A new study indicates that the genetic culprits behind schizophrenia may be much less common than previously believed. Researchers report this week in Science that a rare but devastating change in one of several different genes may dramatically increase the risk of developing the debilitating brain disorder affecting 1 percent of the world's population and marked by psychotic behavior, hallucinations and delusions. Until now, most scientists believed that it was likely that a cluster of relatively common genetic mutations was to blame.
"We're not saying that our results themselves are irrefutable proof that schizophrenia is all rare mutations," says study co-author Jonathan Sebat, a geneticist at Cold Spring Harbor Laboratory in Long Island, N.Y. "But, rare mutations are an important part of the story, and it's this type of risk factors that tend to have the strongest effects."
Until recently, researchers trying to unravel the mysterious disease searched the genomes of schizophrenia patients for flaws not present in the genes of healthy people. Their probes turned up a few possible genetic suspects, but the findings were contradicted by those from other studies. In addition, candidate mutations typically only showed up in no more than 10 percent of schizophrenia sufferers sampled. The new study identifies more than 20 genes that may trigger the disease. If researchers can positively link any or all of these genes to the disease, it would set the stage for development of new therapies.
In this study, researchers combed the genomes of 150 schizophrenia sufferers and 268 healthy individuals for never-before-seen copy number variations (CNVs)—mutations that result in large swaths of DNA encompassing multiple genes either being deleted or duplicated. Some such mutations have been found to be benign, but others have been implicated in ailments such as autism and cancer. The team of scientists, from research facilities across the U.S., found novel gene alterations in 5 percent of the healthy volunteers and 15 percent of the schizophrenia patients; new CNVs showed up in 20 percent of those subjects who developed symptoms at or before the age of 18.
"What we prove is that, collectively, there is a threefold effect in schizophrenia and a fourfold effect in the childhood-onset disorder," says Mary-Claire King, a geneticist at the University of Washington School of Medicine and another co-author, referring to the incidence of these rare variants between the groups.
The researchers determined which affected genes were likely to cause damage—and where in the body that damage that might occur. The flawed genes in the schizophrenia patients were overwhelmingly linked to changes in pathways responsible for communication between and within nerve cells. In fact, one gene, ERBB4, is known to code for a receptor that interacts with neuregulin 1, a protein that's been associated with the illness for a decade. "The silver lining is that these new findings show us … that we were already on the right track," Sebat says.
Daniel R. Weinberger, director of the Genes, Cognition and Psychosis Program at the National Institute of Mental Health in Bethesda, Md., agrees that CNVs likely play a role. But he doesn't believe the new study demonstrates that they operate alone.
King says the next step is to screen the 20 suspect genes to pinpoint specific defects common among large groups of schizophrenia patients.
Sebat acknowledges that the data presented is merely consistent with the rare mutation gene model and not direct proof of it. "It's premature to say that these findings have diagnostic value [right now]," he says. "But, that's exactly where we're headed."