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Genetic basis of schizophrenia involves multiple mutations
Use of high-throughput DNA sequencing techniques has revealed that the underlying genetic cause of schizophrenia appears to lie in damage to several genes rather than being pinpointed to a single gene. The number and types of mutations also influences severity of this devastating psychiatric disorder. These are the main findings of a study published in the journal Neuron from researchers in Columbia University Medical Centre and Pretoria University.

Schizophrenia is a psychiatric disorder characterised by hallucinations, delusions and cognitive issues. With an incidence of 1 in 100, it is relatively common and the risk of schizophrenia is increased in people with a family history of the disease. Previous studies have attempted to identify single genes that could lie behind schizophrenia. However, the rise of high-throughput sequencing techniques means that a more far-reaching approach can be taken, as in the current study.

The research team recruited 231 schizophrenia patients and their non-schizophrenic parents and applied the high-throughput DNA sequencing techniques to the ‘exome’ of these individuals. This means the part of the genome that actually encodes proteins rather than any intervening regions. The results indicated that the schizophrenia patients had DNA damage extending over several genes. The types of mutations were also examined and the research team observed that there was a higher than expected incidence of so-called ‘loss-of-function’ mutations which were not inherited from the patients’ parents. These types of mutations are rare but, as their name implies, have a more severe effect on gene function than other types of mutation.

The team turned their attention to the identities of some of the genes that were mutated and found that there was a preponderance of mutations in genes encoding proteins involved in a process called chromatin regulation. This process dictates how DNA is packaged and how genes are regulated. Alterations in chromatin regulation genes have recently been observed in other psychiatric disorders. In particular, the researchers noted two loss-of-function mutations in a gene called SETD1A, which encodes a subunit of the protein histone methyltransferase, a key enzyme in chromatin regulation.

Study author Dr Joseph Gogos explained the clinical significance of these findings: “A clinical implication of this finding is the possibility of using the number and severity of mutations involved in chromatin regulation as a way to identify children at risk of developing schizophrenia and other neurodevelopmental disorders…Exploring ways to reverse alterations in chromatic modification and restore gene expression may be an effective path toward treatment." The research team is now seeking to identify further genes associated with schizophrenia and identify common functions of these genes.


Takata, A. et al. (2014). Loss-of-Function Variants in Schizophrenia Risk and SETD1A as a Candidate Susceptibility Gene. Neuron 82(4): 773-780.

Press release: Columbia University Medical Centre
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