Effect of COMT Val ^108/158 Met genotype on frontal lobe function and risk for schizophrenia

TLDR

Abnormal prefrontal cortical function is a hallmark of schizophrenia and is linked to genetic risk, with prefrontal dopamine regulation proposed as a key mechanism. The study aimed to investigate how the COMT Val108/158Met polymorphism, which alters enzyme activity and dopamine catabolism, relates to prefrontal cognition and physiology. Using functional MRI during a working memory task in 11–16 participants per subgroup, the authors examined the effect of COMT genotype on prefrontal cortical responses, noting the polymorphism’s 4‑fold impact on enzyme activity. Across 175 patients, 219 siblings, and 55 controls, the Met allele dose was associated with better Wisconsin Card Sorting Test performance and more efficient prefrontal activation, while Val allele transmission was increased to affected offspring, indicating that the Val allele’s higher dopamine catabolism impairs cognition and physiology and modestly raises schizophrenia risk.

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.