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Genetics and Schizophrenia

Light and Dark

Like most mental illness, schizophrenia sucks. Once a friend of mine lost an eye to his schizophrenic brother during a serious episode. That sort of thing will tear a family apart and while he harbors no ill will towards his brother, because the state pressed charges [and he was the defendant] they cannot see each other while he is in prison. When it is not so severe, you would never know he could do something like that, schizophrenia sucks.

Thankfully, a new study offers to shed some light on the issue. As it turns out the overall number and the nature of mutations –rather than any single mutation– influences an individual’s risk of developing schizophrenia, as well as the severity. This is according to  a discovery by Columbia University Medical Center researchers published in the latest issue of Neuron. The findings could have important implications for the early detection and treatment of schizophrenia.


The team of researchers, sequenced the “exome” of 231 schizophrenics and their parents [who were not schizophrenic]. Using that data, the team demonstrated that schizophrenia arises from collective damage across several genes.

[Loony hint: the exome is the region of the human genome that codes for proteins]

“This study helps define a specific genetic mechanism that explains some of schizophrenia’s heritability and clinical manifestation,” said Dr. Karayiorgou– acting chief of the Division of Psychiatric and Medical Genetics at the New York State Psychiatric Institute. “Accumulation of damaged genes inherited from healthy parents leads to higher risk not only to develop schizophrenia but also to develop more severe forms of the disease.”

For those who don’t know much about schizophrenia [you may be confused by the opening story], it is a severe psychiatric disorder. Schizophrenics experience hallucination, delusions, cognitive difficulties, and so on. It is fairly common, schizophrenia affects roughly 1 in 100 people.

The risks of developing schizophrenia is strongly increased if a family member has the disease. Most research has focused on the hunt for individual genes that might trigger schizophrenia. But with the availability of new high-throughput DNA sequencing technology the researchers were able to find different approaches to cracking the disease.

Researchers compared sequencing data to look for genetic differences while searching for new loss-of-function mutations in the cases of schizophrenia not inherited from the parents. What found was an excess of those mutations in a variety of genes from different chromosomes.

Then they used the data they collected to look at what types of mutations are passed on by parents of schizophrenic children. It turned out that most of the mutations passed on are the “loss-of-function” types. Which were also found to occur more frequently in genes with low tolerance for genetic variation.

[Loony Hint: for those wondering loss-of-function mutations are just that, they mean that the affected gene will no longer function, or have minimal functionality. Typically mutations will still allow the gene to do it’s job, which is why these mutations are rare.

Having a low tolerance for genetic variation means that there is little wiggle room for mutations in the gene. This means that where normal genes will still function normally with mutation, these particular genes cannot.]

They also tried to determine the biological functions of the disrupted genes involved in schizophrenia. Researchers were able to verify two key damaging mutations in the gene SETD1A, which suggests that this gene contributes significantly.

SETD1A is involved in a process called chromatin modification. A fancy name for the molecular apparatus that folds DNA into a smaller volume so it can fit into the cell. This also physically regulates how genes are expressed because some DNA will be easier to reach. Chromatin modification is therefore an extremely crucial cellular activity.

This fits with accumulating evidence suggesting that damage to chromatin regulatory genes is a common feature of various psychiatric and neurodevelopmental disorders. By combining the mutational data from this and related studies on schizophrenia, the authors found that “chromatin regulation” was the most common description for genes that had damaging mutations.

In the future researchers hope to identify and characterize more genes that might play a role in schizophrenia and to explain some common biological functions of the genes. Who knows, maybe even find a type of gene therapy to help cure the disease, that would be incredible.

Mastered neurology already? You probably want the full study — here!


Takata, A., Xu, B., Ionita-Laza, I., Roos, J., Gogos, J., & Karayiorgou, M. (2014). Loss-of-Function Variants in Schizophrenia Risk and SETD1A as a Candidate Susceptibility Gene Neuron, 82 (4), 773-780 DOI: 10.1016/j.neuron.2014.04.043

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