A Brain Region-Specific Predictive Gene Map for Autism Derived by Profiling a Reference Gene Set

Abstract

Molecular underpinnings of complex psychiatric disorders such as autism spectrum disorders (ASD) remain largely unresolved. Increasingly, structural variations in discrete chromosomal loci are implicated in ASD, expanding the search space for its disease etiology. We exploited the high genetic heterogeneity of ASD to derive a predictive map of candidate genes by an integrated bioinformatics approach. Using a reference set of 84 Rare and Syndromic candidate ASD genes (AutRef84), we built a composite reference profile based on both functional and expression analyses. First, we created a functional profile of AutRef84 by performing Gene Ontology (GO) enrichment analysis which encompassed three main areas: 1) neurogenesis/projection, 2) cell adhesion, and 3) ion channel activity. Second, we constructed an expression profile of AutRef84 by conducting DAVID analysis which found enrichment in brain regions critical for sensory information processing (olfactory bulb, occipital lobe), executive function (prefrontal cortex), and hormone secretion (pituitary). Disease specificity of this dual AutRef84 profile was demonstrated by comparative analysis with control, diabetes, and non-specific gene sets. We then screened the human genome with the dual AutRef84 profile to derive a set of 460 potential ASD candidate genes. Importantly, the power of our predictive gene map was demonstrated by capturing 18 existing ASD-associated genes which were not part of the AutRef84 input dataset. The remaining 442 genes are entirely novel putative ASD risk genes. Together, we used a composite ASD reference profile to generate a predictive map of novel ASD candidate genes which should be prioritized for future research.

Co-expression Profiling of Autism Genes in the Mouse Brain

“…Some regions of the cerebral cortex are also highlighted by the second clique ( Figure 5 ), but to a lesser extent than the cerebellar cortex. Another recent study of our group examining the expression of the same autism gene set (AutRef84) in different human tissues, found a statistically significant enrichment in the frontal cortex [44]. The cerebral cortex was highlighted in other neuroanatomical studies of autism in both human [45], [46] and mouse [47] and is known to play a central role in cognitive and emotional processing [48], which are key deficits in autism and other neuropsychiatric disorders.…”

The Indispensable Roles of Microglia and Astrocytes during Brain Development

“…Abnormal functional connectivity can be caused by changes in synapse formation, function, and or abnormal synaptic pruning, which are also associated with developmental disorders (Derecki et al, 2012; State and Šestan, 2012; Tang et al, 2014; Washbourne, 2015). Also, variations in genes encoding for synaptic scaffolding proteins and proteins associated with synaptic transmission across cortical regions have been linked to neurodevelopmental disorders (Bourgeron, 2009; Kumar et al, 2011; Voineagu et al, 2011). As we have described in this review, both microglia and astrocytes play important roles in synaptogenesis and pruning and are thus, not surprisingly, found to be involved in the pathogenesis of neurodevelopmental disorders.…”

Synapse Assembly and Neurodevelopmental Disorders

“…Genes involved in neuronal cell adhesion and synaptic scaffolding are collectively the most prevalent genes found to date in genome-wide association studies (GWASs) of NDDs (Corvin, 2010;Kumar et al, 2011;O'Dushlaine et al, 2011). This suggests that cell adhesion events are critical for the correct assembly of synapses ( Figure 1, top left).…”