Rare Gene Mutations Could Explain Schizophrenia

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Main Category: Schizophrenia
Also Included In: Genetics;  Autism;  Neurology / Neuroscience
Article Date: 28 Mar 2008 - 8:00 PDT

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New research by scientists in the US has found that rare gene mutations occur up to 4 times more frequently in people with schizophrenia and may disrupt the development of critical parts of the brain. The researchers found that the rare deletions and duplications of genetic code occurred in up to 20 per cent of schizophrenia patients, supporting the idea that the disease is not caused by one or two gene variations but complex clusters of mutations.

The findings, from two independent studies, are published in one online article in the March 27th issue of Science. One study was led by Drs Judith Rapoport and Anjene Addington, of the National Institute of Mental Health (NIMH), Intramural Research Program, and the other was led by Drs Jonathan Sebat and Shane McCarthy, from Cold Spring Harbor Laboratory, and also by Drs Jon McClellan, Tom Walsh, and Mary-Claire King, of the University of Washington.

The small gene variants were found in 15 per cent of patients whose schizophrenia started in adulthood, and 20 per cent of patients whose schizophrenia started when they were children or teenagers. When found together in one person, the clusters of variations affected potentially hundreds of genes, and were significantly more likely to disrupt brain development compared to a person who did not have them, suggested the researchers.

Dr Thomas R Insel, Director of the NIMH, which partly supported the research, said:

"This is an important new finding in the genetics of schizophrenia."

"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," he added.

Before this research, scientists favoured a genetic model of schizophrenia based on a few mutations in certain suspect individual genes, each contributing a small effect, but working together and also with environmental factors to produce a larger combined effect. The model assumed that disease risk arose because these variants altered the code for specific proteins.

However, about 12 months ago, one of the teams started looking at autism where spontaneous and unique variations in gene copies occurred throughout an individual's genome suggesting that variations in many different genes gave rise to autism spectrum disorders.

The findings of the two studies suggest that the genetic underpinning of schizophrenia could be similar to, perhaps even broader than, that of autism spectrum disorders, and scientists may have to look at brain development and disorders in a different way. Each person with schizophrenia, autism, mental retardation, or no brain disorder at all, could have any pattern of mutations in any combination of the hundreds of genes involved in the development of the brain.

Plus, through interaction with other genes and environmental factors, each pattern will also affect brain function uniquely, said the researchers, which means that any gene containing a deletion or duplication is in effect a "candidate gene", and if a gene contains one such mutation, it will most likely have others, they added.

Although each variant might be rare, when several occur in the same gene, this could explain how many of the illnesses arise, said the researchers.

The main research findings were:

• Compared to healthy participants, schizophrenia patients with disrupted genes tended to have many of them in pathways that were critical for brain development.


• The disrupted genes included those that code for the development of the brain's communication processes, and affect growth, migration, multiplication, differentiation and death of neurons or brain cells.


• These included genes that affect glutamate and neuregulin, two brain chemicals already implicated in schizophrenia.


• The gene variants were often particular to individuals or families.


• In one of the studies, the researchers detected a different mutation in nearly all 150 adult patients with schizophrenia and 268 healthy controls.


• In families where schizophrenia started in childhood or adolescence, researchers found that 28 per cent of the patients (23 of 83 individuals) had mutations, compared with 13 per cent of healthy controls (10 of 77 individuals).


• By comparing the chromosomes of patients' parents with those of the patients, the researchers established that most of the mutations were inherited rather than spontaneous. This supported the widely held idea that schizophrenia is thought to be more influenced by genetics.

The researchers concluded that: "These results suggest that multiple, individually rare mutations impacting genes in neurodevelopmental pathways contribute to schizophrenia."

As well as the NIMH, the research was also sponsored by the National Institute of Child Health and Human Development, National Institute of Neurological Disorders and Stroke, National Center for Research Resources, and the National Institute on Aging.

"Rare Structural Variants Disrupt Multiple Genes in Neurodevelopmental Pathways in Schizophrenia."
Tom Walsh, Jon M. McClellan, Shane E. McCarthy, Anjene M. Addington, Sarah B. Pierce, Greg M. Cooper, Alex S. Nord, Mary Kusenda, Dheeraj Malhotra, Abishek Bhandari, Sunday M. Stray, Caitlin F. Rippey, Patricia Roccanova, Vlad Makarov, B. Lakshmi, Robert L. Findling, Linmarie Sikich, Thomas Stromberg, Barry Merriman, Nitin Gogtay, Philip Butler, Kristen Eckstrand, Laila Noory, Peter Gochman, Robert Long, Zugen Chen, Sean Davis, Carl Baker, Evan E. Eichler, Paul S. Meltzer, Stanley F. Nelson, Andrew B. Singleton, Ming K. Lee, Judith L. Rapoport, Mary-Claire King, and Jonathan Sebat.
Science Published online March 27 2008.
DOI: 10.1126/science.1155174

Click here for Abstract.

Sources: Journal abstract, NIMH press statement.

Written by: Catharine Paddock, PhD
Copyright: Medical News Today
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