How X-chromosome gene expression could influence autism risk

A gene located on the X chromosome could affect how autism manifests, potentially offering an explanation for the sex-based differences in autism prevalence. 

An examination of 18 genes linked with autism, undertaken by researchers at the Boston Children's Hospital in Massachusetts, showed that disrupting a single gene can alter the expression of other genes related to the condition – a phenomenon they describe as 'transcriptomic convergence'. In particular, the team found that the gene ZFX, which is located on the X chromosome, might contribute to the female protective effect observed in autism.

'The point is, if you down-regulate one autism gene, you down-regulate a whole bunch of them,' said Dr Rebecca Andersen, one of two lead authors of the paper, published in Nature. 

The genetic basis for autism has been the subject of study for decades. But the female protective effect, whereby autism is estimated to be three to four times more common in men than women, has proved difficult to explain. It has been theorised that genes positioned on the X chromosome could have a role in this effect, as women typically have two copies of the chromosome, compared with one in men.  

As part of the study, the researchers individually suppressed 18 genes linked to autism spectrum disorder in a human cell model. Such 'knocking-down' of individual genes resulted in disruption to hundreds of other autism-related genes.  

One of the main genes that the team focused on was ZFX, which is found on the X chromosome. Most X-chromosome genes have one copy inactivated to avoid excessive expression when a pair of X chromosomes are present. However, ZFX is not inactivated and is expressed from both the active and inactive X chromosomes in females. The study suggests that this higher expression of ZFX could help maintain the expression of other autism-associated genes, potentially buffering the effects of mutations and contributing to the female protective effect.

'The most important take-home messages are the idea of this transcriptomic convergence in autism and our identification of the ZFX gene as a potential driver of autism's male bias,' said Professor Christopher Walsh, the senior author of the study. 

Research such as this has the potential to shed further light on the genetic basis for autism, as well as raising the possibility of future therapies that could increase the expression of autism-associated genes. However, boosting ZFX expression as a potential treatment remains speculative and would require considerably more research. The authors also propose that this framework could be extended to identify the genetic mechanisms underlying various other conditions.