Transcriptomic dysregulation across the cerebral cortex in autism spectrum disorder

Transcriptomic dysregulation across the cerebral cortex in autism spectrum disorder

A recent study in Nature demonstrated transcriptomic dysregulation in the cerebral cortex in autism spectrum disorders (ASD).

Lernen: Bei ASS tritt eine breite Transkriptom-Dysregulation über die Großhirnrinde auf. Bildnachweis: Ukrolenochka/Shutterstock

background

Risk factors for ASD include a significant genetic component, with hundreds of risk genes involved. Molecular profiling studies have observed consistent epigenetic and transcriptomic dysregulation patterns along the temporal and frontal cortex in most ASD cases. These include upregulation of astrocyte, nerve and microglial genes, downregulation of synaptic genes and attenuation of cortical gene expression gradients. Whether these represent focal, regional or generalized molecular pathology remains unknown.

The study and results

The present study performed RNA sequencing (RNA-seq) of 725 brain samples across 11 cortical areas from autopsy samples from 49 individuals with ASD and 54 neurotypical subjects (controls). Approximately 4,223 genes and 9,474 transcripts were differentially expressed across the cortex. The differential expression signals were clearer and had a greater effect in transcripts than in genes.

The regional consistency of these patterns was assessed by calculating differential expression in each cortical region separately. The regional effect size changes were compared to the corresponding signature of the entire cortex. ASD transcriptomic signatures were consistent across the 11 cortical areas, despite considerable variation in the number of differentially expressed genes (DEGs) due to differences in sample size.

The highest signal was recorded in the primary visual cortex (Brodmann area 17, BA17) at more than 3200 DEG. Furthermore, changes in effect size were more significant at BA17 compared to the whole cortex signal. In addition, the authors evaluated the differential expression of genes and transcripts in 83 pancortex samples from nine individuals with maternal chromosome 15q11.2-13.1 duplication syndrome (dup15q syndrome), a rare genetic disorder and one of the most common forms of syndromic ASD.

The transcriptomic changes between idiopathic ASD and dup15q overlapped significantly, and dup15q showed significantly increased gene expression dysregulation overall. These results suggested that the molecular pathology of idiopathic ASD and dup15q syndrome was widespread across different cortical areas.

Furthermore, the authors found that the typical transcription patterns that distinguish cortical regions were significantly attenuated in ASD, with some posterior areas (BA17 and B39/40) showing strong attenuation patterns. Next, the researchers categorized genes across all samples into modules (clusters with high co-expression levels) using weighted gene correlation network analysis and identified 35 gene co-expression modules.

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Fifteen and nine modules were up- and down-regulated in ASD, respectively. This analysis was repeated for transcript-level quantifications and 61 transcript modules were identified. Of these, nine and five were upregulated and downregulated in ASD.

In total, 38 modules were downregulated or upregulated in at least one cortical region in ASD. Eighteen gene/transcript modules showed consistent cortex-wide expression dysregulation; of these, the IsoformM37 and GeneM5 modules showed significant enrichment for common genetic variations associated with ASD. The GeneM5 module, downregulated in ASD, was significantly enriched in genes harboring ASD-associated rare de novo mutation disrupting proteins.

In contrast, the IsoformM37 module, which is upregulated in ASD, was enriched for common genetic risk variants for ASD and contained genes involved in protein folding and heat shock proteins. In addition, there were 13 modules with regionally different dysregulation patterns in ASD. However, none of these were enriched for known ASD gene risk variants.

Six of these modules were downregulated in ASD, while they were more highly expressed in posterior cortical areas than in frontal regions in neurotypical subjects. Four modules with more expression in anterior regions than posterior regions in neurotypical subjects were upregulated cortex-wide in ASD, attenuating the pattern.

Single nuclear RNA-seq (snRNA-seq) was performed in some subjects to examine the extent to which changes in gene expression reflect changes in cellular proportion in ASD. The researchers sequenced over 250,000 cell nuclei from six people with ASD and six matched controls and identified 26 different cell clusters.

In addition, cell type deconvolution (CTD) was performed using temporal and frontal bulk methylation profiling data from single-cell methylome analyses. CTD analyzes showed nominal increases and decreases in prefrontal cortex (PFC) microglia and temporal lobe oligodendrocytes, respectively, in ASD; nevertheless, these shifts in cell proportions were not maintained after false discovery rate (FDR) correction.

Finally, the authors examined cell type-specific DEG signatures in ASD across occipital, parietal, and temporal lobes. Occipital and parietal cell types showed three to four times more DEGs than PFC. Most DEG signals came from excitatory neurons, with those from the occipital lobe showing the highest DEG signal.

Conclusions

In conclusion, the researchers identified gene and transcript expression changes throughout the cortex that affect multiple neural cell types and biological processes in ASD. Most notable were the changes observed in ASD in the primary visual cortex (BA17).

The downregulated neuronal energy pathway genes and the upregulated reactive microglial and immune response genes were affected cortex-wide in ASD and also showed regional gradients. Overall, these results highlighted the molecular changes in the cortex in ASD that go beyond the previously established upregulated immune/glial and downregulated neuron functional categories.

Reference:

• Gandal MJ, Haney JR, Wamsley B, et al. (2022). Bei ASS tritt eine breite Transkriptom-Dysregulation über die Großhirnrinde auf. Natur. doi: 10.1038/s41586-022-05377-7 https://www.nature.com/articles/s41586-022-05377-7

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