Past studies have indicated that rather than being a single disease, schizophrenia may actually be a collection of different disorders. Now, findings from a new study by researchers at Washington University in St. Louis, MO, suggest that the condition consists of eight distinct genetic disorders, all of which present their own specific symptoms.
The research team, including senior investigator Dr. C. Robert Cloninger, the Wallace Renard Professor of Psychiatry and Genetics at Washington University, says their findings may pave the way for better diagnosis and treatment strategies for schizophrenia.
Schizophrenia is a mental disorder characterized by hallucinations, delusions, abnormal thoughts, cognitive problems and agitated body movements. While scientists haven’t yet pinpointed the specific causes of schizophrenia, it is clear that genetics play a major role, as people with a family history of schizophrenia are at much higher risk of developing the condition. Approximately 1 percent of the general population in the US is diagnosed with schizophrenia, but it occurs in around 10 percent of individuals who have a first-degree relative with the disorder.
Researchers have long sought to identify the specific genes associated with schizophrenia. Earlier this year, researchers from the Cardiff University School of Medicine in the UK, published the largest-ever genetic study on schizophrenia in which they identified 83 new genes linked to the disorder.
But Dr. Cloninger says that rather than trying to pinpoint specific genes to schizophrenia development, he and his colleagues wanted to look at how individual genes work together.
“Genes don’t operate by themselves,” he explains. “They function in concert much like an orchestra, and to understand how they’re working, you have to know not just who the members of the orchestra are but how they interact.”
“What we’ve done here, after a decade of frustration in the field of psychiatric genetics, is identify the way genes interact with each other, how the ‘orchestra’ is either harmonious and leads to health, or disorganized in ways that lead to distinct classes of schizophrenia,” says Dr. Cloninger.
Analyzing genetic variations and identifying clusters
In the new study, which was published this month in The American Journal of Psychiatry, the team analyzed the genomes of 4,200 people with schizophrenia and 3,800 people without the disorder.
Specifically, they looked at almost 700,000 areas of the genome where a variation occurred in a single unit of DNA. This variation is known as a single nucleotide polymorphism (SNP).
By comparing the SNPs of schizophrenic individuals with those of healthy controls, the team was able to identify the genetic variations linked to schizophrenia. Individuals with schizophrenia were divided into groups based on the type and severity of their symptoms. The team looked at how the genetic variations interacted with each other to produce specific symptoms of the disorder.
Dr. Cloninger and colleagues say they identified specific gene clusters associated with eight different types of schizophrenia, all of which present recognizable symptoms. Some genetic clusters gave people higher risks of the disease than others, the team found.
One set of genetic changes, for example, confers a 95 percent chance of developing schizophrenia and is associated with hallucinations and delusions. In the article, the researchers describe a woman with this genetic profile who developed signs of the disorder by age 5, when she taped over the mouths of her dolls to make them stop whispering to her and calling her name. Another patient – whose genetic profile gave her a 71 percent risk of schizophrenia – experienced a more typical disease course and began hearing voices at age 17.
The researchers also analyzed two other databases of individuals with schizophrenia and were able to replicate their findings.
Genes ‘work in concert’ to disrupt brain structure and function, causing schizophrenia
The team explains that individual genes linked to schizophrenia only have weak and inconsistent associations with the disorder. But when these genes interact and work as clusters, they pose a 70-100 percent risk of developing schizophrenia. In some cases – in which a genetic profile conveys close to a 100 percent risk of schizophrenia – people may not be able to escape the disease, Dr. Cloninger says. But if doctors could predict who is at high risk, they might also be able to tailor an early intervention to help a patient better manage their condition, such as by managing stress.
Doctors don’t yet know why one person with a 70 percent risk of schizophrenia develops the disease and others don’t, Dr. Clonginger says. It’s possible that environment plays a key role, so that child with a supportive family and good nutrition might escape the diagnosis, while someone who experiences great trauma or deprivation might become very ill.
The new findings, says co-investigator Dr. Dragan Svrakic, fill in a major gap in the research on schizophrenia’s genetic etiology:
In the past, scientists had been looking for associations between individual genes and schizophrenia. When one study would identify an association, no one else could replicate it. What was missing was the idea that these genes don’t act independently. They work in concert to disrupt the brain’s structure and function, and that results in the illness.
The study also reflects how much has changed in the way that scientists think about the genetic causes of common diseases, the team says. They note that diseases caused by a single gene – such as sickle-cell anemia and cystic fibrosis – affect very few people. Most common diseases, such as cancer, are caused by combinations of genes. Even something as apparently simple as height is caused by combinations of genes, the team says.
Doctors have known for years that breast cancer is not one disease, for example, but at least half a dozen diseases driven by different genes. Today, doctors have tests to predict a woman’s risk of some types of breast cancer, and other tests that help them select the most effective drugs.
Those sorts of tests could be extremely helpful for people with schizophrenia, who often try two or three drugs before finding one that’s effective, Dr. Cloninger says.
“People have been looking at genes to get a better handle on heart disease, hypertension and diabetes, and it’s been a real disappointment,” says Dr. Cloninger. “Most of the variability in the severity of disease has not been explained, but we were able to find that different sets of genetic variations were leading to distinct clinical syndromes. So I think this really could change the way people approach understanding the causes of complex diseases.”
“Most treatment today is trial and error,” he adds.
By identifying genetic variations in people with schizophrenia and linking them to specific symptoms, they say it may be possible to target treatments to specific pathways that contribute to the disorder. Additionally, if doctors could pinpoint which drugs could be the most effective, they might be able to use lower doses, producing fewer of the bothersome side effects that lead many patients to stop taking their medication, says Dr. Cloninger.