Relationship of catechol-O-methyltransferase variants to brain structure and function in a population at high risk of psychosis.
BACKGROUND
There is growing evidence that the gene catechol-O-methyltransferase (COMT) is involved in the etiopathogenesis of schizophrenia. This study sought to clarify the effects of the COMT Val158Met polymorphism on brain structure, function, and risk of developing schizophrenia in a well-characterized cohort of individuals at high risk of schizophrenia for familial reasons.


METHODS
In a sample of 78 people at high genetic risk of schizophrenia, the risk of progression to schizophrenia associated with the COMT Val allele was estimated. The relationship of the Val allele to brain structure and function was investigated using structural magnetic resonance imaging (sMRI) and functional magnetic resonance imaging (fMRI) data collected on the high-risk subjects before their disease outcome was known.


RESULTS
The COMT Val allele increased the risk of schizophrenia in this cohort in a dose-dependent manner. Subjects with the COMT Val allele had reduced gray matter density in anterior cingulate cortex. In addition, there was evidence of increased activation in lateral prefrontal cortex and anterior and posterior cingulated, with increasing sentence difficulty in those with the COMT Val allele despite a similar level of performance.


CONCLUSIONS
The COMT Val allele is associated with an increased risk of schizophrenia in subjects at increased familial risk, in whom it has demonstrable effects on prefrontal brain structure and function. These patterns of altered brain structure and function have previously been associated with schizophrenia in this and other samples.
McIntosh
Andrew M
AM
Division of Psychiatry, University of Edinburgh, Royal Edinburgh Hospital, Edinburgh, United Kingdom.
Baig
Ben J
BJ
Hall
Jeremy
J
Job
Dominic
D
Whalley
Heather C
HC
Lymer
G Katherine S
GK
Moorhead
T William J
TW
Owens
David G C
DG
Miller
Patrick
P
Porteous
David
D
Lawrie
Stephen M
SM
Johnstone
Eve C
EC
D000293:Adolescent; D000328:Adult; D000483:Alleles; D019943:Amino Acid Substitution / Q000235:genetics*; D001921:Brain / Q000473:pathology / Q000503:physiopathology*; D002394:Catechol O-Methyltransferase / Q000235:genetics*; D015331:Cohort Studies; D004292:Dominance, Cerebral / Q000502:physiology; D004298:Dopamine / Q000378:metabolism; D005260:Female; D005500:Follow-Up Studies; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005838:Genotype; D006179:Gyrus Cinguli / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D007091:Image Processing, Computer-Assisted; D021621:Imaging, Three-Dimensional; D008279:Magnetic Resonance Imaging; D008297:Male; D008715:Methionine / Q000235:genetics*; D009483:Neuropsychological Tests; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D017397:Prefrontal Cortex / Q000473:pathology / Q000503:physiopathology; D012307:Risk Factors; D012559:Schizophrenia / Q000175:diagnosis / Q000235:genetics* / Q000503:physiopathology; D012564:Schizophrenic Language; D012565:Schizophrenic Psychology; D012606:Scotland; D014633:Valine / Q000235:genetics*
D008715:Methionine; D002394:Catechol O-Methyltransferase; D014633:Valine; D004298:Dopamine