Schizophrenia not a single disease but multiple genetically distinct disorders

September 15, 2014 by Jim Dryden
Schizophrenia not a single disease but multiple genetically distinct disorders
C. Robert Cloninger, MD, PhD, pictured in his office at Washington University School of Medicine, is a senior investigator of a study that shows that schizophrenia isn’t a single disease but a group of eight genetically distinct disorders. Credit: ROBERT BOSTON

New research 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 research at Washington University School of Medicine in St. Louis is reported online Sept. 15 in The American Journal of Psychiatry.

About 80 percent of the risk for is known to be inherited, but scientists have struggled to identify specific genes for the condition. Now, in a novel approach analyzing genetic influences on more than 4,000 people with schizophrenia, the research team has identified distinct gene clusters that contribute to eight different classes of schizophrenia.

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

Cloninger, the Wallace Renard Professor of Psychiatry and Genetics, and his colleagues matched precise DNA variations in people with and without schizophrenia to symptoms in individual patients. In all, the researchers analyzed nearly 700,000 sites within the genome where a single unit of DNA is changed, often referred to as a single nucleotide polymorphism (SNP). They looked at SNPs in 4,200 people with schizophrenia and 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 patients' symptoms, demonstrating that specific genetic variations interacted to create a 95 percent 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 percent risk of schizophrenia.

"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.

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 percent. 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 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."

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 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.

The investigators also replicated their findings in two additional DNA databases of people with schizophrenia, an indicator that identifying the gene variations that are working together is a valid avenue to explore for improving diagnosis and treatment.

By identifying groups of genetic variations and matching them to symptoms in individual patients, it soon may be possible to target treatments to specific pathways that cause problems, according to co-investigator Igor Zwir, PhD, research associate in psychiatry at Washington University and associate professor in the Department of Computer Science and Artificial Intelligence at the University of Granada, Spain.

And Cloninger added it may 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 said. "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."

Explore further: Obsessive compulsive disorder diagnosis linked to higher rates of schizophrenia

More information: Arnedo J, Svrakic DM, del Val C, Romero-Zaliz R, Hernandez-Cuervo H, Fanous AH, Pato MT, Pato CN, de Erausquin GA, Cloninger CR, Zwir I. Uncovering the hidden risk architecture of the schizophrenias: Confirmation in three independent genome-wide association studies. The American Journal of Psychiatry. vol. 172 (2), 2014. Published online Sept. 15, 2014.

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14 comments

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oliverlu70
5 / 5 (1) Sep 15, 2014
The schizophrenias were originally conceptualized by Eugen Bleuler as a family of diseases, all this shows is that "modern science" is in part rediscovering what was already known about these so-called illnesses.
foolspoo
not rated yet Sep 15, 2014
We will discover these findings to be incomplete as well. hopefully this will be applied to the entire field of psychoanalysis so we can begin to see how little we understand.
JVK
1 / 5 (3) Sep 15, 2014
Cloninger now leads one medical profession away from an observation-only approach to behavior via experimental evidence that will link nutrient-dependent changes in bair pairs to RNA-mediated events, which include alternative splicings of pre-mRNAs, that lead to SNPs and cell type differentiation via amino acid substitutions in all cells of all individuals of all species.

There's a model for that and it clarifies why Cloninger and others have taken the path that leads to progress.

At the same time, others are touting the pseudoscientific nonsense of evolutionary theory, which they think might somehow link DNA mutations via natural selection to the evolution of biodiversity, which includes the behavior of schizophrenics.

Thank God, Cloninger is using what is known about biologically-based cause and effect to make scientific progress towards diagnosis and treatment of a mental disorder."

http://www.ncbi.n...3960065/
anonymous_9001
5 / 5 (1) Sep 16, 2014
alternative splicings of pre-mRNAs, that lead to SNPs


Splicing does not make changes to DNA. Splicing modifies mRNA. That's it. Splicing does not lead to SNPs.
JVK
1 / 5 (2) Sep 16, 2014
The anonymous fool strikes again. With no citation, Andrew Jones (aka anonymous_9001) declares that nutrient-dependent alternative splicings of pre-mRNA does not lead to SNPs.

What would happen if I provide a quote with no citation and claim: "...the interactions between pre-mRNA and proteins fine-tune alternative splicing in a manner that can gradually create new protein functionalities without the need to create additional genes and without affecting existing proteins [4-6]."

What would Andrew Jones say about that claim before or after I add the citation?

We detailed RNA-mediated events in the context of cell type differentiation in section on molecular epigenetics in a 1996 review, and people like Andrew Jones ignore the fact that "Small intranuclear proteins also participate in generating alternative splicing techniques of pre-mRNA and, by this mechanism, contribute to sexual differentiation in at least two species..."

Do mutations lead to sex differences in schizophrenia?
JVK
1 / 5 (2) Sep 16, 2014
Do mutations lead to sex differences in schizophrenia?

See any of my published works or links in 37 blog posts about RNA-mediated events:
http://perfumingt...bmit.y=0

See also: http://jonlieffmd...volution
"It now appears that alternative splicing is, perhaps, the most critical evolutionary factor determining the differences between human beings and other creatures."
tadchem
not rated yet Sep 16, 2014
Diagnosis of any disorder must start with what can be observed - IOW "symptoms". Treatment of any disorder must start with the cause - often much harder to identify than the symptoms. Many different disorders may exhibit similar symptoms, making clinical research such as this critical to identifying the cause for the symptoms exhibited in any particular case.
Medicine faces many challenges where a multiplicity of possible causes confound the practitioner.
Obesity, diabetes, hypertension, CVD, arthritis, allergies, cancers, and others all defy simple treatments because the true causes are nearly impossible to clearly identify.
oliverlu70
not rated yet Sep 16, 2014
Diagnosis of any disorder must start with what can be observed - IOW "symptoms". Treatment of any disorder must start with the cause - often much harder to identify than the symptoms. Many different disorders may exhibit similar symptoms, making clinical research such as this critical to identifying the cause for the symptoms exhibited in any particular case.
Medicine faces many challenges where a multiplicity of possible causes confound the practitioner.
Obesity, diabetes, hypertension, CVD, arthritis, allergies, cancers, and others all defy simple treatments because the true causes are nearly impossible to clearly identify.


You're still presuming that medicine is the right field to be addressing this issue.
JVK
1 / 5 (2) Sep 16, 2014
...the true causes are nearly impossible to clearly identify.


I wrote: See any of my published works or links in 37 blog posts about RNA-mediated events:
http://perfumingt...bmit.y=0

Was there something I left out in the context of biologically-based RNA-mediated cause and effect in species from microbes to man?
anonymous_9001
5 / 5 (1) Sep 16, 2014
With no citation, Andrew Jones (aka anonymous_9001) declares that nutrient-dependent alternative splicings of pre-mRNA does not lead to SNPs.


I don't need a citation for a negative claim. You're the one claiming splicing makes changes to the DNA when there's nothing that suggests that's true.
JVK
1 / 5 (2) Sep 16, 2014
http://www.hawaii...ion.html
-- our 1996 Review

"Small intranuclear proteins also participate in generating alternative splicing techniques of pre-mRNA and, by this mechanism, contribute to sexual differentiation in at least two species, Drosophila melanogaster and Caenorhabditis elegans.... That similar proteins perform functions in humans suggests the possibility that some human sex differences may arise from alternative splicings of otherwise identical genes."

RNA-mediated gene regulation system: now and the future (Review).-- from 2002
http://www.ncbi.n...12239579

What can anyone do with someone as ignorant as Andrew Jones who defies any attempt to detail biologically based cause and effect so that he can keep his ever failing grip on pseudoscientific nonsense touted in the context of mutations, natural selection and the evolution of biodiversity (without describing an evolutionary event)?
anonymous_9001
5 / 5 (1) Sep 16, 2014
Irony is calling me ignorant when you think splicing modifies DNA. Your model is based on splicing, but you don't even know how it works!
JVK
1 / 5 (2) Sep 16, 2014
RNA structure and the mechanisms of alternative splicing

http://www.ncbi.n...3149766/

"The removal of introns and joining together of exons through pre-mRNA splicing is an essential part of eukaryotic gene expression. Shortly after the discovery of introns and split genes [1,2], it was recognized that splicing can be regulated to produce multiple mRNA molecules from a single gene. Although it was initially expected to be rare, alternative splicing has since been found to occur in plants, animals, and fungi. Because many alternative splicing events are tissue-specific, this process plays an important role in cellular differentiation and organismal development.

Much remains to be done before we [others] can truly understand how RNA sequences, structures, and regulatory proteins converge to direct splicing events in specific tissues and cell types."

While you wait for others to figure it out, see: http://youtu.be/DbH_Rj9U524 My approach links atoms + ecosystems
anonymous_9001
5 / 5 (1) Sep 17, 2014
Wonderful. I now hope you actually read and understood that, because it makes it clear as day as to what splicing does. It makes multiple unique transcripts from one gene. It does not *modify* the genes.

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