Genetic polymorphism in catechol-O-methyltransferase associated with the functional connectivity of frontostriatal circuits in first episode schizophrenia patients.

Abstract

Negative symptoms in schizophrenia have been associated with functional changes in frontostriatal pathways. Dysregulation of the dopamine signal in frontostriatal pathways leads to the symptomology observed in schizophrenia. Although the catechol-O-methyltransferase (COMT) gene, one of the susceptibility genes for schizophrenia, has been associated with dopamine activities in prefrontal and striatal regions, it is still unclear whether the disease state and COMT val158 met genotype have an interaction effect on the functional connectivity of frontostriatal pathways. In this study, we evaluated the possible interactions between COMT val158 met variations and the disease state on the resting-state functional connectivity (RSFC) of frontostriatal pathways in fifty-one first episode schizophrenia (FES) patients (val/val: 29, met +: 22) with prominent negative symptoms and forty-eight healthy controls (val/val: 31, met +: 17). Regions of interest were defined by the result of a meta-analysis of frontostriatal pathways using the Neurosynth database. We found a significant genotype×disease interaction effect on the RSFC between the bilateral anterior cingulate (ACC) and right caudate, which overlapped with the main effect of the disease state. Behavioural regression analysis suggested that RSFC between the right ACC and right caudate correlated with the severity of SANS avolition-apathy scores in patients who were met carriers but not in patients who were val homozygous. Our findings suggest that the RSFC of frontostriatal pathways may differentially affected by an individual's COMT val158 met genotype.