Transcriptomic analysis of autistic brain reveals convergent molecular pathology

Abstract

Autism spectrum disorder (ASD) is a common, highly heritable neuro-developmental condition characterized by marked genetic heterogeneity1–3. Thus, a fundamental question is whether autism represents an etiologically heterogeneous disorder in which the myriad genetic or environmental risk factors perturb common underlying molecular pathways in the brain4. Here, we demonstrate consistent differences in transcriptome organization between autistic and normal brain by gene co-expression network analysis. Remarkably, regional patterns of gene expression that typically distinguish frontal and temporal cortex are significantly attenuated in the ASD brain, suggesting abnormalities in cortical patterning. We further identify discrete modules of co-expressed genes associated with autism: a neuronal module enriched for known autism susceptibility genes, including the neuronal specific splicing factor A2BP1/FOX1, and a module enriched for immune genes and glial markers. Using high-throughput RNA-sequencing we demonstrate dysregulated splicing of A2BP1-dependent alternative exons in ASD brain. Moreover, using a published autism GWAS dataset, we show that the neuronal module is enriched for genetically associated variants, providing independent support for the causal involvement of these genes in autism. In contrast, the immune-glial module showed no enrichment for autism GWAS signals, indicating a non-genetic etiology for this process. Collectively, our results provide strong evidence for convergent molecular abnormalities in ASD, and implicate transcriptional and splicing dysregulation as underlying mechanisms of neuronal dysfunction in this disorder.

A genetic model for neurodevelopmental disease

“…Genes involved in synaptic function have been repeatedly shown to play a role in neurological disorders [62,63,65,66]. Recent studies of ASD have identified overrepresentation of CNS development genes in addition to several other pathways [21,65,67]. In our own recent analysis of 209 exomes from patients with sporadic autism, we found that 39% of the de novo disruptive mutations formed a highly interconnected protein-protein interaction network involving beta-catenin upstream and downstream regulation (Figure 3) [52].…”

DNA methylation changes in plasticity genes accompany the formation and maintenance of memory

“…More recent papers studied several brain regions across development. For example, Kang et al (2011) created a network using data from six brain structures across pre-and post-natal development and found modules related to different spatiotemporal profiles 4 , while Voineagu et al (2011) studied changes in expression modules in the autistic brain 7 . In our initial assessment of the first two brains in the Allen Human Brain Atlas 3 , we identified groups of genes related both to major cell types (i.e., astrocytes, choroid plexus, etc.…”

Maternal hospitalization with infection during pregnancy and risk of autism spectrum disorders

“…For example, a number of studies have suggested the involvement of genetic factors influencing immune function in the etiology of ASD (Gregg et al, 2008;Voineagu et al, 2011). It is possible that such genetic involvement may act as a confounder (the genetic factor increases risk of both infection and ASD, resulting in a spurious association between infection and ASD) or as an instrument (the genetic factor increases risk of infection which then increases risk of ASD) or as an effect modifier (the genetic factor amplifies the deleterious effect of infection on risk of ASD) -but the latter two does not change the result that maternal infection is associated with ASD.…”