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Report: Schizophrenia Not a Single Disease But Several Distinct Disorders

Investigators find interacting gene clusters

New research published September 15 in the American Journal of Psychiatry shows that schizophrenia isn’t a single disease but a group of eight genetically distinct disorders, each with its own set of symptoms. The finding could be a first step toward improved diagnosis and treatment for the debilitating psychiatric illness, the authors say.

Approximately 80% of the risk for schizophrenia is known to be inherited, but scientists have struggled to identify specific genes for the condition. Now, in a novel approach analyzing genetic influences in more than 4,000 people with schizophrenia, researchers at Washington University in St. Louis have identified distinct gene clusters that contribute to eight different classes of schizophrenia.

The investigators matched DNA variations in people with and without schizophrenia to symptoms in individual patients. In all, the researchers analyzed almost 700,000 sites within the genome where a single unit of DNA was changed — commonly called a single nucleotide polymorphism (SNP). They looked at SNPs in 4,200 people with schizophrenia and in 3,800 healthy controls, learning how individual genetic variations interacted with each other to produce the illness.

In some patients with hallucinations or delusions, for example, the researchers matched distinct genetic features to the patients’ symptoms, demonstrating that specific genetic variations interacted to create a 95% certainty of schizophrenia. In another group, they found that disorganized speech and behavior were specifically associated with a set of DNA variations that carried a 100% risk of schizophrenia.

Although individual genes have only weak and inconsistent associations with schizophrenia, groups of interacting gene clusters create an extremely high and consistent risk of illness on the order of 70% to 100%, the authors say. That makes it almost impossible for people with those genetic variations to avoid the condition. In all, the researchers identified 42 clusters of genetic variations that dramatically increased the risk of schizophrenia.

“In the past, scientists had been looking for associations between individual genes and schizophrenia,” explained co-investigator Dragan Svrakic, PhD, MD. “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.”

Svrakic said it was only when the research team was able to organize the genetic variations and the patients’ symptoms into groups that they could see that particular clusters of DNA variations acted together to cause specific types of symptoms.

Then they divided patients according to the type and severity of their symptoms, such as different types of hallucinations or delusions, and other symptoms, such as a lack of initiative, problems organizing thoughts, or a lack of connection between emotions and thoughts. The results indicated that those symptom profiles describe eight qualitatively distinct disorders based on underlying genetic conditions.

Senior investigator C. Robert Cloninger, MD, PhD, said that it might be possible to use the same approach to better understand how genes work together to cause other common but complex disorders.

“People have been looking at genes to get a better handle on heart disease, hypertension, and diabetes, and it’s been a real disappointment,” he remarked. “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.”

Source: Washington University in St. Louis; September 15, 2014.

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