TY - JOUR
T1 - Opposite effects of catechol-O-methyltransferase Val158Met on cortical function in healthy subjects and patients with schizophrenia
AU - Prata, Diana P
AU - Mechelli, Andrea
AU - Fu, Cynthia H Y
AU - Picchioni, Marco
AU - Kane, Fergus
AU - Kalidindi, Sridevi
AU - McDonald, Colm
AU - Howes, Oliver
AU - Kravariti, Eugenia
AU - Demjaha, Arsime
AU - Toulopoulou, Timothea
AU - Diforti, Marta
AU - Murray, Robin M
AU - Collier, David A
AU - McGuire, Philip K
PY - 2009/3/15
Y1 - 2009/3/15
N2 - BACKGROUND: Catechol-O-methyltransferase (COMT) is essential for dopamine metabolism in the brain, and normal variation in the COMT Val158Met polymorphism can influence regional brain function during cognitive tasks. How this is affected when central dopamine function is perturbed is unclear. We addressed this by comparing the effects of COMT Val158Met genotype on cortical activation during a task of executive functions in healthy and schizophrenic subjects.METHODS: We studied 90 subjects comprising 48 healthy volunteers (15 Met158/Met158, 20 Val158/Met158, and 13 Val158/Val158) and 42 patients with DSM-IV schizophrenia (13 Met158/Met158, 17 Val158/Met158, and 12 Val158/Val158). Subjects were studied with functional magnetic resonance imaging while performing a verbal fluency task, with performance recorded online. Main effects of genotype and diagnosis and their interaction on cortical activation and functional connectivity were assessed using SPM5.RESULTS: In the right peri-Sylvian cortex, the Met158 allele of the COMT Val158Met polymorphism was associated with greater activation than the Val158 allele in control subjects; the converse applied in patients (Z = 4.3; false discovery rate p = .04). There was also a strong trend for a group x genotype interaction on functional connectivity between this right peri-Sylvian region and the left anterior insula/operculum (Z = 3.4; p < .001, uncorrected). These findings were independent of between-group differences in task performance, medication, demographic factors, or IQ.CONCLUSIONS: Frontotemporal function during verbal generation is modulated by variation in COMT genotype. This effect is altered in schizophrenia, which may reflect the perturbation of central dopamine function associated with the disorder.
AB - BACKGROUND: Catechol-O-methyltransferase (COMT) is essential for dopamine metabolism in the brain, and normal variation in the COMT Val158Met polymorphism can influence regional brain function during cognitive tasks. How this is affected when central dopamine function is perturbed is unclear. We addressed this by comparing the effects of COMT Val158Met genotype on cortical activation during a task of executive functions in healthy and schizophrenic subjects.METHODS: We studied 90 subjects comprising 48 healthy volunteers (15 Met158/Met158, 20 Val158/Met158, and 13 Val158/Val158) and 42 patients with DSM-IV schizophrenia (13 Met158/Met158, 17 Val158/Met158, and 12 Val158/Val158). Subjects were studied with functional magnetic resonance imaging while performing a verbal fluency task, with performance recorded online. Main effects of genotype and diagnosis and their interaction on cortical activation and functional connectivity were assessed using SPM5.RESULTS: In the right peri-Sylvian cortex, the Met158 allele of the COMT Val158Met polymorphism was associated with greater activation than the Val158 allele in control subjects; the converse applied in patients (Z = 4.3; false discovery rate p = .04). There was also a strong trend for a group x genotype interaction on functional connectivity between this right peri-Sylvian region and the left anterior insula/operculum (Z = 3.4; p < .001, uncorrected). These findings were independent of between-group differences in task performance, medication, demographic factors, or IQ.CONCLUSIONS: Frontotemporal function during verbal generation is modulated by variation in COMT genotype. This effect is altered in schizophrenia, which may reflect the perturbation of central dopamine function associated with the disorder.
KW - Adult
KW - Case-Control Studies
KW - Catechol O-Methyltransferase/genetics
KW - Cerebral Cortex/physiopathology
KW - Cognition
KW - Female
KW - Genotype
KW - Humans
KW - Language Tests
KW - Male
KW - Neural Pathways/physiopathology
KW - Polymorphism, Single Nucleotide
KW - Schizophrenia/genetics
KW - Schizophrenic Psychology
U2 - 10.1016/j.biopsych.2008.09.027
DO - 10.1016/j.biopsych.2008.09.027
M3 - Article
C2 - 19054502
SN - 0006-3223
VL - 65
SP - 473
EP - 480
JO - Biological psychiatry
JF - Biological psychiatry
IS - 6
ER -