New research published in the American Journal of Psychiatry suggests that schizophrenia is not a single disease, but rather a group of eight genetically distinct disorders, each of them with its own set of symptoms. The finding could result in improved diagnosis and treatment, while also shedding light on how genes work together to cause complex disorders.

Illustration by Amber Christian Osterhout. Reproduced here with permission. More about this artist and schizophrenia at Gaining Insight.

Schizophrenia is classified as a psychotic disorder, one characterized by an inability to discern what is real and not real, to think clearly, have normal emotional responses, and act normally in social situations. As Elyn Saks told us last year, "it's a waking nightmare, where you have all the bizarre images, the terrible things happening, and the utter terror — only with a nightmare you open your eyes and it goes away. No such luck with a psychotic episode."

Scientists aren't entirely sure what causes it, nor does it manifest identically in all people who have it (leading to the broader diagnosis of being on the 'schizophrenia spectrum'). But links have been made to genetics, social factors (including early development), and neurobiology. The heritability link looks to be particularly promising, however; about 80% of the risk for schizophrenia is genetic. Yet scientists have struggled to identify which genes are responsible for the condition.



But a novel approach to analyzing genetic influences on more than 4,000 people with schizophrenia has finally allowed researchers to identify distinct gene clusters that contribute to eight different classes of schizophrenia.

"Genes don't operate by themselves," noted C. Robert Cloninger, MD, PhD, one of the study's senior investigators in a statement. "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."

Indeed, complex diseases like schizophrenia may be influenced by hundreds or thousands of genetic variants that interact with one another in complicated and dynamic ways, leading to what scientists call "multifaceted genetic architectures." Now, thanks to the work of investigators at the Washington University School of Medicine in St. Louis, the genetic architecture for schizophrenia is starting to take shape.

That's a Match

For the study, Cloninger and his colleagues matched precise DNA variations in people with and without schizophrenia to symptoms in individual patients. In total, they looked at nearly 700,000 sites within the genome where a single unit of DNA is altered (i.e. a single nucleotide polymorphism, or SNP). Specifically, they analyzed the SNPs of 4,200 people with schizophrenia and 3,800 people without it. This allowed them to learn how individual genetic variations interact with each other to produce the illness.

So, for example, hallucinations and delusions were associated with one set of DNA variations, that carried a 95% risk of schizophrenia. Another symptom, disorganized speech and behavior, was found to carry a 100% risk with another set of DNA.

"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," Cloninger said.

A Complex Interplay

When it comes to schizophrenia and other complex conditions, individual genes have only a weak and inconsistent association (which is why it's often silly to look for single-gene factors). But groups of interacting gene clusters create an extremely high and consistent risk of illness — in this case, on the order of 70% to 100%. It's nearly impossible for people with these precise genetic variations to avoid the condition. In all, the researchers found no less than 42 clusters of genetic variations that significantly increase the risk of schizophrenia.

"In the past, scientists had been looking for associations between individual genes and schizophrenia," explained Dragan Svrakic, PhD, MD, a co-investigator and a professor of psychiatry at Washington University. "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."



According to Svrakic, the key to the study was in organizing the genetic variations and the patients' symptoms into groups. This allowed them to see that particular clusters of DNA variations acted together to cause specific symptoms. Patients were then divided according to the type and severity of their symptoms. Results showed that those symptom profiles corresponded to eight qualitatively distinct disorders based on underlying genetic conditions.

A short clip showing the wide range of symptoms.


Importantly, the researchers were able to replicate their findings in two additional DNA databases of people with schizophrenia; they confirmed 34 (81%) or more with similar high risk of schizophrenia with these independent samples.

Looking ahead, this research could allow scientists to target treatments to specific pathways that cause problems. The same approach could also help scientists understand how genes work together to cause other common but complex disorders, including hypertension and diabetes.

Read the entire study at American Journal of Psychiatry: "Uncovering the Hidden Risk Architecture of the Schizophrenias: Confirmation in Three Independent Genome-Wide Association Studies".

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