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

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.

Paracetamol use during pregnancy — a call for precautionary action

“…In vivo, in vitro and ex vivo studies have shown that APAP directly perturbs hormone-dependent processes, including inhibition of androgen production and increased oestrogen production, disruption of steroidogenesis, depletion of sulfated sex hormones, perturbation of immune function, induction of oxidative stress and indirect activation of the endocannabinoid system 1,2,[61][62][63][64][65] . Independently of APAP, these processes have been implicated as mechanisms related to the development of neurodevelopmental [66][67][68][69][70][71][72][73][74][75][76] and reproductive disorders 2 . In addition to potential effects on neuronal and reproductive development, a combination of clinical studies together with experimental work in animal models and cell lines has also suggested that APAP exposure during pregnancy might decrease fetal haematopoietic stem cell numbers alter steroidogenesis in the placenta and induce placental damage 65,[77][78][79][80] .…”

The epilepsy–autism spectrum disorder phenotype in the era of molecular genetics and precision therapy

“…33,34 However, we know that an altered connectivity is shared between the two and that many of the mutations related to these disorders converge on biological pathways involved in neuronal communication. Therefore, according to previous studies, 35 some of the main risk genes are clustered into three groups that could guide in the understanding of the epilepsy-ASD phenotype with respect to being a problem of connectivity: (a) ion channels, (b) synaptic function and structure, and (c) transcriptional regulators. Figure 3 shows genes classified by family of mechanisms for both ASD and epilepsy.…”

Molecular Dysregulation in Autism Spectrum Disorder

“…WES studies have extended our in-depth knowledge on the rare de novo SNVs and CNVs impacting protein coding genes leading to dysregulation of signaling pathways controlling nervous system development, neuronal activity, synaptic homeostasis, immune response, chromatin modification, transcription and translation [ 9 , 10 , 11 , 12 ].…”

“…Autism etiology has many key players, including common genetic variants, inherited gene-disruptive mutations and rare variants of large effect outside of the coding region [ 6 , 7 , 8 ]. A number of pathways dysregulated in ASD, involve chromatin remodeling, RNA transcription and splicing, synaptic function, ion-channels, MAPK and calicium signaling [ 9 , 10 , 11 , 12 ]. This review will provide current information on innovative technologies like WES, WGS, non-coding RNAs, ASD models, pharmacogenomics and endophenotypes in ASD.…”