Scientists have taken a major step forward in their search for the causes of schizophrenia, a serious mental health illness that afflicts about 1 out of 100 people. On Wednesday, an international team of researchers published two of the largest and most comprehensive studies yet on the genetics underlying the common psychiatric disorder. Psychiatrists say the studies, both published in the journal Nature, provide a much-needed starting point for developing new diagnostics and treatments.
One study, helmed by the Broad Institute of MIT and Harvard, identifies a small number of rare genetic mutations that make a person 10, 20 or even 50 times more likely to develop schizophrenia, whose symptoms can include delusions, hallucinations, agitation, and other debilitating behavior.
The second study identifies hundreds of common genetic variants that individually contribute only a tiny degree to schizophrenia, but together point to faulty communications between brain cells as a major cause of the disorder.
Dr. Joshua Gordon, director of the National Institute of Mental Health, which partially funded the studies, said that knowing the genes involved in schizophrenia will allow biologists to study what goes wrong in the brain and find ways to fix it. “They give us potential targets for treatment. That is the big advance here,” he said.
The researchers involved in the investigations emphasize that there is a long way to go before new drugs are available. But the results open “a new line of inquiry” into the cause of the disorder, said Benjamin Neale, director of genetics at the Stanley Center for Psychiatric Research at the Broad Institute, who was involved in both studies. “It gives us new things to work on.”
It is well known that the majority of a person’s risk of developing schizophrenia comes from their genes, but the specifics of what genes are involved and how they contribute to the disease have been hard to pin down. “The picture is becoming less fuzzy” with these new studies, said Kristen Brennand, a professor of psychiatry and genetics at the Yale School of Medicine.
The Broad study compared the genomes of about 24,000 people with schizophrenia and 97,000 people who did not have the condition. Researchers discovered rare mutations in 10 genes that drastically increased a person’s likelihood of becoming schizophrenic.
“The risk from these variants is really high,” said Tarjinder Singh, lead analyst of the Broad study and a psychiatric geneticist at the institute. While some of the genes helped validate existing hypotheses about the cause of schizophrenia, many of them came as a complete surprise. “We don’t know what a lot of these genes do. And that is quite daunting,” he added.
The second study was conducted by the Psychiatric Genomics Consortium, an international team made up of hundreds of geneticists, psychiatrists, and data scientists. In 2014, the group identified 108 spots along the human genome where there seemed to be differences between people who do and don’t have schizophrenia. Their new study, which compared DNA from more than 76,000 people with schizophrenia to 243,000 people without the condition, notches the tally of genetic variants up to 287.
Several of the genes in that study are important for communication between brain cells, which takes place at a junction called the synapse, explained James Walters, one of the leaders of the consortium study and director of the MRC Centre for Neuropsychiatric Genetics and Genomics at Cardiff University in Wales.
The receiving end of the synapse in particular is often faulty in people suffering from schizophrenia. “That hasn’t been implicated as specifically in the past, and that of course gives you clues about where to direct treatments,” he said.
Although there are treatments for schizophrenia, they are only partially effective and they don’t work for everyone. Those medications primarily block the activity of a molecule in the synapse called dopamine.
Neuroscientists have long hypothesized that another molecule in the synapse, called glutamate, plays a more fundamental role in the disorder. The genetic studies implicate multiple genes linked to glutamate as important for schizophrenia, adding new urgency to the theory.
More importantly, some of the same genes popped up in both studies, suggesting that studying the rare mutations — which have large effects and may be easier to understand — may lead to insights, or even treatments, that are relevant for people with the more common mutations. “It gives you not just hope but actual evidence that there is overlap in mechanism,” Gordon said.
Dr. Joshua Roffman, a psychiatrist and neuroscientist at Mass General Hospital, is optimistic that work on the rare mutations will lead to new drugs. He notes that rare genetic mutations that increase the risk of heart attacks helped scientists identify a drug target that led to the development of cholesterol-lowering statins decades ago.
“That is the model that we aspire to in psychiatric genetics,” he said. “It may be a very small number of people who are affected by a particular mutation, but it identifies a tractable biological pathway that can then be leveraged to understand what is going on in the brain and potentially develop better treatments.”
Scientists are already working to create engineered human cells or lab animals such as mice that have these mutations linked to schizophrenia. The goal will be to understand how, exactly, those mutations affect brain cells, and to find drugs that can prevent, stop, or reverse the damage.
Conrad Iyegbe, a computational biologist at the Icahn School of Medicine at Mount Sinai, said that although the studies offer “unprecedented insights” into the genes and brain cells involved in schizophrenia, “it is still incomplete information.”
The studies still only explain a small fraction of the total genetic contribution to schizophrenia, and even larger and more diverse studies will be needed to fill the gap, he said. Part of the problem is that these genetic studies often rely primarily on data from white people. Although the new studies were more diverse than prior ones, Black and Hispanic people still accounted for a relatively small proportion of participants.
“If we can expand the diversity of populations in these studies, we can expand the catalogues of disease-causing variants,” Iyegbe said.
One day, when more of those genes are catalogued, doctors may be able to predict a person’s risk of developing schizophrenia just by looking at their genes. For now, scientists say that the biggest risk-factor genes are too rare to justify testing for, and the common variants contribute too small an amount to the risk to make for a meaningful prediction.
“We are inching our way forward to knowing enough about genetics to have some clinical testing,” Roffman said. “So in the long run, I am optimistic that these kinds of studies will be very impactful.”
Singh is hopeful that the new genetic clues will ultimately “pave the way to new therapies” that are more effective and have fewer side effects, but he also says that the studies are far from the final word on the genetics of schizophrenia. “This is still the beginning phase of gene discovery. We have the first 10 genes, and there are hundreds.”