Effect of COMT Val(108/158) Met genotype on frontal lobe function and riskfor schizophrenia

Abnormalities of prefrontal cortical function are prominent features of sch izophrenia and have been associated with genetic risk, suggesting that susc eptibility genes for schizophrenia may impact on the molecular mechanisms o f prefrontal function. A potential susceptibility mechanism involves regula tion of prefrontal dopamine, which modulates the response of prefrontal neu rons during working memory. We examined the relationship of a common functi onal polymorphism (Va(108/158) Met) in the catechol-O-methyltransferase (CO MT) gene, which accounts for a 4-fold variation in enzyme activity and dopa mine catabolism, with both prefrontally mediated cognition and prefrontal c ortical physiology. In 175 patients with schizophrenia, 219 unaffected sibl ings, and 55 controls, COMT genotype was related in allele dosage fashion t o performance on the Wisconsin Card Sorting Test of executive cognition and explained 4% of variance (P = 0.001) in frequency of perseverative errors. Consistent with other evidence that dopamine enhances prefrontal neuronal function, the load of the low-activity Met allele predicted enhanced cognit ive performance. We then examined the effect of COMT genotype on prefrontal physiology during a working memory task in three separate subgroups(n = 11 -16) assayed with functional MRI, Met allele load consistently predicted a more efficient physiological response in prefrontal cortex. Finally, in a f amily-based association analysis of 104 trios, we found a significant incre ase in transmission of the Val allele to the schizophrenic offspring. These data suggest that the COMT Val allele, because it increases prefrontal dop amine catabolism, impairs prefrontal cognition and physiology. and by this mechanism slightly increases risk for schizophrenia.