Coupling of autism genes to tissue-wide expression and dysfunction of synapse, calcium signalling and transcriptional regulation.

Jamie Reilly,Geraldine Leader,Sanbing Shen,Louise Gallagher,Nirakar Sahoo

doi:10.1371/journal.pone.0242773

Abstract

Autism Spectrum Disorder (ASD) is a heterogeneous disorder that is often accompanied with many co-morbidities. Recent genetic studies have identified various pathways from hundreds of candidate risk genes with varying levels of association to ASD. However, it is unknown which pathways are specific to the core symptoms or which are shared by the co-morbidities. We hypothesised that critical ASD candidates should appear widely across different scoring systems, and that comorbidity pathways should be constituted by genes expressed in the relevant tissues. We analysed the Simons Foundation for Autism Research Initiative (SFARI) database and four independently published scoring systems and identified 292 overlapping genes. We examined their mRNA expression using the Genotype-Tissue Expression (GTEx) database and validated protein expression levels using the human protein atlas (HPA) dataset. This led to clustering of the overlapping ASD genes into 2 groups; one with 91 genes primarily expressed in the central nervous system (CNS geneset) and another with 201 genes expressed in both CNS and peripheral tissues (CNS+PT geneset). Bioinformatic analyses showed a high enrichment of CNS development and synaptic transmission in the CNS geneset, and an enrichment of synapse, chromatin remodelling, gene regulation and endocrine signalling in the CNS+PT geneset. Calcium signalling and the glutamatergic synapse were found to be highly interconnected among pathways in the combined geneset. Our analyses demonstrate that 2/3 of ASD genes are expressed beyond the brain, which may impact peripheral function and involve in ASD co-morbidities, and relevant pathways may be explored for the treatment of ASD co-morbidities.

Highlights

Autism Spectrum Disorder (ASD) is a heterogeneous and complex neurodevelopmental disorder [1], with core features including stereotypical behaviours and impaired social and communication skills, and with various comorbidity
Our analyses suggest that a third of ASD risk genes (CNS geneset) is expressed in the Central Nervous System (CNS), which are involved in brain development, synaptic function and ion transport, whereas the majority of ASD factors are highly expressed in both CNS and peripheral tissues (CNS+Peripheral Tissue (PT) geneset), with pathways of brain development, chromatin organisation and gene regulation, which may account for ASD peripheral comorbidity
By utilizing multiple scoring systems, we have identified recurrent ASD candidate genes, with convergence on multiple pathways and processes involved in ASD (Fig 10)

Summary

Introduction

Autism Spectrum Disorder (ASD) is a heterogeneous and complex neurodevelopmental disorder [1], with core features including stereotypical behaviours and impaired social and communication skills, and with various comorbidity. The CNS comorbidity of ASD includes epilepsy, sleeping disorders [2], intellectual disabilities, language delay, anxiety and hyperactivity [3, 4], and the peripheral comorbidity includes gastrointestinal, metabolic disorders, auto-immune disorders, tuberous sclerosis, attention-deficit hyperactivity disorder, and sensory problems associated motor problems [2, 5,6,7,8]. It appears that genetic heterogeneity and environmental factors impact the severity of ASD, and the presence and severity of comorbid disorders [9]. Little is known about which set of genetic factors links to peripheral comorbidity, and it is crucial to decipher factors/pathways which are associated with the comorbidities

Methods

Findings

Discussion

Conclusion