article

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

Atsushi Takata et al. Cell Rep. .
Free article

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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