From Genotype to Risk

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Science  15 Jun 2001:
Vol. 292, Issue 5524, pp. 1969
DOI: 10.1126/science.292.5524.1969b

The complexity and heterogeneity of psychiatric disorders have contributed to the difficulty in identifying the underlying genetic factors. Egan et al. have taken a bold step forward in proposing a tenuous, yet plausible linkage of a polymorphism in the gene encoding catechol-O-methyl transferase (COMT) to an elevated risk for schizophrenia.

An evolutionarily recent mutation in this gene results in the replacement of a valine residue with a methionine. This newer enzyme is less stable and exhibits only a quarter of the activity of COMT(Val). The anticipated biochemical result is that dopamine, the substrate of this enzyme, would be inactivated less rapidly. In turn, this would have the consequence in vivo of elevating dopamine levels, particularly in the prefrontal cortex where synaptic transporters that retrieve and sequester released dopamine are less abundant than in other areas of the brain. Dopamine is known, from animal and human studies, to be important for executing cognitive tasks involving working memory. Thus, it was expected that individuals homozygous for the Met allele would display enhanced performance in behavioral tests and that functional brain imaging would reveal larger areas of activation in Val/Val subjects (due to relatively “inefficient” processing in the prefrontal cortex).

Behavioral and genetic analysis of a sample of 175 schizophrenic patients, 219 healthy siblings, and 55 controls revealed an association of the Met allele with better performance on the Wisconsin Card Sorting Test and an association of the Val allele with schizophrenia; both were weak, but significant, effects. Imaging analysis of two groups of siblings showed the anticipated “excess” brain activation in Val/Val individuals. The authors emphasize that the Val allele is not an all-or-none determinant, but rather that it may increase the risk for schizophrenia by slightly compromising prefrontal function. — GJC

Proc. Natl. Acad. Sci. U.S.A.98, 6917 (2001).

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