Abstract
Autism is a highly heritable neurodevelopmental disorder, yet the genetic underpinnings of the disorder are largely unknown. Aberrant brain overgrowth is a well-replicated observation in the autism literature; but association, linkage, and expression studies have not identified genetic factors that explain this trajectory. Few studies have had sufficient statistical power to investigate whole-genome gene expression and genotypic variation in the autistic brain, especially in regions that display the greatest growth abnormality. Previous functional genomic studies have identified possible alterations in transcript levels of genes related to neurodevelopment and immune function. Thus, there is a need for genetic studies involving key brain regions to replicate these findings and solidify the role of particular functional pathways in autism pathogenesis. We therefore sought to identify abnormal brain gene expression patterns via whole-genome analysis of mRNA levels and copy number variations (CNVs) in autistic and control postmortem brain samples. We focused on prefrontal cortex tissue where excess neuron numbers and cortical overgrowth are pronounced in the majority of autism cases. We found evidence for dysregulation in pathways governing cell number, cortical patterning, and differentiation in young autistic prefrontal cortex. In contrast, adult autistic prefrontal cortex showed dysregulation of signaling and repair pathways. Genes regulating cell cycle also exhibited autism-specific CNVs in DNA derived from prefrontal cortex, and these genes were significantly associated with autism in genome-wide association study datasets. Our results suggest that CNVs and age-dependent gene expression changes in autism may reflect distinct pathological processes in the developing versus the mature autistic prefrontal cortex. Our results raise the hypothesis that genetic dysregulation in the developing brain leads to abnormal regional patterning, excess prefrontal neurons, cortical overgrowth, and neural dysfunction in autism.
Highlights
Clinical and subclinical manifestations of autism begin during the first years of life [1]
We found age-dependent gene expression differences between young and adult autistic brains as well as rare and common genetic variants associated with autism that have important roles in neurodevelopment
Using genome-wide expression and copy number variations (CNVs) detection techniques, we discovered specific developmental pathways and processes in the prefrontal cortex that are significantly abnormal in younger autistic cases, other non-developmental processes that are dysregulated in older autism cases and, processes common across younger and older ages in autism
Summary
Clinical and subclinical manifestations of autism begin during the first years of life [1]. Neuroimaging studies of living infants and young children with autism have revealed abnormal brain overgrowth in the majority of cases, in prefrontal, temporal and amygdala regions [2–13]. These studies have shown abnormal functional asymmetry and activation in the cortex and cerebellum [14–16]. Excess neuron numbers in the prefrontal cortex, a substantial pathology that points to disruption of early developmental mechanisms that govern neuron numbers, and an 18% increase in brain weight at autopsy [17]. The underlying developmental molecular defects in the majority of autistic cases seem likely to be most evident at younger rather than older ages
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