BioWorld International Correspondent

LONDON - A gene variant known to be linked to a higher risk of schizophrenia, which alters levels of the protein it encodes, has been shown to affect brain function in individuals at risk of schizophrenia. The finding explained how the variant can cause the disease, even though the part of the gene that encodes the protein contains no mutation.

The study, the latest in a string of papers linking the gene NRG1, which encodes the protein neuregulin 1, to schizophrenia, also showed that people with the variant have alterations in brain function.

Armed with the new information, those seeking novel therapies to treat schizophrenia will be able to probe many new avenues leading to the development of rational treatments for the disease.

Jeremy Hall, clinical lecturer in the division of psychiatry at the University of Edinburgh in Scotland, told BioWorld International: "All existing antipsychotic medication, used for the treatment of schizophrenia, works through dopamine antagonism. Since the development of these treatments 50 years ago, there has been little progress because we have not known what causes the disease. But we can now expect in our lifetimes to see a totally new and different range of treatments for schizophrenia become available, based on entirely different mechanisms to those that currently exist."

Hall is the first author of a paper in Nature Neuroscience reporting the work. Its title is "A neuregulin 1 variant associated with abnormal cortical function and psychotic symptoms."

The research is part of the Edinburgh High Risk Study, which is funded by the Medical Research Council and coordinated by Eve Johnstone, also of the University of Edinburgh. The study followed 200 young people at risk of developing schizophrenia for 10 years.

All those taking part in the study had two or more relatives with schizophrenia, and were therefore at high risk of developing the disease themselves. They had functional MRI scans, cognitive assessments and clinical assessments every 18 months or so, beginning in their late teens or early 20s. The period of the study therefore covered the age - early to mid-20s - at which the onset of schizophrenia peaks.

Since the Edinburgh High Risk Study began, genetic studies have suggested that mutations in various genes were linked to the development of schizophrenia. One of the genes under investigation has been NRG1, which encodes the protein neuregulin 1. NRG1 lies in a region of chromosome 8 that, in linkage studies, tends to be inherited by those with schizophrenia. Its role in nervous system development also makes it plausible that it could have a role in schizophrenia.

Oddly, studies failed to find any mutation in the protein-coding region of NRG1. One variant, however, involves a polymorphism in the promoter region of the gene: Scientists speculated that this could affect how much protein the gene makes.

Earlier this year, a paper appeared that backed up the theory. Looking at the brains of people with schizophrenia who had died, the study reported that the expression levels of NRG1 varied according to whether the polymorphism in the NRG1 promoter was present or not.

In Edinburgh, Johnstone, Hall and their colleagues invited the participants in their study to give blood for genetic analysis.

Hall said: "We looked at the most commonly associated genetic variants of NRG1, and we found that inheritance of the one associated with an alteration in the promoter function was strongly associated with the development of psychotic symptoms. That finding strongly suggests that this mutation, which is altering gene expression, may be the functional mutation that people have been looking for."

When the researchers compared the MRI brain scans of people who had that particular genotype with the scans of those who did not, they found differences in activation in parts of the brain. Specifically, those with the risk genotype had decreased activation of the frontal and temporal cortices when asked to carry out a task that normally activates those parts of the brain.

A further finding was that those with the risk genotype had lower scores in IQ tests than those without it.

Hall said: "Our study provides stronger evidence that a particular genetic variation in NRG1 can influence the development of the symptoms of schizophrenia, and that it directly alters brain function. It has been difficult to find genetic mutations leading to faulty proteins that are responsible for psychiatric disorders and perhaps this is not so unexpected - without neuregulin, you would be dead, so we should be seeking more subtle changes such as alteration in gene expression level."