Schizophrenia gene mutation

February 3, 2011 — Scientists have discovered a gene mutation that is strongly linked to schizophrenia and a signalling pathway that may be treatable with existing drugs.

"This discovery is the latest in a series of studies by our group and by others that have changed the tables in terms of genetic studies in schizophrenia," Jonathan Sebat, PhD, assistant professor of psychiatry and cellular and molecular medicine at the University of California (UC), San Diego, who led the team that made the discovery, told Medscape Medical News.

"Mutations in the VIPR2 gene, which can be found in about 1 in 300 patients, are responsible for some amount of schizophrenia, but the fact that this mutation is rare does not necessarily diminish its importance because this is a drug-able gene," he said.

The findings were published online February 3 in Nature.

Important Piece of the Puzzle

Uncovering such a gene affords important insight into the biology of schizophrenia, he said.

"Just because only 1 in 300 patients has this mutation doesn't mean that only 1 in 300 patients has a problem with this signaling pathway. There may actually be a broader segment of schizophrenia patients who have something that is related to this, so uncovering this particular piece of the puzzle is actually quite important."

Schizophrenia is thought to be caused by environmental and genetic factors and occurs in 1% of the population or 10% of those with a first-degree relative, such as a parent or sibling, who has the disorder.

In previous research, Dr. Sebat, together with renowned geneticist Mary-Claire King, PhD, a professor of medical genetics at the University of Washington, Seattle, discovered that rare mutations at many locations in the human genome resulted in a significantly higher risk for schizophrenia.

These mutations consisted of copy number variants (CNVs) — a type of genetic variation in which the number of copies of a gene differs between individuals.

"This work showed that mutations that cause schizophrenia in individuals can be quite rare and that the primary cause of the disease in one patient is different than the cause of the disease in another patient," said Dr. Sebat, who is also chief of the Beyster Center for Molecular Genomics of Neuropsychiatric Diseases and a member of the Institute for Genomic Medicine at UC San Diego.

However, the work did not identify the specific genes involved.

Turning Down the Volume

In this research, Dr. Sebat and his team scanned for CNVs in the genomes of 8290 patients diagnosed as having schizophrenia and 7431 healthy controls.

"We found very strong links to multiple sites in the genome. Some had been picked up in our earlier work, but we uncovered an important new finding — duplications at the tip of chromosome 7q were detected in individuals with schizophrenia at a rate that was 14 times higher than in healthy controls. These CNVs impact the VIPR2 gene, which is important for brain development."

Vasoactive intestinal peptide receptor 2 (VIPR2) is expressed in the nervous system, in blood vessels and the gastrointestinal tract, in addition to the brain.

When the scientists measured the expression of the VIPR2 gene in blood cells from the patients with schizophrenia, they found that individuals with mutations had greater expression of VIPR2 and greater activity of the receptor.

"We concluded that the effect of the causal mutations is to raise the volume on the VIP signaling pathway," Dr. Sebat said.

"VIP is already in clinical trials because of its known roles in regulating vasodilation. It regulates the nervous system, and the cardiovascular system, and the gut. In the case of patients with schizophrenia, you wouldn't want to use VIP because their problem is that the volume is already turned up too high on VIP signaling, so in this case you'd want to use an antagonist that would turn the volume down," he said.

New Diagnostics

In addition to the opportunity to develop new drugs, there is also the opportunity to develop new diagnostics, Dr. Sebat added.

A genetic test for mutations in VIPR2 could help to identify people who are at risk for schizophrenia and could also help to identify those who would most likely benefit from treatment.

"A genetic test for mutations in VIPR2 could help to identify people who are at risk for schizophrenia and could also help to identify those who would most likely benefit from treatment."

It has been known for decades that genetics plays an important role in schizophrenia, and yet genetics has not been used at all in the diagnosis of the disorder. Dr. Sebat called this a paradox.

"This is a segment of the population that is completely underserved in terms of molecular diagnostics. So you would want to apply a genetic test like this for VIPR2 in mental illness. It may only identify a small group of patients, but it would still provide very valuable information."

Psychiatry is in serious need of new, more effective drugs, and in the absence of any strong genetic findings uncovering a clear drug target, there really haven't been any leads or any real avenues for the rational development of new therapies.

Discovery of this gene means that there is hope for the development of new drugs for schizophrenia, he said.

"The first antipsychotics were developed in the 1950s and little has changed since then. Psychiatry is in serious need of new, more effective drugs, and in the absence of any strong genetic findings uncovering a clear drug target, there really haven't been any leads or any real avenues for the rational development of new therapies," he said.

"The fact that large-scale genetic studies can uncover something like this is very encouraging, and we are hopeful that this and other findings that are likely to emerge from this type of research will kick start the development of new drugs," Dr. Sebat added.