Genetic association of DNMT variants can play a critical role in defining the methylation patterns in autism

Abstract

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder with impairments in social communication, restricted, repetitive and stereotyped behaviors. Both genetic and environmental factors are known to contribute toward pathophysiology of Autism. Environmental influences on gene expression can be mediated by methylation patterns which are established and maintained by DNA methyltransferases. Several studies in the past have investigated the role of global methylations in Autism. The present study is aimed to investigate the role of genetic variations in the DNA methyltransferase which might be critical in defining the threshold for environmental factors toward susceptibility to autism. Polymorphisms in DNA methyltransferases, DNMT1, DNMT3A, DNMT3B, and DNMT3L were screened for association with ASD in 180 autistic patients and 260 healthy controls from a south Indian population. DNMT1 rs10418707 and rs10423341, and DNMT3A rs2289195 were found to be significantly associated at genotypic and allelic level with ASD. Functional prediction indicates that these SNPs have a role in transcriptional regulation and increased expression, indicating that hypermethylation might be induced by its genotype status. The study might reflect the role of genetics variants in DNMTs in defining the threshold of environmental impact in influencing the disease or phenotype variations in ASD. © 2019 IUBMB Life, 2019

Invited Review: Epigenetics in neurodevelopment

“…Additionally, mutations in DNMT3B have been associated with immunodeficiency, centromere instability, facial anomalies (ICF) syndrome, also leading to global histone modification changes [48]. Furthermore, single‐nucleotide polymorphisms (SNPs) in DNMTs have been associated with autism spectrum disorder (ASD) [49]. Mutations to the ‘readers’ of DNA methylation also have neurodevelopmental consequences, particularly in the case of MeCP2: MECP2 loss‐of‐function mutations have been found to cause Rett syndrome [50], a progressive childhood neurological disorder characterized by developmental stagnation and subsequent regression, in which previously learned motor, communicative and social skills are lost [51].…”

Impacts of cannabinoid epigenetics on human development: reflections on Murphy et. al. ‘cannabinoid exposure and altered DNA methylation in rat and human sperm’ epigenetics 2018; 13: 1208-1221.

“…Several cannabinoids in addition to Δ9-tetrahydrocannabinol (THC) were implicated in such actions including cannabidiol, cannabinol, cannabichromene, cannabigerol and tetrahydrocannabivarin. A rich literature demonstrates the impacts of epigenomics on brain development and its involvement in autistic spectrum disorders [156][157][158][159][160][161]. Whether cannabis is acting by epigenetic or other routes including those outlined above remains to be demonstrated.…”

Statistical model integrating interactions into genotype-phenotype association mapping: an application to reveal 3D-genetic basis underlying Autism

“…(Chahrour and Zoghbi 2007; Gabel et al 2015). Additionally, mutations on DNMT3A have been widely reported in ASD (Alex et al 2019; Yokoi et al 2020) as well as those with intellectual disabilities (Tatton-Brown et al 2014). As such, our proposed mechanism is that mutations in the region on or surrounding DNMT3A in conjunction with mutations of FOXP2 binding sites jointly confer the risk of ASD.…”