CHOP, Penn research points to genetic link in autism

By analyzing DNA from more than 2,000 autistic children, researchers have uncovered the best evidence yet for genetic links to the disorder - all tied to the way brain cells form and dissolve connections.
The research effort, led by Hakon Hakonarson at Children's Hospital of Philadelphia, used much larger samples than had been analyzed before to identify genetic differences between autistic subjects and controls.

The CHOP group collaborated with Penn, UCLA, and other institutions, announcing their findings in two papers in today's issue of the journal Nature.

One paper revealed the first common genetic variation found to occur more often among autistic people. The other paper announced 13 rarer genetic mistakes that are strongly associated with autism.

Both papers back the consensus that there is no single autism gene, but perhaps 100 ways to develop the disorder.

"These papers point to some really surprising things," said Jonathan Pevsner, head of bioinformatics at the Kennedy Krieger Institute in Baltimore, who was not involved in the study. "This is high-quality work."

Autism affects about one in 150 people, and is characterized by restricted interests, limited social interaction, and sometimes learning difficulties and repetitive behaviors.

For years, scientists have been seeking mutations and common genetic variations associated with autism to understand the root of this baffling condition. But none of the previous genetics studies packed the statistical power of this latest work, Pevsner said.

Some of that power came from techniques pioneered at CHOP's Center for Applied Genomics - a research group established in 2006 with the goal of gathering DNA from thousands of children and sifting it for clues to diabetes, asthma, autism, and other conditions.

Last year, the project started to yield results with the first known gene tied to the childhood cancer neuroblastoma.

Hakonarson, who directs the center, said the autism findings relied on DNA samples from 2,600 autism patients, 2,000 of their family members, and 7,000 healthy controls. With genome scanning technology, the researchers sought variations that were overrepresented in the autism group.

Humans carry a genetic code that is three billion characters long, written in the four chemical building blocks of DNA - adenine, thymine, cytosine, and guanine, abbreviated as A, T, C, and G.

Scientists have known for years that this code differed between people at several hundred thousand points, referred to as single nucleotide polymorphisms (SNPs). At such sites, one person may have a C, another a T, for example.

The more prominent autism paper released today described the results of scanning 550,000 known SNPs. That revealed just one stretch of DNA, on chromosome 5, where people with autism were more likely to have one of several SNPs.

It took a huge study to bring this out because these autism-related spellings also show up in half the general population. They are somewhat more frequent in autistic children - occurring in about 65 percent of cases.

Researchers call this a risk factor - one that increases the odds of being autistic by just a small amount. The SNPs may not be causing the added risk, Hakonarson said, but pointing to a nearby gene that is.

The telltale SNPs were found between two genes called cadherins, which are critical in the development of synapses - the links between nerve cells.

The cadherins work primarily in the frontal parts of the brain, said neuroscientist Joseph Buxbaum, a collaborator on the paper who directs the Seaver Autism Research Center of the Mount Sinai School of Medicine. "That's where we learn and do our thinking," he said.

The other paper described a search for whole genes or even groups of genes that were duplicated or missing more often in the autistic children. Geneticists were surprised to discover in 2004 that a few of these larger genetic glitches happen in all people. Most such missing or copied genes don't seem to do much harm.

A few, however, were associated with autism in previous studies. Hakonarson and his collaborators began by examining those, including six genes that appeared to be duplicated more often in autistic people and four that were deleted more often.

With many more subjects and controls, the new study could only confirm four of the 10 previous findings. The rest, the team found, cropped up very rarely in either group and were not appreciably more concentrated among the autistic.

The researchers also identified nine new places where stretches of DNA were either deleted or duplicated more often in the autistic subjects. None of these are likely to cause autism alone. Most were passed down from a parent, who would presumably not be autistic.

Kennedy-Krieger's Pevsner said he thought someone should study the parents with these genetic mistakes to see if they had any unusual or autistic-type traits.

All the duplicated or deleted genes were involved in brain function. Some were involved in creating new connections between neurons. The rest coded for a class of proteins called ubiquitin, associated with metabolizing waste.

"That was really fascinating," said Mount Sinai's Buxbaum. "We used to think of that as the Dumpster of the cell."

But it turns out to be a very dynamic disposal system, he said. "If you want to re-craft connections between one nerve cell and another, you have to chew up something and bring in something new," he said.

Hakonarson said the findings back the long-standing suspicion that autism is caused by different combinations of genetic factors, some common and some rare. He hopes that uncovering the biological roots of autism will help dispel fears that it's triggered by childhood vaccines.

Buxbaum said he's now optimistic that scientists will gradually learn to distinguish different causes - perhaps with genetic tests - and find individualized treatments.

Already doctors can identify about 1 percent to 2 percent of autistic children as having a distinct chromosome abnormality called fragile X syndrome, for which therapies are now in the testing stage. A few other rare genetic diseases make up smaller fractions of the total.

Eventually, "we can apply personalized medicine to treat each of the different causes," he said. "With time we'll get them all." link...