Earlier this year we reported on studies that identified genetic linkages to autism, a condition that comprises a spectrum of behavioural and cognitive disturbances of childhood development and is known to be highly heritable. Despite efforts to identify the genetic components, fewer than 10% of autism cases have been attributed to single gene disorders.
In new work from Duke University Medical Center, researchers have unexpectedly identified an epigenetic component of autism. The study revealed a genomic deletion containing the oxytocin receptor gene (OXTR), previously implicated in autism, in an autistic child and his mother (who exhibits symptoms of obsessive-compulsive disorder). The child’s sibling, also autistic, did not have the deletion but exhibited DNA methylation at CpG sites known to be involved in regulation of OXTR expression. Further analysis in a larger set of affected individuals confirmed a significant increase in methylation of these sites compared to controls and that this correlated with decreased expression of OXTR mRNA in temporal cortex tissue.
Oxytocin is a hormone secreted into the bloodstream from the brain, and also released within the brain, where it has a bearing on social interaction. Previous studies have shown that giving oxytocin can improve an autistic person’s social engagement behaviour and it is being explored as a potential treatment. Increased methylation of the oxytocin receptor gene may make a person less sensitive to the hormone and the results of this study, published in the journal BMC Medicine, could provide information about which individuals will respond better to treatment with oxytocin.
Autism, the best known of the autism spectrum disorders (ASDs), is a relatively common condition affecting around 1 in 150 children in the US, with about four times more boys than girls affected. People with autism spectrum disorders struggle with social communication and interactions, and have difficulty relating to other people and their emotions. A number of factors – both genetic and environmental – have been suggested to be linked to autism and two recent studies have now provided evidence of associations with genetic variations.
In the first study, which is published in the journal Nature, variations in a region close to the genes for two neuronal cell-adhesion molecules, cadherin 9 (CDH9) and cadherin 10 (CDH10) were found to occur more frequently in children with ASDs than in unaffected children. These cadherin molecules, which are expressed on the surface of neurons, mediate calcium-dependent cell-cell adhesion and are important in shaping the physical structure of the developing brain as well as the functional connections between different areas of the brain. The researchers propose that these gene variants are new susceptibility factors for ASDs and estimate that they may contribute to up to 15% of cases.
The second study, also published in the journal Nature, identified copy number variations – deletions or duplications of DNA – in genes belonging to two biological pathways. Interestly, one pathway involved the same neuronal cell-adhesion molecule gene family that was identified in the first study, whilst the other involved genes in the ubiquitin degradation pathway. The role of ubiquitin, which tags proteins – including the neuronal cell-adhesion molecules – for proteasome-mediated degradation, presents a mechanism that links the two gene pathways. The new data support previous evidence from functional magnetic resonance imaging studies showing that children with ASDs may have reduced connectivity among neural cells, and with anatomy studies that have found abnormal development in the frontal lobes in autistic patients.
Although the new information does not fully explain why some children develop ASDs and cannot immediately be used to provide clinical treatments, it should provide ideas for further experiments that may eventually lead to strategies for the prevention or early treatment of ASDs.