Largest-ever search for autism genes reveals new clues
(19 February 2007: VIDYYA MEDICAL NEWS SERVICE) -- The largest search for autism genes to date, funded in part by the National Institutes of Health (NIH), has implicated components of the brain's glutamate chemical messenger system and a previously overlooked site on chromosome 11. Based on 1,168 families with at least two affected members, the genome scan adds to evidence that tiny, rare variations in genes may heighten risk for autism spectrum disorders (ASD)*.
The study is the first to emerge from the Autism Genome Project (AGP) Consortium, a public-private collaboration involving more than 120 scientists and 50 institutions in l9 countries. Their report is published online in the February 18, 2007 issue of Nature Genetics.
With NIH support, the AGP is pursuing studies to identify specific genes and gene variants that contribute to vulnerability to autism. These include explorations of interactions of genes with other genes and with environmental factors, and laboratory research aimed at understanding how candidate susceptibility genes might work in the brain to produce the disorders.
"This is the most ambitious effort yet to find the locations of genes that may confer vulnerability to autism," said NIH Director Elias A. Zerhouni, M.D. "The AGP is revealing clues that will likely influence the direction of autism research for years to come."
"Although we know autism is highly heritable, complex gene interactions and submicroscopic anomalies create a din of statistical noise that drowns out detection of signals from linked sites in the genome," explained Dr. Bernie Devlin, University of Pittsburgh, who served as a corresponding author on the project along with the University of Toronto's Dr. Stephen Scherer. "To amplify these signals, we brought to bear gene chip technology with a huge sample, and also screened for these fine-level anomalies, factoring them into the analysis."
Clues emerged adding to evidence that implicates components of the brain's glutamate neurotransmitter system in autism. Glutamate increases neuronal activity and plays an important role in wiring up the brain during early development. Since autism likely stems from faulty wiring, a genetic blueprint gone awry in this pivotal neurotransmitter system is a prime suspect. Some key genes associated with the glutamate system are located in chromosome regions previously associated with autism, note the researchers.
Previous studies have also linked abnormal glutamate functioning to disorders such as Fragile X syndrome and tuberous sclerosis, which share some symptoms with autism. It's not unusual for individuals with either syndrome to be diagnosed with autism.
Among the new clues is stronger evidence for an association between autism and sites of genes for neurexins, molecules that build glutamate synapses – the connection machinery by which brain cells communicate.
A site on chromosome 11 most strongly linked to autism in this study harbors genes for proteins that shuttle glutamate across the synapse. Although detected previously, the linkage signal at this site was regarded as less important until now.
Submicroscopic anomalies – tiny deletions, or the doubling, tripling or even multiplying of stretches of genetic material – are relatively common in the human genome and aren't necessarily harmful. However, recent evidence suggests that these anomalies may contribute to risk for – or rarely even cause – autism if they affect certain sites associated with the disorder. The AGP researchers found a number of these variations in such suspect chromosomal locations in affected individuals, including deletion of a neurexin gene.
These anomalies can also make it more difficult to detect the genes that more commonly account for autism risk, say the researchers. Since each major autism candidate gene likely contributes to risk for a relatively small percentage of families, its linkage signal can easily be lost in the statistical noise generated by those of the anomalies – just as a high level of static can drown out a weak radio signal.
To amplify the power of possible linkages detected, the researchers analyzed many subsets of data, variously excluding from the sample factors like the submicroscopic anomalies, female sex, and ethnicity. These analyses unmasked several suggestive linkages that would otherwise have eluded detection.
Researchers last Fall reported (http://www.nimh.nih.gov/press/autismmetgene.cfm ) discovery of a gene version linked to autism and how it likely works at the molecular level to increase risk. The AGP researchers propose that multiple such gene variants, perhaps interacting with each other and with the tiny anomalies, contribute to risk. As more such genes are identified, studies of how they work in the brain – in mice and other model systems – will help to sort out the genetic and proposed environmental influences on autism spectrum disorders, say researchers.
A second phase of AGP studies will follow up on leads suggested in this first phase.
Joachim Hallmayer, MD, associate professor of psychiatry at Stanford and a member of the autism working group, chaired the collaboration's executive committee. In addition, he recently co-authored a paper in Nature Reviews Neuroscience describing the disconnect in autism research between the focus of research conducted by scientists and the research topics considered newsworthy in the media. Here he discusses the research findings.
Question: What are autism spectrum disorders? How many people are affected?
Hallmayer: Children with autism find it difficult to relate to others. They have problems with language and social interactions, and many exhibit significant mental impairment. Those with Asperger's disorder have similar social difficulties but they achieve normal language milestones. A third category, known as "pervasive developmental disorders - not otherwise specified," is used for children who don't have all the symptoms of autism or Asperger's, but who still struggle in these areas. On Feb. 9, the Centers for Disease Control released a 14-state study that suggested the incidence of autism spectrum disorders could be as high as one in 150 children.
Q: Are autistic spectrum disorders genetic? If so, why do they vary in severity?
Hallmayer: Autism is strongly genetic. If one identical twin individual is affected the chance that the co-twin is also affected is between about 70 and 90 percent vs. about 3 to 5 percent in the case of a non-identical twin. However, this does not mean that environmental factors are unimportant.
For example, the specific symptoms experienced by affected individuals within a family or twin pair can vary widely. This leads us to believe that, while certain genes increase the risk that a child may develop some type of autism, the presence and severity of particular symptoms experienced by that child depends on other genetic and environmental factors.
Finally, about 10 percent of autism cases can be ascribed to single-gene disorders (such as fragile X syndrome, tuberous sclerosis complex and Rett syndrome), or to chromosomal abnormalities - all of which affect brain development. Abnormal brain development early in life is probably another risk factor for developing clinical symptoms seen in autism spectrum disorders.
Q: This isn't the first time researchers have tried to identify genetic regions important in ASD. What's different about this research?
Hallmayer: This study is by far the largest study ever conducted, in terms of both researchers and research subjects. In it, we analyzed over 1,400 families with more than one affected family member. Furthermore, we combined two types of data to determine which chromosomal regions might be involved in the development of autism: linkage analysis, which tests whether specific genetic markers are located near a putative autism susceptibility gene; and chromosomal copy number variation, in which we track subtle chromosomal abnormalities among affected individuals.
Although substantial evidence suggests that about 7 to 8 percent of individuals with autism have chromosomal abnormalities, standard tests miss many subtle chromosomal aberrations. Detection of such changes not only helps to identify candidate genes, but also improves linkage analysis by allowing us to separate chromosome abnormality-bearing families from those with other types of mutations.
Finally, our large sample size allowed us to subdivide our families based on specific characteristics such as the gender of affected individuals.
Q: What did the research find?
Hallmayer: Results from our linkage analyses implicate portions of chromosomes 11 and 15 as candidate autism susceptibility regions. We also found a family with a deletion in a gene called neurexin 1 that appeared to correlate with a diagnosis of autism in this family. Neurexin 1 is involved in neuronal contact and communication between a kind of nerve cell called a glutamate neuron. While promising, these results need to be followed up with more refined genetic maps to home in on other specific candidate genes. We also need to look more closely at chromosomal anomalies in large samples of children with autism.
Q: What might this research mean for the parent of a child with autism?
Hallmayer: It can be very difficult to parent a child with autism. Our hope is that identifying candidate autism susceptibility genes will allow us to better understand how these genes interact with environmental factors to influence early brain development. It is likely that a number of autism genes will be identified in the next couple of years, so we are making slow but significant progress toward our goal of developing possible therapies for this condition.
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