Hypomethylation of MB-COMT promoter is a major risk factor for schizophrenia and bipolar disorder

Hum Mol Genet. 2006 Nov 1;15(21):3132-45. doi: 10.1093/hmg/ddl253. Epub 2006 Sep 19.


The variability in phenotypic presentations and the lack of consistency of genetic associations in mental illnesses remain a major challenge in molecular psychiatry. Recently, it has become increasingly clear that altered promoter DNA methylation could play a critical role in mediating differential regulation of genes and in facilitating short-term adaptation in response to the environment. Here, we report the investigation of the differential activity of membrane-bound catechol-O-methyltransferase (MB-COMT) due to altered promoter methylation and the nature of the contribution of COMT Val158Met polymorphism as risk factors for schizophrenia and bipolar disorder by analyzing 115 post-mortem brain samples from the frontal lobe. These studies are the first to reveal that the MB-COMT promoter DNA is frequently hypomethylated in schizophrenia and bipolar disorder patients, compared with the controls (methylation rate: 26 and 29 versus 60%; P=0.004 and 0.008, respectively), particularly in the left frontal lobes (methylation rate: 29 and 30 versus 81%; P=0.003 and 0.002, respectively). Quantitative gene-expression analyses showed a corresponding increase in transcript levels of MB-COMT in schizophrenia and bipolar disorder patients compared with the controls (P=0.02) with an accompanying inverse correlation between MB-COMT and DRD1 expression. Furthermore, there was a tendency for the enrichment of the Val allele of the COMT Val158Met polymorphism with MB-COMT hypomethylation in the patients. These findings suggest that MB-COMT over-expression due to promoter hypomethylation and/or hyperactive allele of COMT may increase dopamine degradation in the frontal lobe providing a molecular basis for the shared symptoms of schizophrenia and bipolar disorder.

MeSH terms

  • Alcoholism / genetics
  • Amino Acid Substitution
  • Antipsychotic Agents / therapeutic use
  • Bipolar Disorder / drug therapy
  • Bipolar Disorder / genetics*
  • Bipolar Disorder / metabolism
  • Case-Control Studies
  • Catechol O-Methyltransferase / genetics*
  • CpG Islands / genetics
  • DNA Methylation*
  • Epigenesis, Genetic
  • Frontal Lobe / metabolism*
  • Genetic Predisposition to Disease
  • Heart Diseases / genetics
  • Humans
  • Polymorphism, Genetic
  • Promoter Regions, Genetic*
  • Receptors, Dopamine D1 / genetics
  • Risk Factors
  • Schizophrenia / drug therapy
  • Schizophrenia / genetics*
  • Schizophrenia / metabolism


  • Antipsychotic Agents
  • Receptors, Dopamine D1
  • Catechol O-Methyltransferase