The symbol for autism spectrum disorder has long been a puzzle piece, and a global team of researchers has come a little closer to understanding the shape of this puzzel, according to research published online in January in the journal Cell. In the largest genetic autism study to date, they identified 102 genes that appear to be associated with the disorder. Prior studies had identified just 65.
Each person has about 26,000 genes on their DNA map. We inherit them from our parents, and they instruct our cells to make proteins that perform different functions in the body. They shape us. Sometimes, though, one of the 3 billion points (also called markers) on a person’s genetic map has a mutation. John Jay Gargus, director of the Center for Autism Research and Translation at UC Irvine – one of more than 50 centers involved in the study – calls these “spelling errors” and explains that they are pretty common.
Most people, he says have about one variant per thousand markers. “Many of them don’t do anything that we’re able to recognize at this time,” says Gargus. “There are lots and lots of these variants that are found in everybody.” But some of these variations can lead to diseases and disorders. Autism, one of the disorders that has a genetic component, is also quite common, impacting one in every 59 children in the U.S.
There are two basic types of genetic variation. One type causes the gene to stop functioning, meaning it doesn’t produce its protein. In the other, the gene keeps functioning, but produces a different type of protein than it normally would. Previous autism studies were only able to spot the first, more common, type of variation. This new study, which looked at more than 35,000 people including 12,000 with autism, allowed researchers to spot variations of the second type as well.
Identifying these variations could eventually lead to new drug-based treatments because they so precisely suggest how the variant changed the biology. For instance, one of the variations spotted was in a gene that makes nerve cells signal each other less. The gene functions like an electrical gateway or channel, with carefully controlled opening and closing, but the variation causes it to be open all the time. “The variant doesn’t cause the channel to go away, but rather you have too much of that channel’s silencing activity,” Gargus says. This is the type of finding that could lead to a possible treatment – for instance, a drug to block that channel.
Some of the variations the researchers found seem to be connected. “We found mutations in gene A, and we know that normally gene A talks to gene B. When we look at gene B, we find the same kinds of mutations. And gene B talks to gene C and we find mutations there as well,” says Gargus. “They’re not just random, scattered things, but they’re in a whole pathway that works together.”
In fact, the researchers found a handful of pathways featuring these mutations. “So that’s a very powerful target,” says Gargus. “It tells us that if we could alter the activity of that pathway, it wouldn’t just be fixing one gene’s work. You might really powerfully change the pathophysiology of the disorder by doing that.”
While pharmaceutical companies are already beginning to search for drug treatments that might work, Gargus stresses that these genetic associations cannot be used to diagnose autism. “We really, really aren’t there,” he says, though he says some labs are starting to offer tests and that testing could even be done in utero. “If you don’t have a real strong map of how the genetic variant is going to change that person’s life, you’re treading on very dangerous waters to try to tell somebody something like that. I really strongly object to laboratories offering it. I think it’s very unethical at this point.”
Meanwhile, researchers will continue to look for even more genetic associations. “We’ve had hints that about 800 genes play a role,” Gargus says. He and other researchers will continue to expand the size of this largest-ever study in the hope of nailing those associations down.
