Abstract
BackgroundNumerous studies have highlighted the elevated degree of comorbidity associated with autism spectrum disorder (ASD). These comorbid conditions may add further impairments to individuals with autism and are substantially more prevalent compared to neurotypical populations. These high rates of comorbidity are not surprising taking into account the overlap of symptoms that ASD shares with other pathologies. From a research perspective, this suggests common molecular mechanisms involved in these conditions. Therefore, identifying crucial genes in the overlap between ASD and these comorbid disorders may help unravel the common biological processes involved and, ultimately, shed some light in the understanding of autism etiology.ResultsIn this work, we used a two-fold systems biology approach specially focused on biological processes and gene networks to conduct a comparative analysis of autism with 31 frequently comorbid disorders in order to define a multi-disorder subcomponent of ASD and predict new genes of potential relevance to ASD etiology. We validated our predictions by determining the significance of our candidate genes in high throughput transcriptome expression profiling studies. Using prior knowledge of disease-related biological processes and the interaction networks of the disorders related to autism, we identified a set of 19 genes not previously linked to ASD that were significantly differentially regulated in individuals with autism. In addition, these genes were of potential etiologic relevance to autism, given their enriched roles in neurological processes crucial for optimal brain development and function, learning and memory, cognition and social behavior.ConclusionsTaken together, our approach represents a novel perspective of autism from the point of view of related comorbid disorders and proposes a model by which prior knowledge of interaction networks may enlighten and focus the genome-wide search for autism candidate genes to better define the genetic heterogeneity of ASD.
Highlights
Numerous studies have highlighted the elevated degree of comorbidity associated with autism spectrum disorder (ASD)
We extracted all the International Classification of Diseases (ICD-9) codes of autism and its comorbid conditions in these studies and, when ICD-9 code lists were not directly available, we matched the co-occurring conditions mined from these sources to their corresponding codes and references under the ICD-9 system, broadly used in healthcare [25]; we mapped each ICD-9 code in our comorbid disorder list to MeSH (Medical Subject Headings form from U.S National Library of Medicine) terms in order to facilitate the subsequent automated gene search
For ASD, we completed our resulting list of associated genes by adding the autism genes included in Simons Foundation Autism Research Initiative (SFARI) gene [28], as well as those reported as candidates in Iossifov et al [21] and De Rubeis et al [29]
Summary
Numerous studies have highlighted the elevated degree of comorbidity associated with autism spectrum disorder (ASD). These comorbid conditions may add further impairments to individuals with autism and are substantially more prevalent compared to neurotypical populations. These high rates of comorbidity are not surprising taking into account the overlap of symptoms that ASD shares with other pathologies. Identifying crucial genes in the overlap between ASD and these comorbid disorders may help unravel the common biological processes involved and, shed some light in the understanding of autism etiology. Despite recent scientific advances shedding light into the molecular agents and biological mechanisms responsible for ASD, contributing to the discovery and validation of its causative genes [14], the exact factors still remain elusive and no unifying hypothesis about the molecular pathology of autism has emerged
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