Schizophrenia Daily News Blog

Rare Genetic Variations May Significantly Increase Risk of Schizophrenia

A new research study has discovered that rare and previously undetectable genetic variations may significantly increase the risk that a person will develop schizophrenia. Genetic variations and prenatal environment factors are thought to predispose people to schizophrenia, and later environmental factors such as ongoing high levels of stress, street drug use, and other factors are believed to further increase the risk and ultimately trigger the disorder.

In this new study the team of investigators examined whether the genetic variations and errors, which are individually rare DNA deletions and duplications, contribute to the development of schizophrenia.

Some deletions and duplications are common and found in all humans. The researchers studied such mutations that were found only in individuals with the illness, and compared them to mutations found only in healthy persons. They theorized that rare mutations found only in schizophrenic patients would be more likely to disrupt genes related to brain functioning and thus may cause schizophrenia.

The study was conducted using DNA from 150 people with schizophrenia and 268 healthy individuals. The investigators found rare deletions and duplications of genes present in 15 percent of those with schizophrenia, versus only 5 percent in the healthy controls. The rate was even higher in patients whose schizophrenia first presented at a younger age, with 20 percent of those patients having a rare mutation. The mutations varied from person to person but were concentrated in genes known to be involved in brain development.

The results were replicated by a second research team, led by Anjene Addington and Judith Rapoport at the National Institutes of Mental Health. They found a higher rate of rare duplications or deletions in patients whose schizophrenia began before age 12 years, a very rare and severe form of the disorder.

The findings suggest that the genetic factors that provide the initial susceptibility (increased risk of) schizophrenia may be many different mutations in many different genes, with each mutation leading to a disruption in key pathways important to a developing brain.

“This is an important new finding in the genetics of schizophrenia,” said NIMH Director Thomas R. Insel, M.D. “Identifying genes prone to harboring these mutations in brain development pathways holds promise for treatment and prevention of schizophrenia, as well as a wide range of other neurodevelopmental brain disorders.”

Experts say that the study demonstrated how new gene-scanning technologies will open new pathways to understanding the biology of mental disorders.

The new study suggests that the genetics of schizophrenia may be even more complex than many researchers had presumed. This type of research, if confirmed in additional studies, could eventually move schizophrenia genetics research into entirely new directions.

The New York times noted “This paper represents a paradigm shift in the way we think about identifying genes in schizophrenia,” said Dr. Matthew State, director of the neurogenetics program at Yale University School of Medicine, who was not involved in the research. “That is what the authors say in the paper, and it’s true.”

However, the NY Times also noted that Dr. Samuel Barondes, a genetics-focused professor of psychiatry at the University of California, San Francisco, said the new findings in no way disproved the idea that multiple common variations could act together to increase schizophrenia risk. Studies searching for such dark conspiracies of genes are under way and still promising.

The new findings in schizophrenia echo those in autism, but also broaden their implications. The results suggest a new approach for discovering genes for schizophrenia and other mental disorders, say the researchers. Any mutation in the hundreds of genes involved in brain development could lead to a different set of neurodevelopmental consequences – schizophrenia, autism, mental retardation, or no illness at all. Each person with one of the illnesses could have a different genetic causal factor for the disorder.

Among key study findings:

* Genes disrupted in patients, as opposed to healthy participants, were significantly over-represented in pathways critical for brain development. These included genes involved in creating the infrastructure by which neurons communicate -- and for neuronal growth, migration, proliferation, differentiation, and cell death. Among these were genes important for neuronal communications via glutamate and neuregulin, both of which have previously been implicated in schizophrenia.

* The mutations were often specific to single cases or families. Virtually every mutation detected by King, Sebat and colleagues was different in a sample of 150 adults with schizophrenia and 268 healthy controls.

* In families affected by childhood onset schizophrenia, Rapoport and colleagues found that 28 percent (23) of 83 patients harbored mutations, compared with 13 percent (10) of 77 controls. By using the non-transmitted chromosomes of the patients’ parents as controls, the researchers were able to determine if the mutations in their children were likely inherited or spontaneous. The majority turned out to be inherited rather than spontaneous, some from parents unaffected by the illness. Childhood onset schizophrenia is thought to be a more severe and more genetically influenced form of the illness.

“This part of our findings indicates something we didn’t know before: that rare structural mutations in genes, while present in both healthy people and people with schizophrenia, are much more likely to occur among people with the illness. This suggests a previously unknown role for rare mutations in the causation of schizophrenia,” said Dr. Sebat.

Implications and Future Studies

While the study, as the scientists directly concede in their paper, “does not prove the involvement with the illness of any specific variant, or even the involvement of any specific gene,” it does, however, indicate a role for rare mutations that disrupt genes in pathways of neuronal development and regulation.

The results are powerful because they link specific structural variation in genes with specific functions known to be important in the early years of life, during which schizophrenia develops in many patients.

This important result leads the scientists to advocate broad use of the method they employed in the study. Gene discovery in complex psychiatric illnesses “should focus on methods that allow detection of structural mutations” across the genome in affected individuals, the team urges.

“Although each mutation discovered may be individually rare,” they maintain, “collectively the total number of disease-causing variants in a gene [found to be] relevant to the disorder may explain a substantial number of cases.”

Dr. Sebat is currently applying the mutation-screening method in studies involving a greater number of patients and in other illnesses. Among other things, he seeks to determine whether spontaneous mutations play as significant a role in schizophrenia as they do in autism, as revealed by a study he co-authored a year ago with CSHL Professor Michael Wigler.

Source Research Paper: Rare Structural Variants Distrupt Multiple Genes in Neurodevelopmental Pathways in Schizophrenia, Science Magazine, March 2008

Related Reading:

Autism and Schizophrenia Linked (US News Blog)

Causes of Schizophrenia

Prevention Tactics for Schizophrenia