An ambitious multi-million dollar Canadian project to identify hundreds of genes essential to communication between brain cells has led to the discovery that random mutations not inherited from either parent play a role in schizophrenia.
The scientists also found the same kind of genetic glitches in patients with autism, which adds to the growing understanding of the genetic overlap between the two disorders.
De novo point mutations, as they are called, are almost like typos. One letter in the genetic code gets changed for another. Two or three of them are present in everyone at birth, and most of the time, they are harmless. But researchers at the University of Montreal have found that if they occur on genes that help neurons connect, they can predispose people to develop schizophrenia or autism.
The work could lead to prenatal screening for both disorders, or for new, more personalized approaches to treating people depending upon their genetic profile.
The findings, published in the American Journal of Human Genetics, also help explain why rates of schizophrenia remain relatively stable around the world, even though people with the disorder are less likely to have children and pass on their genes to the next generation.
"It is a new way to think about how these diseases can develop," says Guy Rouleau, senior author on the paper.
It still unclear what percentage of cases of autism or schizophrenia are caused by or related to de novo mutations. It may be as low as 5 per cent or high as high as 50 per cent, says Dr. Rouleau. That's because there are an estimated 4,000 genes involved in the complicated communication between brain cells, and this study looked for mutations in only 400 genes.
Before new screening tests can be developed, Dr. Rouleau says researchers have to learn how likely it is that someone with one of these kinds of mutations would develop either disorder.
"There are always confounding environmental factors. Will it lead to disease in 25 per cent of people, or 85 per cent of people?" he says.
The study did, however, find that random mutations to the same gene can lead to schizophrenia in one person and autism in another, fuelling the notion that the same genes may be involved in different neuropsychiatric disorders. It's an idea that researchers are increasingly focusing on, says Stephen Scherer, a senior scientist at the Hospital for Sick Children in Toronto.
"It is really going to dominate in the next few years."
Schizophrenia affects one in 100 Canadians, and can cause disorganized thinking, paranoia hallucinations and social withdrawal.
One in every 110 children have autism or a related condition, known under the catch-all term autism spectrum disorders, which affect communication and social interaction. In severe cases, children can't speak.
The findings fit with the emerging international consensus that schizophrenia has a wide variety of genetic as well as environmental risk factors, says Philip Seeman, a University of Toronto researcher known for his groundbreaking work on the biology of disease. Environmental factors including brain injury at birth or the use of street drugs, he says.
They also answer an important question, says Simon Fraser University's Bernard Crespi.
"This is showing us the first clear picture of new, quite bad genes entering the human genome and what are they and what kind of effects they have."
Dr. Rouleau is the head of the Synapse 2 Disease project, funded by federal and provincial agencies, which has spent $10-million and several years identifying more than 400 genes that play a role in communication between brain cells, which occurs at the junction, or synapse, between two neurons.
New technology is making it faster and cheaper to identify the rest of the estimated 4,000 genes involved, he says.
This study involved 285 volunteers with either autism or schizophrenia and their parents. It found that 15 of the patients, roughly half with each disorder, had random, damaging mutations to one of the 400 genes.