From The Quarterly, Spring 2011



Within the last several years, scientists, a number of them working with NARSAD Grants, have capitalized on the discovery that some people with schizophrenia and other brain and behavior disorders have extra or missing sections in their genomes – sections which sometimes correlate with the location of genes known from previous studies to be associated with heightened risk for these illnesses.



Brain & Behavior Research Foundation Grantee Jonathan Sebat, Ph.D., of the University of California, San Diego, is one of the pioneers in finding these extra and missing genome areas, which are called copy-number variations, or CNVs. In a new study published in March, a large international team led by Dr. Sebat and including Foundation Grantees Mary- Claire King, Deborah L. Levy, and Elliot S. Gershon announced the discovery of a new gene that evidence shows to be mutated in a small but significant subset of schizophrenia patients. Those who carry the mutation have greatly elevated risk for the disease – some 14 times the risk of those who don’t have it.



The gene, called VIPR2, encodes a receptor expressed in important brain areas including the hippocampus (connected to learning and memory), amygdala (connected to fear and other emotions) and suprachiasmatic nucleus (regulator of day/night cycles).



Some CNVs cover comparatively large chunks of the genome, in which several or many genes are found. In such instances, it is difficult to discern which gene is important. The new region identified by Dr. Sebat and colleagues is on chromosome 7. Many of the

duplications in this region impacted just one gene – VIPR2. The VIPR2 gene encodes a receptor that binds to a neuropeptide hormone and transmitter called “VIP.”



“The link between VIPR2 duplications and schizophrenia may have significant implications for the development of molecular diagnostics and treatments,” Dr. Sebat notes. “For example, genetic testing for this duplication could enable early detection of a subtype of patients who have over expression of the VIPR2 gene.”



Although the mechanism of how such over expression might contribute to the onset of schizophrenia is still not known, that will surely be a subject of ongoing studies.



Additionally, Dr. Sebat said, the discovery points to a potentially important new schizophrenia drug target. “A drug that selectively blocks that receptor could have therapeutic potential in patients who have the VIPR2 mutation,” Dr. Sebat says.



“This is the kind of gene that drug developers have been waiting for,” Dr. Sebat says. “Molecules have already been created that are known to modulate VPAC2. This is what genomic medicine is all about: finding the relevant genes and using this information to inform the development of new treatments.”



In 2010, Dr. Sebat was a recipient of a NARSAD Independent Investigator Grant.