TY - JOUR T1 - Hierarchical cortical transcriptome disorganization in autism JF - bioRxiv DO - 10.1101/042937 SP - 042937 AU - Michael V. Lombardo AU - Eric Courchesne AU - Nathan E. Lewis AU - Tiziano Pramparo Y1 - 2016/01/01 UR - http://biorxiv.org/content/early/2016/07/20/042937.abstract N2 - Autism spectrum disorder (ASD) is genetically heterogeneous and complex. Functional genomics work has begun to identify specific dysregulated transcriptomic pathways. However, it remains unclear whether such dysregulation reveals evidence for independent or higher-level coordinated systems-level pathology. Here we find replicable evidence across 2 datasets for 10 gene co-expression modules that are differentially expressed in ASD cortex. Rather than being distinct non-interacting pathology, these modules work in synergy and interact 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. Hierarchical organization of meta-modules (clusters of highly correlated modules) is also highly affected in ASD. These results support a new viewpoint of pathophysiology affecting ASD characterized by multiple coordinated dysregulated transcriptomic processes that produce emergent systems-level pathology and which may be overlooked by focusing on dysregulated elements in isolation. ER -