Impact of interacting functional variants in COMT on regional gray matter volume in human brain.
BACKGROUND
Functional variants in the catechol-O-methyltransferase (COMT) gene have been shown to impact cognitive function, cortical physiology and risk for schizophrenia. A recent study showed that previously reported effects of the functional val158met SNP (rs4680) on brain function are modified by other functional SNPs and haplotypes in the gene, though it was unknown if these effects are also seen in brain structure.


METHODS
We used voxel-based morphometry to investigate the impact of multiple functional variants in COMT on gray matter volume in a large group of 151 healthy volunteers from the CBDB/NIMH Genetic Study of Schizophrenia.


RESULTS
We found that the previously described rs4680 val risk variant affects hippocampal and dorsolateral prefrontal (DLPFC) gray matter volume. In addition, we found that this SNP interacts with a variant in the P2 promoter region (rs2097603) in predicting changes in hippocampal gray matter volume consistent with a nonlinear effect of extracellular dopamine.


CONCLUSIONS
We report evidence that interacting functional variants in COMT affect gray matter regional volume in hippocampus and DLPFC, providing further in vivo validation of the biological impact of complex genetic variation in COMT on neural systems relevant for the pathophysiology of schizophrenia and extending observations of nonlinear dependence of prefrontal neurons on extracellular dopamine to the domain of human brain structure.
Honea
Robyn
R
Genes, Cognition and Psychosis Program, National Institute of Mental Health, Division of Intramural Research, National Institutes of Health, Department of Health and Human Services, Bethesda, MD 20892, USA.
Verchinski
Beth A
BA
Pezawas
Lukas
L
Kolachana
Bhaskar S
BS
Callicott
Joseph H
JH
Mattay
Venkata S
VS
Weinberger
Daniel R
DR
Meyer-Lindenberg
Andreas
A
D000328:Adult; D002394:Catechol O-Methyltransferase / Q000235:genetics*; D005260:Female; D014644:Genetic Variation / Q000235:genetics; D006624:Hippocampus / Q000166:cytology* / Q000502:physiology*; D006801:Humans; D021621:Imaging, Three-Dimensional / Q000379:methods; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D008875:Middle Aged; D009474:Neurons / Q000166:cytology* / Q000502:physiology*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D017397:Prefrontal Cortex / Q000166:cytology* / Q000502:physiology*; D013223:Statistics as Topic
D002394:Catechol O-Methyltransferase