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Vol. LVII, No. 25
December 16, 2005

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Genetic Contribution to Mental Illness Tough to Figure, Weinberger Shows

Finding out how genes contribute to mental illness has not been easy for Dr. Daniel Weinberger and other NIMH researchers. What they have discovered is that the path from gene to psychiatric illness seems to be varied and complex.

But complex doesn't mean unapproachable, said Weinberger, director of NIMH's Genes, Cognition and Psychosis Program, during a presentation titled, "Complex Genetics in the Human Brain: Lessons from COMT," at the G. Burroughs Mider Lecture on Oct. 12.

According to him, a lot can be learned about the genetic basis for psychiatric illnesses from research involving a susceptibility gene implicated in schizophrenia. In his talk, he revealed how pieces of the complex puzzle involving a gene that
Dr. Daniel Weinberger  
codes for an enzyme, catechol-O-methyltransferase (COMT), may fit together and offer clues about how mental illnesses develop.

"Genes don't code for hallucinations, delusions, panic attacks and depression," said Weinberger. "They don't code for complex human behavior."

Rather, genes code for proteins, which in turn affect the activity of cells, circuits and, ultimately, the brain systems disturbed in mental illness.

Weinberger cited evidence from several NIH-funded studies on the COMT gene that explain some of these intermediate steps. When considered together, these studies provide a better understanding of the complex path from gene to psychosis.

According to Weinberger, it's not surprising that this path is tortuous. Psychiatric illnesses such as schizophrenia are complex diseases that can arise due to various influences — both genetic and non-genetic — including multiple genes, different functional domains within a single gene, the environment and developmental factors. These factors are likely to work together in complex manners to impair various aspects of cognition including attention, memory and perception — the behaviors underlying many psychiatric illnesses — and increase risk of schizophrenia.

The COMT gene, for example, codes for an enzyme that affects dopamine, a chemical in the brain. Research shows the two common versions of the gene, called val and met, have opposite effects on dopamine metabolism. According to Weinberger, people who inherit two copies of val are likely to perform worse on learning and memory tasks — the same tasks impaired by schizophrenia — because they have less available dopamine in the region of the brain that executes these tasks.

Genetic variations in COMT influence the processing of emotional stimuli in the brain's hippocampus and prefrontal cortex, explained Weinberger. They also have an effect on the efficiency of information processing in the cortical systems involved in executive function, memory and emotions, and may have variable effects on these systems depending on the nature of the information being processed.

COMT may also interact with other genes to confer schizophrenia risk. Researchers suspect there may be more than 10 genes involved. The genes may interact with each other to modify the expression of their individual effects leading to exaggerated, compensated or novel effects.

Genetic variants of COMT may also interact with environmental and developmental factors to increase risk of schizophrenia, said Weinberger. Therefore, looking at genes alone is not enough. For example, a recent study found that people who inherit two copies of the val version and used marijuana heavily as teens were 10 times more likely to develop schizophrenia than the general population. In this case, age, marijuana use and COMT were all involved.

Adding to the complexity is emerging evidence that multiple sites of variability in the COMT gene interact with one another to influence risk of schizophrenia.

While it's clear that there is a genetic contribution to psychiatric illness, such interaction must be examined to understand how genes exert their influence.

Weinberger's lecture is available online at Information on several of the studies he mentioned is available on NIMH's web site at

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