Abstract
Autism spectrum disorders (ASDs) are highly heritable, and six genome-wide association studies (GWASs) of ASDs have been published to date. In this study, we have integrated the findings from these GWASs with other genetic data to identify enriched genetic networks that are associated with ASDs. We conducted bioinformatics and systematic literature analyses of 200 top-ranked ASD candidate genes from five published GWASs. The sixth GWAS was used for replication and validation of our findings. Further corroborating evidence was obtained through rare genetic variant studies, that is, exome sequencing and copy number variation (CNV) studies, and/or other genetic evidence, including candidate gene association, microRNA and gene expression, gene function and genetic animal studies. We found three signaling networks regulating steroidogenesis, neurite outgrowth and (glutamatergic) synaptic function to be enriched in the data. Most genes from the five GWASs were also implicated—independent of gene size—in ASDs by at least one other line of genomic evidence. Importantly, A-kinase anchor proteins (AKAPs) functionally integrate signaling cascades within and between these networks. The three identified protein networks provide an important contribution to increasing our understanding of the molecular basis of ASDs. In addition, our results point towards the AKAPs as promising targets for developing novel ASD treatments.
Highlights
Autism spectrum disorders (ASDs) are a group of pervasive neurodevelopmental disorders that are characterized by qualitative impairments in reciprocal social interaction and communication as well as restricted, repetitive and stereotyped patterns of behavior, interests and activities
Six genome-wide association study (GWAS) of ASDs have been published to date (Table 1)
In order to test whether the GWAS genes included in this study were likely to constitute false positive findings, we looked for confirmation from other types of genetic studies and we performed a comparative analysis of the top ranked GWAS findings from unrelated disorders
Summary
Autism spectrum disorders (ASDs) are a group of pervasive neurodevelopmental disorders that are characterized by qualitative impairments in reciprocal social interaction and communication as well as restricted, repetitive and stereotyped patterns of behavior, interests and activities. Individuals with autism show impairments in all three core symptom domains and an onset of symptoms before 3 years of age, whereas Asperger’s syndrome is characterized by social and behavioral impairments in the presence of a normal language development before age 3 years. We find that signaling cascades within and between the three networks are functionally connected by A-kinase anchor proteins (AKAPs), which seem to Center for Human Genetic Research, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
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