October 24, 2005

Genetic Mutations Cause Schizophrenia

A new study by a team of international schizophrenia researchers from Stanford University, Tel Aviv University (and others) suggests they may have made a breakthrough in understanding the biological basis of schizophrenia. The findings could result in earlier diagnosis in children and young people, and lead to the development of new drugs and better treatment. The increasing proof of the biological underpinnings of schizophrenia also increases the pressure on US health insurance laws that allow lower levels of coverage for brain disorders like schizophrenia - a policy that is essentially a blatant form of genetic discrimination.

The new study found that a genetic defect in some people can trigger a dangerous increase in levels of a natural brain chemical called dopamine, which may lead to schizophrenia.

Although the genetic mutation that was studied applies to only a small proportion of people who develop the illness, scientists who conducted the study believe it could result in a fundamental shift in the understanding of schizophrenia, as the general process that has been identified could be at the core of the dozen or so genes and genetic mutations that have been linked to schizophrenia. According to the lead researcher, Dr. Gothelf, schizophrenia appears to be inherited about 70 percent of the time.

The study reports that a major risk factor for schizophrenia is a genetic mutation -- 22q11.2 microdeletion -- which occurs in 1 of 4,000 people. One third of people with that mutation develop schizophrenia or another psychotic disorder. (demonstrating, as have many other studies, that the genetics is just a predisposing factor and that some special environmental conditions are also required for the development of schizophrenia).

"We have strong evidence that this deletion is a major risk factor for the development of schizophrenia or related psychotic disorders," said Reiss. "We asked, 'What is it about this deletion that causes such an increase in risk?'"

The answer lay in the fact that one of the missing genes encodes a dopamine-degrading protein called COMT. Natural variations in the gene generate two versions of the protein: one with high activity, one with low.

Because most people have two copies of the gene, it doesn't usually matter which versions of COMT they inherit; high-high, high-low and low-low all seem to provide enough COMT activity to get the job done (though some combinations confer a mild advantage for some cognitive tasks).

But children with the deletion have only the one copy that remains on their intact chromosome 22. Reiss and Gothelf, who is also an assistant professor at Tel Aviv University in Israel, surmised that a single copy of the low-activity COMT might not dispose of enough dopamine to produce optimal brain function. They set out to determine if the clinical course of the children with deletions who developed schizophrenia varied with the version of the COMT protein they had.

Stanford University researchers led by Doron Gothelf gave psychological tests to children with and without the mutation and later examined them again in early adulthood.

The study participants with the gene mutation had an abnormal decrease in the size of their prefrontal cortex, as well as lower IQs and more frequent psychotic symptoms.

The study found one of the genes on the part of the chromosome that is missing is responsible for a protein that degrades dopamine, a critical chemical messenger, or 'neurotransmitter', in the brain. Children with the deletion suffer higher-than-normal levels of dopamine, interfering with what scientists call the 'Goldilocks effect', when it is important not to have too much or too little, but just enough dopamine.

The researchers state, in their conclusions, that "The 22q11.2 deletion syndrome is a promising model for identifying biomarkers related to the development of schizophrenia" - which gives hope that there will eventually be genetic tests to identify people that have a particularly high genetic predisposition towards schizophrenia - a test that will be of particular value to people that have already experienced schizophrenia somewhere in their family tree.

'The hope is we will one day be able to identify the highest-risk groups and intervene early to prevent a lifetime of problems and suffering,' Allan Reiss, of Stanford University in California, said. 'As we gain a better understanding of these disorders, we can design treatments that are more specific and effective.'

'Although this particular genetic deletion probably causes less than 5 per cent of schizophrenia cases, it's the only well-defined genetic risk factor we have right now,' Dr Reiss said.

The researchers next plan to extend their studies to younger children, and to repeat the above study using multiple time points to more precisely catch the ongoing development of the disorder.

The findings could lead to genetic screening for schizophrenia among children, Kates said. But there's controversy over whether to give drugs to those children or wait until they have symptoms, she said. "At the very least, though, (the patient) can be monitored, and the family and patient can be given more support."

What this mean in terms of changes in medical treatment? Currently, schizophrenics are treated with anti-psychotic drugs, but they aren't always effective.

Gothelf said the future on the drug front isn't clear. "In general, in psychology the path from genes to biochemistry to a new medication is not straightforward," he said.

The research was funded by the National Institute of Mental Health, the National Institute of Child Health and Human Development and the Swiss National Science Foundation.

For More Information on this topic, visit Schizophrenia Genetics

Source: Nature Neuroscience, (November) - COMT genotype predicts longitudinal cognitive decline and psychosis in 22q11.2 deletion syndrome Doron Gothelf, Stephan Eliez, Tracy Thompson, Christine Hinard, Lauren Penniman, Carl Feinstein, Hower Kwon, Shuting Jin, Booil Jo, Stylianos E Antonarakis, Michael A Morris & Allan L Reiss

For more information on this news item:

Teens with deletion syndrome confirm gene's role in psychosis (NIMH)

Stanford Study Reveals Genetic Trigger Behind Some Schizophrenia Cases (Stanford University)


If less than 5% of patients get schizophrenia due genetic deletion; how can this be a valid study?

Posted by: captain johann at October 25, 2005 07:11 AM

This study is on a single genetic mutation that is thought to be responsible for a small percent (1 to 5 percent - I don't have the exact figure in front of me) of schizophrenia cases. There are about a dozen different genes that some of the researchers we've talked to believe are the key early predisposition factors in schizophrenia (that could account for the other 95%).

I think that what the authors of this study are trying to say is that the fact that a small genetic deletion has been shown to be a likely prediposing factor for shizophrenia demonstrates that we are learning a great deal more about how schizophrenia starts - and that it may be representative of the type of process is all the genetic contributors of schizophrenia.

This is definitely a valid study, in my opinion.

Posted by: szadmin at October 25, 2005 02:44 PM

I think the idea is that this deletion would be just one of many different yet to be found gene defects that could cause the symptoms we see. Since neurotransmitters are related in very complex ways, a defect in another neurotransmitter could have an effect on dopamine. It doesn't bother me that only some people with the gene defect get schizophrenia, genes are complex, and for example, another gene might have to be expressed or not expressed, to in turn cause this deletion to be significant.

Posted by: slc2 at October 25, 2005 08:45 PM

It likely we are talking about a separate entity, an organic cause of psychosis in kids with VCFS. The problem is in extrapolating this to the DSM-IV diagnosis of schizophrenia. An increase in dopamine can produce psychosis in most people as has been demonstrated with “amphetamine psychosis”. On the other hand, in some people blockage of 90% of their dopamine receptors with little to no reduction in the psychosis. Psychosis can also be induced by blocking NMDA receptors which is not explained by dopamine function. Furthermore, the studies on the size are conflicting and unable to address the question of which came first. Anyways, size doesn’t always matter; it is function that makes the difference. In addition, function cannot simply be described by a single gene, chemical, receptor or neurotransmitter. The permutations and combinations of these as well as other factors is so great and in dynamic flux inferring that we can reduce it to a few factors is over simplistic. It seems that this should be an obvious concept to grasp, but obviously it is not.
The crucial and underlying question is, is do we know what we are saying when we say someone has the diagnosis of schizophrenia. Are we talking about a group of over generalized symptoms that likely result from distant and varying reasons? ( Moreover, most predominantly they have to do with the problems in life. For example, it is known that two-thirds of all people diagnosed with schizophrenia have been physically or sexually abused as a child. ) Look at the DSM-IV, you only need 2 of 5 symptoms (hallucinations, delusions, disorganized speech, grossly disorganized behavior, or negative symptoms). These are generalities judged by a clinician to be met when the symptoms cause significant distress or impairment in daily functioning. An analogy of generalizing these symptoms to a single “disorder” would be someone who presents with increased fatigue, decreased appetite and increased sleep. These can result from an array of conditions such as depressive symptoms, a viral illness, cancer or unknown causes. If you are thinking ahead; interrater reliability has nothing to do with the validity. Before the 1400’s the worlds experts agreed that the world was flat. This did not make it valid. It makes it an agreed up idea and an agreed upon idea does not make it immune to the possibility that the idea is erroneous. In addition, treatment response varies so greatly that this is not as reliable validity reference either.

So to say, that the discovery of this deletion proves that what DSM-IV calls schizophrenia is likely of genetic origin is a gross overgeneralization, especially when the definition of schizophrenia itself is an overgeneralization and there are no validity testing to support the DSM-IV.

Posted by: WIT at October 31, 2005 09:01 PM

What are factors that cause the genetic shift?

Posted by: phuctran at July 29, 2006 11:25 PM

I have one question to ask you. Or whoever i'm asking this to. Does the Mutation in schizophrenia affect any cellular processes?
I need to know asap.
Just reply on this comment thing because, I never check my email. Too many fans try to attack me.
Thank you.

Posted by: Angolina at December 18, 2006 01:47 PM

i think it is multifactorial disorder..it is very wrong to select one disease as the cause..

Posted by: diar akrawi at May 20, 2007 01:30 AM

Post a comment

Please enter this code to enable your comment -
Remember Me?
(you may use HTML tags for style)
* indicates required