Missing Enzyme-Producing Gene May Increase Schizophrenia Risk

One-third of individuals with the chromosome deletion syndrome, in which part of chromosome 22 is missing, are known to develop schizophrenia or other psychosis. Thus the syndrome is the most common known risk factor for these disorders.

And the reasons why persons with the syndrome develop schizophrenia or psychosis may have now been pinpointed. It may be because they possess an insufficient amount of the gene that makes the COMT enzyme or possess an insufficient amount of the gene coupled with a slow-acting variant of the gene.

The study was headed by Allan Reiss, M.D., a professor of psychiatry at Stanford University, and results are published in the November Nature Neuroscience.

Individuals with the chromosome deletion syndrome are missing one copy of approximately 30 different genes. One of these genes is the COMT gene. Reiss and his group decided to focus on this particular gene not just because previous research has suggested that it might play a role in schizophrenia, but because it seems to be especially relevant to the illness—it makes an enzyme that breaks dopamine down in the prefrontal cortex area of the brain, an area thought to play an important role in schizophrenia.

They followed 24 children with the chromosome deletion syndrome, as well as 23 children with other kinds of disabilities into adolescence and early adulthood to see which ones developed schizophrenia or psychosis. Seven of the syndrome group and one of the control group did—a significant difference.

Moreover, six of the chromosome deletion syndrome subjects who developed schizophrenia or psychosis had a slow-metabolizing variant of the COMT gene.

Thus, one can conclude that having only one copy of the COMT gene, and especially only one copy of a slow-acting variant of the gene, might lead to an excessive buildup of dopamine in the prefrontal cortex, with ensuing schizophrenia or psychosis.

The larger question, of course, is whether the COMT gene, and especially its slow-metabolizing variant, play a causative role in schizophrenia in general. The answer is “maybe,” Reiss told Psychiatric News. “I suspect that COMT contributes to the risk for psychosis in some families. But at the same time, you have to remember that these [chromosome deletion syndrome] individuals are different from the majority of individuals with schizophrenia who have two copies of the COMT gene.”

Nonetheless, Reiss added, studying the genes of persons with chromosome deletion syndrome could impact the diagnosis and treatment of schizophrenia patients in general. “In this group,” he explained, “we can develop a full model of gene-brain-environment interactions and identify those at highest risk very precisely—that is, before they develop psychosis.”

The study was funded by the National Institutes of Health, the Swiss National Science Foundation, the European Union, and ChildCare Foundation.

An abstract of “COMT Genotype Predicts Longitudinal Cognitive Decline and Psychosis in 22q11.2 Deletion Syndrome” is posted at<www.nature.com/neuro/journalv8/n11/abs/nn1572.html>.▪