Thursday October 30 2014
Genetic mutations may disrupt the brain’s synapses
“A massive international study has started to unpick the ‘fine details’ of why some people develop autism,” BBC News reports.
A team of international researchers looked for variations in the DNA sequences of the genes in 3,871 people with autistic spectrum disorder (ASD) and 9,937 unaffected family members or unrelated controls.
The researchers identified 107 genes containing variations associated with ASD. In more than 5% of the people with ASD, these genes had new (not inherited) mutations that led to genes either not working at all, or working less well.
The genes encoded proteins involved in synaptic formation, the (expression) activity of other genes, and proteins involved in modifying the packaging of DNA inside cells.
Synapses are junctions where signals are passed from one nerve cell to another, and are found in the brain and nervous system. They are thought to be essential in underpinning consciousness, thinking and behaviour.
This study sheds more light on ASD, but does not necessarily mean that screening for the condition is closer.
Deciding whether screening is a good option involves considering a wide range of issues in addition to determining how well people with ASD can be identified, including an assessment of the options open to someone identified as having or being at risk of ASD.
For example, if screening was going to be offered during pregnancy, would it be ethical to terminate a viable pregnancy on the grounds that the child would develop ASD? Many people with ASD live fulfilling and rewarding lives.
Where did the story come from?
The study was carried out by an international team of researchers and was funded by the US National Institutes of Health and other sources.
The study was published in the peer-reviewed scientific journal Nature.
The news stories differed in terms of the number of genes reportedly associated with ASD; these figures differed depending on what they took to be statistically significant. For the record, there was strong evidence for 22 genes and weaker evidence for another 107 genes.
Despite headlines suggesting that autism screening is closer, this is debatable. ASD is a highly complex condition and we still don’t fully understand what causes it.
While mutations in many genes have been found to be associated with the disorder, environmental factors may also play a role.
None of the UK media considered whether screening for ASD would actually be desirable. As there is currently no cure for ASD, screening could offer the option of terminating a pregnancy (or rejecting an embryo for an IVF procedure).
However, a case could be made that screening, either during pregnancy or once the child was born, would allow parents to be given information about what to expect, and treatment could be started soon after birth.
What kind of research was this?
This was a case-control study that compared the sequence of genes in people with ASD (the cases) and controls, who were either family members or unrelated people. Any changes that were only found in people with ASD, or in more people with autism than without, could be contributing to the condition. They also looked at whether these variations had been inherited by the person with ASD from one of their parents, or if they were “new” variations that had happened in their very early development.
This is the ideal study design to identify variants that are associated with ASD. It is a complex condition, with many genes potentially associated with it – each contributing a small amount to a person’s risk. Environmental factors may also play a role. Different people with ASD may have different combinations of genetic risk factors, and some people without the condition may have some of these genetic risk factors. This complexity makes it very difficult to say for certain that all of the genetic variations identified definitely contribute to the condition, and to justify screening.
What did the research involve?
The researchers sequenced all of the parts of genes that contained instructions for making proteins (called “the exome”), and that lay on any chromosomes other than the X and Y chromosome (called the “autosomes”).
They did this in 3,871 people with ASD and 9,937 controls, and compared them to look for variations associated with ASD. The researchers noted that this is the largest sample ever studied in this way.
The researchers used new statistical methods to look for variations associated with ASD. Because of the large number of genes being looked at, and the multiple comparisons involved, there is a risk that some of the statistically significant associations found will be false (for example a significant association is seen when none exists). One way of overcoming this problem is to adjust the thresholds for what is considered a statistically significant result – called controlling the “false discovery rate”. For example, setting a false discovery rate of 0.05 means that 5% of significant associations would be expected to be false. The researchers looked at which genes were associated with ASD using different false discovery rates.
The researchers also looked at what the genes with variations did in the body, to understand how they might be contributing to causing ASD.
What were the basic results?
The researchers identified 22 autosomal genes that were associated with ASD when they set the cut-off so that at least 95% of associations are expected to be true (false discovery rate <0.05).
33 autosomal genes were associated with ASD when the cut-off was set so that at least 90% of associations seen are expected to be true (false discovery rate <0.1). Of these 33 genes, 15 were considered to already have good evidence of being associated with ASD, 11 had some previous evidence of association but not as strong, and seven had never been reported as being associated with autism before.
When the cut-off was set so that at least 70% of associations seen are expected to be true (false discovery rate <0.30), 107 autosomal genes were associated with ASD. More than 5% of the people with ASD had new (not inherited) mutations in these genes that either stop the gene from working entirely, or make it work less well.
This study would not have identified all genes associated with ASD risk, and the researchers estimated that, based on their results, there could be 1,150 genes contributing to autism risk.
The genes associated with ASD contained instructions for making proteins involved in various processes, including:
- making the junctions between nerve cells (synapses)
- changing how active other genes are
- modifying the packaging of DNA inside cells
How did the researchers interpret the results?
The researchers conclude that people with ASD have more loss-of-function mutations than would be expected in the population as a whole, and that these mutations are concentrated in a “handful” of genes.
They say that their findings suggest that genes involved in synapses (nerve junctions), transcription (gene activity) and DNA packaging are involved in ASD.
This large study compared the sequence of the genes in 3,871 people with ASD with 9,937 unaffected family members or unrelated controls.
Overall, 107 autosomal genes were found to be associated with ASD, with about 30% of these expected to not to be associated with the condition. These genes had new (not inherited) mutations, resulting in less or no function in more than 5% of the people with ASD. The researchers also estimated that over 1,000 genes could be contributing to autism risk. This gives some idea of how complex the genetics of autism appear to be – not all people with the condition will carry the same genetic risk factors, and some people without the condition will carry some of these genetic risk factors.
The researchers looked at what processes the genes they identified are involved in. The genes encoded proteins involved in synaptic (nerve junction) formation, the (expression) activity of other genes, and proteins involved modifying the packaging of DNA inside cells. This gives researchers more of an idea of what might be going wrong within the cells of people with ASD.
ASD is a complex condition, and mutations in many genes have been found to be associated with the disorder – with many more yet to be found. This study sheds more light on the condition, but we still have a lot to learn. This means that using this type of genetic information to screen for this condition is unlikely to happen in the foreseeable future.
There is also the possibility that learning more about the genetics of ASD could lead to new treatments.
Analysis by Bazian. Edited by NHS Choices. Follow Behind the Headlines on Twitter. Join the Healthy Evidence forum.