Scientists have identified “rogue genes that could unlock the riddle of autism”, according to the Daily Mail. The newspaper says that new research is a ‘breakthrough that could help millions,’ potentially improving the understanding and treatment of autism.

The research involved three separate studies, two from the US and one from the University of Oxford, which carried out analysis of the genetic material in children with autistic spectrum disorder (ASD) and their parents, comparing their genes with genetic samples from unaffected people.

This identified several variations in the genetic sequence which are possibly linked to autism. All of the genes concerned appeared to be involved in the formation and function of nerve cells in the brain. These findings offer further understanding of the development of ASD and hope for possibly developing future treatments. However, a lot more research will be needed. It is also likely that many non-genetic factors are involved in the development of ASD. While this area of research is important, genetic variations may not hold the entire answer.

 

Where did the story come from?

The research findings come from three scientific papers. Two of these were US studies published in the journal Nature, authored by Kai Wang, Joseph Glessner and colleagues of Center for Applied Genomics, Children’s Hospital of Philadelphia and various other US institutions. The third paper was authored by E Maestrini and colleagues of Wellcome Trust Centre for Human Genetics, University of Oxford and published in the journal, Molecular Psychiatry.

The studies received funding from numerous sources, including The Wellcome Trust, the National Institute of Neurological Disorders and Stroke (NINDS), National Institute of Mental Health (NIMH), the Children’s Hospital of Philadelphia and the Autism Speaks action group.

 

What kind of scientific study was this?

The research involved three genome-wide association studies attempting to find out the genes that increase susceptibility to autistic spectrum disorder (ASD).

Autism and other related conditions, such as Asperger’s syndrome, are characterised by difficulties in communication, social interaction and in understanding the thoughts, feelings and behaviour of others. They develop in childhood and affect mostly boys.

The largest of the three studies, published in Nature, involved a cohort of 780 families (3,101 people) which included children affected with autistic spectrum disorders (ASDs), a second cohort of 1,204 individuals with ASD and 6,491 control subjects. All subjects were of European ancestry. This research examined the genetic sequence from all chromosomes in the body looking for genetic differences between those affected and those not affected. Specifically they were looking for single-letter changes in the sequence of molecules in DNA or single nucleotide polymorphisms (SNPs),

The second US paper reported on another study examining the genetic sequence in 859 children with ASD (the cases group) and 1,409 healthy children (the controls group) to try and find out whether any genes were duplicated or deleted in individuals with ASD. Once again, all subjects were of European ancestry.

Individuals usually have two copies of each gene, one on each chromosome; any variation in this is known as a copy number variation (CNV). The researchers looked at 550,000 single-letter changes in the DNA across all chromosomes in order to try and identify CNVs at these sites that could increase susceptibility to autistic spectrum disorders. Any positive findings were evaluated in a further group of 1,336 ASD cases and 1,110 controls.

The University of Oxford focused their research on chromosomes 2 and 7, as a major autism study has previously associated certain regions on these chromosomes (AUTS1 and AUTS5) with ASDs.

The researchers performed a fine scan of these suspect regions within chromosome 2, using samples of 126 children with autism and their parents. For analysis of chromosome 7, samples came from 127 individuals and their parents. They also looked at the DNA of 188 people acting as controls.

In the second part of their research, the scientists carried out further investigation based on the strongest association results found, in an independent European family sample containing 390 affected individuals.

The researchers’ fine scan involved analysing SNPs in the DNA at over 3,000 positions within the AUTS1 and AUTS5 regions of chromosomes 2 and 7. The researchers also looked at whether cases and controls had any larger deletions or duplications (CNVs) of whole chunks of DNA in these regions.

 

What were the results of the study?

The research found links between autism and certain genes that are involved in the development of nerve cells in the brain and, in particular, the formation of the junction between nerve cells, known as the synapse.

In the largest Nature study, six SNP variants were found to be commonly associated with autism spectrum disorders, all located between two CDH9 and CDH10 genes on chromosome 5. Both genes code for nerve cell surface proteins that allow adhesion between nerve cells. The findings were replicated in two separate cohorts. Cell adhesion proteins are involved during brain development, helping nerve cells to migrate to the correct places in the brain and to connect with surrounding nerve cells.

In the second Nature study, which looked at at gene duplications or deletions in individuals with ASD, the researchers found few cases where variations occurred. Where CNVs did occur, they tended to affect genes once again involved in nerve cell adhesion, such as NLGN1 and ASTN2.

They also found children with ASD to have CNVs located in or around several genes involved in the ‘ubiquitin pathways’, which are suspected to be involved in the breakdown and turnover of adhesion proteins at the cell surface.

The University of Oxford study group identified CNVs on two genes associated with autism in chromosome 7, called DOCK4 and IMMP2L. The DOCK4 gene association was also supported by the replication in the independent European family cohort.

The DOCK4 gene is associated with the development of dendrites, the numerous branched projections coming from the body of the nerve cell. When an electrical impulse crosses the synapse from a neighbouring nerve cell, it is received by a dendrite, and this impulse is then transmitted along the dendrite to the cell body.

 

What interpretations did the researchers draw from these results?

The researchers concluded that they had identified genetic variations that were associated with autistic spectrum disorders. They called for future studies to further investigate their findings and potential roles of the candidate genes identified.

These findings are aptly summarised by Professor Monaco of the Wellcome Trust Centre for Human Genetics, who is quoted in the University of Oxford press release. He says that ‘the picture that emerges from these studies is a complex one. There are many genes involved in autism spectrum disorders, each has only a small effect or is found in only a minority of cases. This is not a surprise when clinicians and doctors see such different cases every day.’

‘The studies have implications for future diagnostic testing of autism spectrum disorders. I do believe such testing will become a possibility in the future, and may offer some clinical benefit to affected children and their families.’

 

What does the NHS Knowledge Service make of this study?

The three research studies have identified several genes that may play a role in susceptibility to autistic spectrum disorders. The genes tended to be involved in the formation of the junctions between nerve cells, called the synapses.

It is possible that because of these findings, new inroads can be made into further understanding the physiological processes that may be affected in people with ASD. Although further understanding of risk factors for ASDs and ASD biology gives hope for the development of new treatments and possibly even genetic tests, these are still some way off. However, these promising findings will spark much further research that might one day lead to these advances.

There may be numerous gene variations that could slightly increase an individual’s susceptibility to ASD, including variations not yet identified as playing a role. Further research will also be needed to investigate the variations identified in these studies, and determine how they or nearby variations might be having an effect on nerve cell development.

Also, it should be considered whether these various genetic links found may not be present in all people with autistic spectrum conditions, or whether people with these genetic variations might not go on to develop autism and other ASDs.

The causes of ASDs are not understood and there is likely to be a complex relationship of many different factors (genetic, possibly environmental, social and medical) that may contribute to the development of these disorders in any one individual.