Merging Data from Genetic and Epigenetic Approaches to Better Understand Autistic Spectrum Disorder

Abstract

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder that is characterized by a wide range of cognitive and behavioral abnormalities. Genetic research has identified large numbers of genes that contribute to ASD phenotypes. There is compelling evidence that environmental factors contribute to ASD through influences that differentially impact the brain through epigenetic mechanisms. Both genetic mutations and epigenetic influences alter gene expression in different cell types of the brain. Mutations impact the expression of large numbers of genes and also have downstream consequences depending on specific pathways associated with the mutation. Environmental factors impact the expression of sets of genes by altering methylation/hydroxymethylation patterns, local histone modification patterns and chromatin remodeling. Herein, we discuss recent developments in the research of ASD with a focus on epigenetic pathways as a complement to current genetic screening.

Transcriptome analysis of microglia in a mouse model of Rett syndrome: differential expression of genes associated with microglia/macrophage activation and cellular stress

“…In addition, Voineagu et al showed that the transcriptome changes they observed in the ASD brains converge with GWAS data, which are enriched for neuronal genes, in particular genes coding for synaptic proteins; immune changes have a less pronounced genetic component, suggesting that the differential expression found in ASD is secondary [58]. This idea is consistent with the key role of microglia in synaptic pruning [59–61]. A reasonable hypothesis is that a primary defect in neurons leading to dysfunctional synaptogenesis is triggering microglial activation and synaptic pruning, which is then reflected in the postmortem gene expression findings.…”

Autism genes are selectively targeted by environmental pollutants including pesticides, heavy metals, bisphenol A, phthalates and many others in food, cosmetics or household products

“…In addition the offspring show impaired motor coordination and motor learning ability coupled with a reduction in the cerebellar size and impairment in the cerebellar foliation profile [263,264]. A 3 day exposure to 2.5 mg/kg tretinoin (gestational days [11][12][13] produces a 10% reduction in weight of cerebellum at 4 weeks of age, not accompanied by other malformations [265]. In rats treated with retinoic acid at gestational day E10, the foetuses show structural changes similar to humans with Arnold-Chiari malformation, including downward displacement of the cerebellum to just above the foramen magnum and compression of the developing medulla into a small posterior fossa [266].…”

“…Epigenetic changes have been observed in autism, and these too may be related to environmental agents [12,13] as reported for Bisphenol A and heavy metals (see Table 1) and for flame retardants and other endocrine disruptors, including soy formula and phytoestrogens such as genistein [14][15][16] and also for other nutritional agents such as Vitamin D and folic acid [17][18][19]. However, epigenetics is not the subject of this study, which is limited to the 206 autism-related polymorphic genes reported from gene association studies.…”

Epigenetic regulation of RELN and GAD1 in the frontal cortex (FC) of autism spectrum disorder (ASD) subjects

“…Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by impaired social interactions, language deficits, as well as, restrictive or repetitive behaviors. As recently iterated (Grayson and Guidotti, 2016; Zhubi et al, 2014a), to better understand the complexity of ASD etiopathogenesis, it is essential to conceptualize genetic and environmental factors as complementary factors that modify ASD risk through changes in gene expression. Environmental factors and genetic background interact and amplify the contribution of individual components.…”