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
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| Dr. Daniel Weinberger |
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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 http://videocast.nih.gov/.
Information on several of the studies he mentioned is available
on NIMH's web site at http://www.nimh.nih.gov/. 
