A perturbed gene network containing PI3K-AKT, RAS-ERK and WNT-β-catenin pathways in leukocytes is linked to ASD genetics and symptom severity
A perturbed gene network containing PI3K-AKT, RAS-ERK and WNT-β-catenin pathways in leukocytes is linked to ASD genetics and symptom severity
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DOI：
10.1038/s41593-019-0489-x
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发表时间：
2019-10-01
影响因子：
25
通讯作者：
Lewis, Nathan E.
中科院分区：
文献类型：
--
作者：
Gazestani, Vahid H.;Pramparo, Tiziano;Lewis, Nathan E.
数百个基因与自闭症谱系障碍（ASD）有关，但它们促成 ASD 病理生理学的机制仍然难以捉摸。在这里，我们分析了患有 ASD 或一般人群典型发育的 1 至 4 岁男幼儿的白细胞转录组学。我们发现了一个受干扰的基因网络，其中包括胎儿大脑发育过程中高表达的基因。该网络在人类诱导多能干细胞衍生的自闭症谱系障碍神经元模型中失调。高置信度的 ASD 风险基因作为网络的上游调节因子出现，许多风险基因可能通过调节 RAS-ERK、PI3K-AKT 和 WNT-β-catenin 信号通路影响网络。我们发现该网络的失调程度与幼儿自闭症谱系障碍症状的严重程度相关。这些结果表明，自闭症谱系障碍的异质遗传学可能会失调核心网络，从而影响产前和产后早期的大脑发育，从而影响后期自闭症谱系障碍症状的严重程度。
Hundreds of genes are implicated in autism spectrum disorder (ASD), but the mechanisms through which they contribute to ASD pathophysiology remain elusive. Here we analyzed leukocyte transcriptomics from 1- to 4-year-old male toddlers with ASD or typical development from the general population. We discovered a perturbed gene network that includes highly expressed genes during fetal brain development. This network is dysregulated in human induced pluripotent stem cell-derived neuron models of ASD. High-confidence ASD risk genes emerge as upstream regulators of the network, and many risk genes may impact the network by modulating RAS-ERK, PI3K-AKT and WNT-beta-catenin signaling pathways. We found that the degree of dysregulation in this network correlated with the severity of ASD symptoms in the toddlers. These results demonstrate how the heterogeneous genetics of ASD may dysregulate a core network to influence brain development at prenatal and very early postnatal ages and, thereby, the severity of later ASD symptoms.