Discovery of new gene mutation in schizophrenia offers a new target for drug therapies
24 February 2011
Schizophrenia is a chronic, severe and disabling brain disorder, with symptoms that include hallucinations, delusions and thought disorder. Schizophrenia is believed to be caused by environmental and genetic factors. The illness occurs in 1 per cent of the general population, but 10 per cent of people who have a first-degree relative with the disorder (such as a parent or sibling) are affected. Current therapies are only partially effective, and little progress has been made in identifying effective new treatments over several decades.
In the past three years, researchers have discovered that rare genetic mutations at many locations in the human genome can confer a significantly higher risk of 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. The findings were the first conclusive evidence that rare mutations can cause schizophrenia but did not identify the specific genes involved.
Professor Aiden Corvin, of the Psychosis Research Group at Trinity College Dublin - funded by Science Foundation Ireland and the Wellcome Trust - and an author on this paper, says that the latest study goes substantially further.
Researchers scanned for CNVs in the genomes of 8290 individuals with diagnosed cases of schizophrenia and 7431 healthy controls. The study confirmed CNVs identified in earlier studies but uncovered an important new finding. Duplications at the tip of chromosome 7q were detected in individuals with schizophrenia at a rate 14 times higher than in healthy individuals. These duplications impact on a gene coding for a brain receptor, VIPR2.
Formally known as the vasoactive intestinal peptide receptor 2, VIPR2 is expressed in the nervous system, including in the brain, blood vessels and gastrointestinal tract. Previous studies have shown that VIPR2 helps to regulate the formation and activity of neurons in the brain. Furthermore, in mice, VIPR2 has been found to have important roles in behavioural processes, including learning and timing of daily activity. The study also measured expression of the VIPR2 gene in blood cells from patients and found that individuals with mutations had greater expression of VIPR2 and greater activity of the receptor.
"This suggests that the mutations increase signalling in the vasoactive intestinal peptide pathway," says Professor Corvin. "We know that this activity can be modulated by synthetic peptides, compounds where amino acids are linked together, and the next step is to see if these compounds have a therapeutic effect in mice or in cultured human cells that carry the VIPR2 gene mutation."
The Psychosis Research Group at Trinity College Dublin were involved in the study design, analysis and data interpretation. Irish patients and their families from Trinity teaching hospitals contributed to the original test sample of 802 cases and 742 controls, along with participants from Columbia University, Harvard, NYU, McLean and University of Washington medical teaching hospitals. The larger replication set of approximately 8290 cases and controls also included Irish participants.
The global collaborative research was led by Assistant Professor of Psychiatry and Cellular and Molecular Medicine, Jonathan Sebat, at the University of California, San Diego School of Medicine.
The findings are published online this week in the journal 'Nature'.
Image: ‘Schizophrenia - hearing voices’. Artist’s illustration. Credit: Adrian Cousins, Wellcome Images.
Reference
Vacic V et al. Duplications of the neuropeptide receptor gene VIPR2 confer significant risk for schizophrenia. Nature 2011 [Epub ahead of print].
