Despite its heterogeneity, autism is characterized by a defined behavioral phenotype, suggesting that the molecular pathology affects specific neural substrates to cause behavioral dysfunction. Previous studies identified genes dysregulated in autism cortex but did not address their cell-type specificity. Moreover, it is unknown whether there is a core of genes dysregulated across multiple neocortical regions. We applied RNA sequencing to postmortem brain tissue samples from autism patients and neurologically normal controls and combined our data with previously published datasets. We then identified genes, pathways, and alternative splicing events which are dysregulated in five neocortical regions in autism. To gain information about cell-type specificity of the dysregulated genes, we analyzed single-nuclei RNA sequencing data of adult human cortex and intersected cell-type-specific gene signatures with genes dysregulated in autism in specific cortical regions. We found that autism-associated gene expression changes across 4 frontal and temporal cortex regions converge on 27 genes related to immune response and enriched in human astrocytes, microglia, and brain endothelium. Shared splicing changes, however, are found in genes predominantly associated with synaptic function and adult interneurons and projection neurons. Finally, we demonstrate that regions of DNA differentially methylated in autism overlap genes associated with development and enriched in human cortical oligodendrocytes. Our study identifies signatures of autism molecular pathology shared across neocortical regions, as well as neural cell types enriched for common dysregulated genes, thus paving way for assessing cell-type-specific mechanisms of autism pathology.

中文翻译：

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自闭症分子病理学的细胞类型特异性分析确定了受新皮质区域影响的常见基因和途径。

尽管具有异质性，但自闭症的特征在于明确的行为表型，这表明分子病理学会影响特定的神经基质，从而导致行为功能障碍。以前的研究确定了自闭症皮层中失调的基因，但没有解决它们的细胞类型特异性。此外，尚不清楚是否存在跨多个新皮质区域失调的基因核心。我们将 RNA 测序应用于自闭症患者和神经正常对照的死后脑组织样本，并将我们的数据与先前发布的数据集相结合。然后，我们确定了在自闭症的五个新皮质区域中失调的基因、通路和可变剪接事件。为了获得有关失调基因的细胞类型特异性的信息，我们分析了成年人皮层的单核 RNA 测序数据，并将细胞类型特异性基因特征与特定皮层区域自闭症中失调的基因相交。我们发现，4 个额叶和颞叶皮层区域的自闭症相关基因表达变化集中在 27 个与免疫反应相关的基因上，这些基因富含人类星形胶质细胞、小胶质细胞和脑内皮细胞。然而，在主要与突触功能和成人中间神经元和投射神经元相关的基因中发现了共享剪接变化。最后，我们证明了自闭症中差异甲基化的 DNA 区域与与发育相关的基因重叠并富含人类皮质少突胶质细胞。我们的研究确定了新皮质区域共有的自闭症分子病理学特征，