Opposite effects of catechol-O-methyltransferase Val158Met on cortical function in healthy subjects and patients with schizophrenia.
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.
Prata
Diana P
DP
Division of Psychological Medicine and Psychiatry, Institute of Psychiatry, King's College, London, United Kingdom. d.prata@iop.kcl.ac.uk
Mechelli
Andrea
A
Fu
Cynthia H Y
CH
Picchioni
Marco
M
Kane
Fergus
F
Kalidindi
Sridevi
S
McDonald
Colm
C
Howes
Oliver
O
Kravariti
Eugenia
E
Demjaha
Arsime
A
Toulopoulou
Timothea
T
Diforti
Marta
M
Murray
Robin M
RM
Collier
David A
DA
McGuire
Philip K
PK
D000328:Adult; D016022:Case-Control Studies; D002394:Catechol O-Methyltransferase / Q000235:genetics*; D002540:Cerebral Cortex / Q000503:physiopathology*; D003071:Cognition; D005260:Female; D005838:Genotype; D006801:Humans; D007807:Language Tests; D008297:Male; D009434:Neural Pathways / Q000503:physiopathology; D020641:Polymorphism, Single Nucleotide; D012559:Schizophrenia / Q000235:genetics* / Q000503:physiopathology*; D012565:Schizophrenic Psychology
D002394:Catechol O-Methyltransferase