Integrative Analyses of De Novo Mutations Provide Deeper Biological Insights into Autism Spectrum Disorder
Integrative Analyses of De Novo Mutations Provide Deeper Biological Insights into Autism Spectrum Disorder
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DOI：
10.1016/j.celrep.2017.12.074
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发表时间：
2018-01-16
期刊：
影响因子：
8.8
通讯作者：
Matsumoto, Naomichi
中科院分区：
文献类型：
--
作者：
Takata, Atsushi;Miyake, Noriko;Matsumoto, Naomichi
最近的研究确定了新基因突变(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个起源于日本的ASD前谱带中的DNM，并确认了ASD跨种族的“从头开始的范例”。基于这种一致性，我们结合了我们和已发表的ASD队列中的破坏性DNM列表(TRIO总数为4,244)，并进行了综合的生物信息学分析。除了复制以前的研究结果外，我们的分析还强调了ATP结合基因和胎儿小脑/纹状体回路。对单个基因的分析确定了61个富含破坏DNMS的基因，其中包括我们的数据集现在有助于统计意义的10个基因。对通过破坏DNMS而影响基因表达的化合物的筛选显示，丙戊酸具有全球下调作用，丙戊酸是一种已知的自闭症风险因素，而心脏苷类药物则上调这些基因。总体而言，我们的综合方法为ASD提供了更深层次的生物学和潜在的医学见解。
Recent studies have established important roles of de novo mutations (DNMs) in autism spectrum disorders (ASDs). Here, we analyze DNMs in 262 ASD pro-bands 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 down-regulating 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.