Brain Advance Access originally published online on December 5, 2005
Brain 2006 129(2):399-410; doi:10.1093/brain/awh702
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The association between the Val158Met polymorphism of the catechol-O-methyl transferase gene and morphological abnormalities of the brain in chronic schizophrenia
1 Department of Radiology, National Center Hospital of Mental, Nervous and Muscular Disorders, National Center of Neurology and Psychiatry, 2 Department of Mental Disorder Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 3 Department of Psychiatry, National Center Hospital of Mental, Nervous, and Muscular Disorders, National Center of Neurology and Psychiatry, Tokyo and 4 Department of Investigative Radiology, Research Institute, National Cardiovascular Center, Osaka, Japan
Correspondence to: Takashi Ohnishi, Department of Radiology, National Center Hospital of Mental, Nervous, and Muscular Disorders, National Center of Neurology and Psychiatry 4-1-1 Ogawa Higashi, Kodaira City, Tokyo, Japan 187-0031 E-mail: tohnishi{at}hotmail.com
The catechol-O-methyl transferase (COMT) gene is considered to be a promising schizophrenia susceptibility gene. A common functional polymorphism (Val158Met) in the COMT gene affects dopamine regulation in the prefrontal cortex (PFC). Recent studies suggest that this polymorphism contributes to poor prefrontal functions, particularly working memory, in both normal individuals and patients with schizophrenia. However, possible morphological changes underlying such functional impairments remain to be clarified. The aim of this study was to examine whether the Val158Met polymorphism of the COMT gene has an impact on brain morphology in normal individuals and patients with schizophrenia. The Val158Met COMT genotype was obtained for 76 healthy controls and 47 schizophrenics. The diagnostic effects, the effects of COMT genotype and the genotype-diagnosis interaction on brain morphology were evaluated by using a voxel-by-voxel statistical analysis for high-resolution MRI, a tensor-based morphometry. Patients with schizophrenia demonstrated a significant reduction of volumes in the limbic and paralimbic systems, neocortical areas and the subcortical regions. Individuals homozygous for the Val-COMT allele demonstrated significant reduction of volumes in the left anterior cingulate cortex (ACC) and the right middle temporal gyrus (MTG) compared to Met-COMT carriers. Significant genotype-diagnosis interaction effects on brain morphology were noted in the left ACC, the left parahippocampal gyrus and the left amygdala-uncus. No significant genotype effects or genotype-diagnosis interaction effects on morphology in the dorsolateral PFC (DLPFC) were found. In the control group, no significant genotype effects on brain morphology were found. Schizophrenics homozygous for the Val-COMT showed a significant reduction of volumes in the bilateral ACC, left amygdala-uncus, right MTG and left thalamus compared to Met-COMT schizophrenics. Our findings suggest that the Val158Met polymorphism of the COMT gene might contribute to morphological abnormalities in schizophrenia.
Key Words: schizophrenia; polymorphism; COMT; ACC; DLPFC
Abbreviations: ACC = anterior cingulate cortex; COMT = catechol-O-methyl transferase; DLPFC = dorsolateral prefrontal cortex; FDR = false discovery rate; IQ = intelligence quotient; JART = Japanese version of National Adult Reading Test; ROI = region of interest; SPM = statistical parametric mapping; TBM = tensor-based morphometry
Received July 15, 2005. Revised September 21, 2005. Accepted October 27, 2005.
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