基于自闭症谱系障碍成人血液中全局基因表达变化鉴定异常先天和适应性免疫。
Identification of aberrant innate and adaptive immunity based on changes in global gene expression in the blood of adults with autism spectrum disorder.
机构信息
Department of Neuropsychiatry, Molecules and Function, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime, 791-0295, Japan.
出版信息
J Neuroinflammation. 2021 Apr 30;18(1):102. doi: 10.1186/s12974-021-02154-7.
BACKGROUND
Autism spectrum disorder (ASD) is characterized as a neurodevelopmental disorder, and one of the main hypotheses regarding its cause is genetic factors. A previous meta-analysis of seven microarray studies and one RNA sequencing (RNA-seq) study using the blood of children with ASD identified dysregulation of gene expressions relevant to the immune system. In this study, we explored changes in global gene expression as the phenotype of ASD in the blood of adults with ASD.
METHODS
We recruited an RNA-seq cohort (ASD vs. control; n = 6 each) and a replication cohort (ASD vs. control; n = 19 each) and conducted RNA-seq to explore changes in global gene expression. We then subjected the significantly up- and downregulated genes to gene ontology (GO) and core analyses. Weighted gene correlation network analysis (WGCNA) was performed with all 11,617 genes detected in RNA-seq to identify the ASD-specific gene network.
RESULTS
In total, 117 significantly up- and 83 significantly downregulated genes were detected in the ASD compared with the control group, respectively (p < 0.05 and q < 0.05). GO analysis revealed that the aberrant innate and adaptive immunity were more obvious in the 117 upregulated than in the 83 downregulated genes. WGCNA with core analysis revealed that one module including many immune-related genes was associated with the natural killer cell signaling pathway. In the results for the replication cohort, significant changes with same trend found in RNA-seq data were confirmed for MAFB (p = 0.046), RPSAP58 (p = 0.030), and G2MK (p = 0.004).
LIMITATIONS
The sample size was relatively small in both the RNA-seq and replication cohorts. This study examined the mRNA expression level, so the interaction between mRNA and protein remains unclear. The expression changes between children and adults with ASD were not compared because only adults with ASD were targeted.
CONCLUSIONS
The dysregulated gene expressions confirmed in the blood of adults with ASD were relevant to the dysfunction of innate and adaptive immunity. These findings may aid in understanding the pathogenesis of ASD.
背景
自闭症谱系障碍（ASD）是一种神经发育障碍，其病因的主要假说之一是遗传因素。先前对七项微阵列研究和一项使用自闭症儿童血液的 RNA 测序（RNA-seq）研究的荟萃分析确定了与免疫系统相关的基因表达失调。在这项研究中，我们探索了成人自闭症血液中的 ASD 表型的全局基因表达变化。
方法
我们招募了一个 RNA-seq 队列（ASD 与对照；n = 6 例）和一个复制队列（ASD 与对照；n = 19 例），并进行 RNA-seq 以探索全局基因表达的变化。然后，我们将显著上调和下调的基因进行基因本体论（GO）和核心分析。使用 RNA-seq 检测到的所有 11617 个基因进行加权基因相关网络分析（WGCNA），以识别 ASD 特异性基因网络。
结果
总共在 ASD 与对照组相比，分别检测到 117 个显著上调和 83 个显著下调的基因（p < 0.05 和 q < 0.05）。GO 分析表明，在 117 个上调基因中，先天和适应性免疫的异常更为明显。使用核心分析的 WGCNA 显示，一个包含许多免疫相关基因的模块与自然杀伤细胞信号通路相关。在复制队列的结果中，在 RNA-seq 数据中发现具有相同趋势的显著变化得到了验证，包括 MAFB（p = 0.046）、RPSAP58（p = 0.030）和 G2MK（p = 0.004）。
局限性
RNA-seq 和复制队列的样本量都相对较小。本研究检测了 mRNA 表达水平，因此 mRNA 与蛋白质之间的相互作用尚不清楚。由于仅针对成人自闭症患者，因此未比较儿童和成人自闭症患者之间的表达变化。
结论
在成人自闭症患者血液中证实的失调基因表达与先天和适应性免疫功能障碍有关。这些发现可能有助于理解 ASD 的发病机制。
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