Fuzzy genetic and environmental associations, variable phenotypes, and difficult to measure symptoms argue for comprehensive pathway studies on neuropsychiatric disease. Here, dopamine metabolism was dissected in the frontal cortex of ill individuals using a combination of measurement.

The activity of MB-COMT was assessed in 115 post-mortem frontal lobe samples as a function of genotype (VAL158MET), promoter methylation status, and mRNA level using conventional methods. Also analyzed were the promoter methylation status and mRNA expression levels of DRD1, DRD2, DRD4 and RELN.

MB-COMT promoter methylation was lower, and mRNA expression level higher in patients versus the control subjects (p=0.02). Further, hyper expression of MB-COMT was associated with hypo expression and hyper promoter methylation of DRD1, DRD2 and RELN. An enrichment of the overactive Val allele with MB-COMT hypomethylation in patients vs controls. For example, 87% vs 13%, ill vs well, respectively, were homozygous for Val/Val genotype and had an unmethylated MB-COMT promoter. In contrast, 18% of the samples with Met/Met genotype and a methylated MB-COMT promoter were among the SCZ/BD patients versus 82% in the controls (p=0.001). Preliminary studies on patients suggests, COMT antagonist are useful as adjunct therapeutics.

MB-COMT over-activity from the presence of an hyperactive allele (VAL), or promoter hypo-methylation may increases dopamine degradation in the frontal lobe, fine-tuning of down-stream gene expression, and provide a molecular basis for the shared symptoms of SCZ and BD. Hence, down regulation of COMT activity is a useful target for therapeutic intervention.