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New Autism Gene Found: Patient Group Played Critical Role

Posted Aug 27 2009 11:37pm

A major new genetic link to autism has just been announced that supports the theory that autism is caused by disruptions in the brain’s ability to create connections between neurons.  Approximately 30 medical research groups collaborated on a pair of studies that represent the largest to date on this disease and included over 10,000 people with autism or autism spectrum disorder (ASD), their family members, and many healthy patients who served as controls.

The study was fueled by samples and clinical data from an  autism advocacy group — the Autism Genetic Resource Exchange (AGRE).  According to a UCLA release, “AGRE has played a role in almost every major autism genetics paper in the past five years,” said Jon Shestak, who is involved with the organization.

This study represents a small but important step forward.  It’s a solid start towards being able to diagnose autism with a blood test and towards findings cures.“Our findings are highly consistent with the hypothesis that autism involves abnormal connections between brain cells,” says researcher Hakon Hakonarson of Children’s Hospital in Philadelphia.  The two papers are being published in the journal Nature. This press release from Children’s Hospital has more details.

The two studies focused on tiny, single-base pair variations that pepper the genome.  Such variations can be responsible for the differences between people and can point researchers to the locations of disease genes.  To do such studies requires access to DNA from patients, which is often difficult to come by.  AGRE was started by autism patient advocates to create a “library of genetic findings” that will help accelerate research on this disease.

The researchers first studied the DNA of about 3,000 individuals from families that all have at least two autistic children. They analyzed about 500,000 sites in the genome that are known to vary a lot between individuals.  Variants in a region between the genes CDH9 and CDH10, on chromosome 5, were seen 20% more often in autistic patients.   These appear to be genes that affect cell adhesion, or stickiness, which is critical to building connections between cells.  CDH10 is also seen in high amounts in the brain’s frontal cortex – an area important for language, social behavior, and judgment, among other things.

The link was confirmed and extended by looking at another 1,200 people from families affected by autism and 6,500 healthy people. The second study pointed to two biological pathways: One that includes the same cell adhesion genes (CDH9 and CDH10) found in the first study.  The other involves the ubiquitin degradation pathway.  Ubiquitins are a class of enzymes that help neurons process proteins they need to get rid of.  The two pathways are linked and it makes sense that these genes could influence brain development.

“Our research suggests that CDH10 is switched on at a very early stage and plays an important role in regulating the developing brain.  This prenatal activity [of the gene] somehow makes the infant more susceptible to autism,” said Daniel Geschwind, of the UCLA Center for Autism Treatment and Research, according to a UCLA press release.

“Multiple genes cause autism,” said Gerard Schellenberg of the University of Pennsylvania School of Medicine, and another of the scientists involved in the study.  Experts think environmental triggers are also involved in the disease.  Until this study, most of the genetic links to autism were relatively rare, did not seem be strongly linked to the disease, and were not validated in a second large-scale study.   This gene finding is relatively strong as such studies go:  Someone carrying these variants has a 13% to 18% higher risk of autism than someone without them.

“We need to more studies, and we need more patient samples to get more answers,” said Schellenberg.  He pointed out that while this study seems very large, genetic studies need many samples. Some studies use as many as 50,000 patients.  After all, there are about 3 billion base pairs in the genome. When many different mixes of genes can cause a disease, it is particularly difficult to track down all the suspects.

Families that include two or more children with autism or ASD and who would like to participate in such studies can find out more at the AGRE website.  “When parents like me first formed AGRE, this was our dream, that talented scientists would use our gene bank to collaborate and bring us closer to understanding autism,” Shestak said, according to the UCLA release.

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