Hypomethylation of MB-COMT promoter is a major risk factor for schizophrenia and bipolar disorder
| Autor: | Panagiotis Papageorgis, Hongjie Pan, Stephen V. Faraone, Batol Aeali, Kuang-hung Cheng, Jose F. Ponte, Fangming Gao, Stephen J. Glatt, Marsha A. Wilcox, Cassandra L. Smith, Ming T. Tsuang, Hamid Mostafavi Abdolmaleky, Rahim Shafa, Vadivelu Sivaraman, Julie Carnevale, Sam Thiagalingam |
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| Rok vydání: | 2006 |
| Předmět: |
Psychosis
Bipolar Disorder Heart Diseases Epigenetics of schizophrenia Biology Catechol O-Methyltransferase behavioral disciplines and activities Article Epigenesis Genetic Risk Factors mental disorders Genetics medicine Humans Genetic Predisposition to Disease Bipolar disorder Allele Promoter Regions Genetic Molecular Biology Genetics (clinical) Polymorphism Genetic Catechol-O-methyl transferase Receptors Dopamine D1 fungi General Medicine Methylation DNA Methylation medicine.disease Frontal Lobe Alcoholism Amino Acid Substitution Frontal lobe Case-Control Studies DNA methylation Schizophrenia CpG Islands Antipsychotic Agents |
| Zdroj: | Human Molecular Genetics. 15:3132-3145 |
| ISSN: | 1460-2083 0964-6906 |
| DOI: | 10.1093/hmg/ddl253 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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