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- Title
Hypomethylation of MB-COMT promoter is a major risk factor for schizophrenia and bipolar disorder.
- Authors
Abdolmaleky, Hamid Mostafavi; Cheng, Kuang-Hung; Faraone, Stephen V; Wilcox, Marsha; Glatt, Stephen J; Gao, Fangming; Smith, Cassandra L; Shafa, Rahim; Aeali, Batol; Carnevale, Julie; Pan, Hongjie; Papageorgis, Panagiotis; Ponte, Jose F; Sivaraman, Vadivelu; Tsuang, Ming T; Thiagalingam, Sam
- Abstract
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.
- Publication
Human molecular genetics, 2006, Vol 15, Issue 21, p3132
- ISSN
0964-6906
- Publication type
Journal Article
- DOI
10.1093/hmg/ddl253