Effect of COMT Val108/158 Met genotype on frontal lobe function and risk for schizophrenia

Abstract

Abnormalities of prefrontal cortical function are prominent features of schizophrenia and have been associated with genetic risk, suggesting that susceptibility genes for schizophrenia may impact on the molecular mechanisms of prefrontal function. A potential susceptibility mechanism involves regulation of prefrontal dopamine, which modulates the response of prefrontal neurons during working memory. We examined the relationship of a common functional polymorphism (Val(108/158) Met) in the catechol-O-methyltransferase (COMT) gene, which accounts for a 4-fold variation in enzyme activity and dopamine catabolism, with both prefrontally mediated cognition and prefrontal cortical physiology. In 175 patients with schizophrenia, 219 unaffected siblings, and 55 controls, COMT genotype was related in allele dosage fashion to 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 cognitive 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 family-based association analysis of 104 trios, we found a significant increase in transmission of the Val allele to the schizophrenic offspring. These data suggest that the COMT Val allele, because it increases prefrontal dopamine catabolism, impairs prefrontal cognition and physiology, and by this mechanism slightly increases risk for schizophrenia.

Figure 1

WCST perseverative error t scores (± SE) by genotype for each group (population mean = 50, SD = 10, lower scores indicate worse performance). Main effect of genotype: F = 4.93, df = 2,224, P = 0.008.

Figure 2

Effect of COMT genotype on fMRI activation during the two-back working memory task. Regions showing a significant effect of genotype on fMRI activation (voxelwise P < 0.005) are in red (shown clockwise from upper left in right lateral, left lateral, right medial, and left medial views, respectively). In dorsolateral prefrontal cortex (e.g., Brodmann area 46; x = 58, y = 32, z = 12; cluster size = 47; Z = 2.55) and anterior cingulate (e.g., Brodmann 32; x = 6, y = 60, z = 8; cluster size = 77; Z = 2.36), Val/Val individuals showed a greater fMRI response (and by inference, greater inefficiency, as performance is similar) than Val/Met individuals who have greater activation than Met/Met individuals. Post hoc analysis of genotype group contrasts confirmed these significant relationships in dorsolateral prefrontal and cingulate cortices across all groups.

Figure 3

Effect of COMT genotype on fMRI activation during the two-back working memory task in a second group of subjects. Again, Val/Val individuals showed greater activation (and by inference greater inefficiency) than Val/Met individuals who showed less efficiency than Met/Met individuals in the dorsal prefrontal cortex and several other locales.