Hierarchical Cortical Transcriptome Disorganization in Autism

Background: The pathophysiology behind atypical brain development in autism spectrum disorder (ASD) is highly complex. Several elegant genetic studies have unveiled a diverse array of biological mechanisms associated with ASD and functional genomics work has begun to identify specific dysregulated transcriptomic pathways. In particular, examination of the ASD cortical transcriptome at the systems-level has highlighted dysregulation in two important gene modules (i.e. collections of genes whose expression levels are highly correlated). The first module is downregulated and enriched for synaptic processes and neuronal markers, while the second module is upregulated and enriched for immune/inflammation processes and astrocyte and M2 microglia activation state markers.

Objectives: A key question that remains unclear is whether these pathways are independently dysregulated or some convergence/interaction exists between such systems.

Methods:  To address this question we analyzed the cortical transcriptome of two independent ASD datasets (Gupta et al., 2014; Voineagu et al., 2011) using different statistical and network-based gene expression and protein-protein interaction approaches. We tested the hypothesis that diverse molecular mechanisms are hierarchically disrupted in the cortical transcriptome of ASD and point towards interacting systems-level pathology rather than multiple independent types of pathology in synaptic and immune processes. Specifically, we hypothesize that dysregulated gene co-expression modules may work in synergy to form emergent pathology not visible by looking at single modules in isolation.

Results: We identify replicable evidence for 10 gene co-expression modules that are differentially expressed (DE) in ASD cortical tissue. Rather than underlying distinct non-interacting pathology, these modules DE modules are highly correlated and such correlations increased in ASD. Moreover, this synergy and interaction was present at the protein level. This systems-level pathology is characterized by downregulated synaptic and neural developmental processes and upregulated catabolism, viral processes, translation, protein targeting and localization, interferon signaling, glia-relevant, and apoptosis processes. Our hierarchical examination of the ASD cortical transcriptome also shows important disorganization at the level of meta-modules (clusters of highly correlated modules). We identify subtle and specific changes in summary measures of networks organization or global patterns of network reorganization providing important insights on how the ASD cortical transcriptome is affected at the systems-level.

Conclusions: This work highlights a hierarchical view of cortical transcriptome dysregulation in ASD. In doing so, we provide novel insight into new dysregulated processes coordinated with other previously described dysregulated signals. Our approach allows for a better bird’s eye view of how multiple pathophysiological processes may operate in ASD and may hint at new systems level phenomena as a potentially more accurate description of the pathophysiology affecting the brain in ASD. This perspective may have important translational and clinical implications as well as potential to help enable cross-level work connecting systems biology with systems neuroscience.