March 7, 2011

Clues for Schizophrenia in Rare Gene Glitch

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Scientists have found a rare genetic mutation that, while appearing in only one-third of 1% of schizophrenia patients, may hold clues to improved treatments.

Researchers have known that genes must play a significant role in schizophrenia. Having a parent or sibling with the disorder increases risk by tenfold. But as large genomic studies have explained relatively few cases, the hope of finding solutions in common genetic variations has been waning.

It now appears that schizophrenia patients are more likely to harbor individually rare copy number variations (CNVs). These variations within the genome result from deletions or duplications of genomic segments. CNVs can involve millions of bases of DNA. Some are shared in families, but many are unique to an individual. Previous studies have implicated CNVs spanning dozens of genes in schizophrenia, but no specific genes or neurobiological pathways have been identified.

Dr. Jonathan Sebat of the University of California, San Diego, and colleagues at 14 research centers worldwide set out to further examine CNVs in schizophrenia patients. Their work was funded by NIH's National Institute of Mental Health (NIMH) and others.

The scientists first searched 802 patients and 742 controls for genomic regions with CNVs in at least 2 cases and in no controls. In the online edition of Nature on February 23, 2011, they reported finding 114 genomic regions of interest. They next assessed whether these regions were associated with schizophrenia by examining them in a much larger group of almost 7,500 patients and over 6,500 controls.

Schizophrenia patients proved to be 14 times more likely than controls to harbor multiple copies of a gene on Chromosome 7 for a protein called VIPR2. VIPR2 is the receptor for vasoactive intestinal peptide (VIP) — a chemical messenger involved in brain development. VIP and its receptor are known to play a role in regulating the growth of neurons and in learning and memory. When VIP binds to the VIPR2 receptor on a neuron, it triggers a key relay chemical within the cell called cyclic AMP. Further experiments showed that both VIP and cyclic AMP were overactive in blood cells of patients with VIPR2 CNV.

Only 29 of 8,290 patients (0.35%) harbored VIPR2 CNV, but NIMH Director Dr. Thomas R. Insel says, "Although such copy number variations may explain only a small fraction of cases, these rare mutations can yield important clues to the underlying causes of more common forms."

"We hypothesize that the many different genetic causes of schizophrenia may have something in common," Sebat says. "There may be larger groups of patients who may not share the same mutation but may share the same underlying neurobiological defect."

Agents that block VIPR2 already exist, so these results suggest a potential new treatment strategy for schizophrenia. "It's likely that cyclic AMP signaling is disturbed in a larger fraction of patients," Sebat says, "so it's possible that a treatment that targets VIPR2 might have benefits even for people who don't have mutations in the VIPR2 gene."

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