Department of Human Genetics, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan.
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.
Cell Rep. 2018 Jan 16;22(3):734-747. doi: 10.1016/j.celrep.2017.12.074.
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.
最近的研究已经确定了新生突变（DNMs）在自闭症谱系障碍（ASD）中的重要作用。在这里，我们分析了 262 名日本裔 ASD 先证者的 DNMs，并证实了 ASD 在不同种族中的“新生范例”。基于这种一致性，我们将我们和已发表的 ASD 队列中的破坏性 DNMs 列表（三核苷酸总数为 4244）进行组合，并进行综合生物信息学分析。除了复制之前研究的发现外，我们的分析还突出了 ATP 结合基因和胎儿小脑/纹状体回路。对个体基因的分析确定了 61 个富含破坏性 DNMs 的基因，其中包括十个基因，我们的数据集现在为这些基因的统计显著性做出了贡献。对受破坏性 DNMs 影响的基因表达的化合物进行筛选，揭示了丙戊酸（一种已知的 ASD 风险因素）的全局下调作用，而强心苷则上调这些基因。总的来说，我们的综合方法为 ASD 提供了更深入的生物学和潜在医学见解。
