Apr 30 2009

The Genetics of Autism

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A new genome-wide analysis of families with autism has found significant gene associations, adding to the growing evidence for strong genetic contribution to autism.  While this is still a long way away from explaining autism, it represents a significant advance in a very fruitful area of research.

But to put this into context, we need some background. Autism spectrum disorder (ASD) is not a single discrete pathophysiological disease. In fact, the term “disease” is probably not appropriate at all, which is why it is termed a “disorder.” Like many neurological conditions with primarily cognitive and behavior effects, ASD likely correlates with the organization and function of neurons in the brain – not a pathological disease process.

What this means is that there is likely to be a complex set of many factors that contribute to ASD – not one single cause. ASD is defined by the clinical symptoms that are evident – decreased social and verbal skills with a tendency to display repetitive behaviors or a narrow focus of interest. Brain function itself is highly complex, and these higher-order behaviors may just be the final common pathway of many potential underlying changes.

The same exact situation is true for other entities, like schizophrenia and attention deficit disorder (ADD). These syndromes are defined by clinical features, they represent a varied set of disorders with complex underlying causes. One difference, however, is that schizophrenia and ADD likely represent changes to particular parts of the brain, while autism is likely due to changes in the global architecture of the brain.

What all this means is that the genetics of autism is likely to be a complex puzzle, and so far that is what researchers are finding. ASD is not a genetic disease in the sense that, say, hemophilia is a genetic disease. Over the years, geneticists have identified a long list of simple genetic diseases – where a single mutation in a single gene causes disruption in the function of a single protein.  This class of genetic disorders is directly inherited, with various known patterns (autosomal vs X or Y linked or mitochondrial, and dominant vs recessive).

A separate class of genetic disorders is not directly inherited but for which there is a genetic predisposition. In these entities, certain genetic variants convey an increased risk of developing a disease or disorder, but it does not directly cause them.  ASD falls into this broad category.

How does a particular gene variant predispose to a disorder without “causing” it? There are two primary hypotheses to answer this question. The first is that one gene variant is not sufficient to cause a disease, but must be combined with other gene variants. Therefore, a person can have any of the gene variants that predispose to the disorder without having the disorder. No single implicated gene variant will correlate 100% with the disorder in question.

In these disorders predisposing gene variants are like a giant puzzle, but one that has many potential solutions. Perhaps there is a critical threshold – an individual will need to have a certain critical number of the predisposing variants, but in any combination, in order to manifest the disorder. This situation likely results from each variant decrease some physiological function by a small amount, but the cumulative effect of many variants impairs the function significantly enough to cause clinical manifestations.

The second way in which a genetic variant predisposes to without directly causing a disease or disorder is if there needs to be an environmental trigger. Perhaps the genetic variant only manifests if there is a particular environment in the womb. Some diseases, like multiple sclerosis, are now thought to be triggered, for example, by certain kinds of viral infections. Or a genetic variant may leave an individual more susceptible to a specific toxin or other environment stressor.

In fact, the interplay of environment and genetics is likely critical to the understanding of most genetic conditions, even the more direct genetic diseases. Genetics is only one factor in determining development. The environment of the womb (exposures to varying levels of maternal hormones, for example) is also critical.

Getting back to the genetics of autism, current models are therefore consistent with what is being found when the genetics of autism is researched – researchers are finding many genes that predispose to autism in a subset of cases but no single or simple universal cause. At present, 133 different gene variants have been linked to autism.

This new research, conducted by Dr. Hakon Hakonarson of the Children’s Hospital of Philadelphia, is a genome wide analysis involving about 10,000 individuals. This is a relatively new technique made possible by advances in computer technology and rapid DNA sequencing. They can compare genes across the entire genome among thousands of individuals and look for statistical patterns.

While this is a powerful technique, it is primarily a process of data mining for correlations. By itself this type of data cannot answer questions – but it can point us in the direction of the answers.

From the press release:

The new study has found a robust link between autism and six such variants. These do not invariably cause the condition, but they are about 20 per cent more common in children with autism than they are in those who are unaffected.

The results are especially significant because the variants lie between two genes, called CDH9 and CDH10, which are known to play an important role in forming nerve connections in the brain.

It is the last bit that makes these findings so interesting – more than a statistical fluke.  The gene variants that correlated with ASD are for proteins that are involved in the process of neurons forming connections with each other. There is already other lines of evidence that suggest what is different in ASD brains is a decrease in the amount of interconnectedness and communication among neurons. It is therefore likely no coincidence that this study found genetic correlations for proteins involved with neuronal connections.

This also is compatible with the finding that many separate genes are potentially involved with ASD – for there are many separate genes and processes involved with forming and maintaining neuronal connections. Perhaps each variant associated with ASD, by itself, does not result in any significant difference in the ability of neurons to connect to each other. But when a sufficient number of variants are present, with the proper environmental factors, neuronal connections are decreased resulting in ASD.

Researchers in this area are being properly cautious about the interpretation of this latest research. This is a significant finding, which strengthens the evidence for an important genetic role in ASD and advances our understanding of the ultimate causes of ASD. This, of course, creates the potential for biological interventions, although it is always difficult to predict the outcomes of translational research (developing clinical applications from basic science).

Autism researcher, Professor Simon Baron-Cohen, summed up the current situation:

The challenge for future research will be to establish which of these findings can be well-replicated in independent samples and by independent labs; what the functions of these genes are and where they are expressed; which aspects of the phenotype of autism they can explain; whether they relate to one sub-group or the whole autism spectrum; how many of these genes are necessary and sufficient to cause autism; and how they may interact with environmental factors. The puzzle is slowly being pieced together, and the science of autism is accelerating in promising ways.

The best research not only leads to answers, but more questions.  There are many questions to be researched in follow up to these current findings. But a picture of what is likely going on in ASD is emerging.

Further – this study shows how the technology of genetic research is accelerating. This is one avenue of research that is very information intensive and is yielding to the law of accelerating returns. As computer and sequencing technology continues to improve, our ability to rapidly gather data about the genome and its relationship to clinical entities is improving and accelerating.

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