title: Hypomethylation of MB-COMT promoter is a major risk factor for schizophrenia and bipolar disorder.
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.
authors.affiliation: Department of Psychiatry at Massachusetts Mental Health Center and Harvard Institute of Psychiatric Epidemiology and Genetics, Harvard Medical School, Boston, MA, USA. hamostafavi@yahoo.com
authors.forename: Hamid Mostafavi
authors.initials: HM
authors.lastname: Abdolmaleky
authors.forename: Kuang-Hung
authors.initials: KH
authors.lastname: Cheng
authors.forename: Stephen V
authors.initials: SV
authors.lastname: Faraone
authors.forename: Marsha
authors.initials: M
authors.lastname: Wilcox
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Glatt
authors.forename: Fangming
authors.initials: F
authors.lastname: Gao
authors.forename: Cassandra L
authors.initials: CL
authors.lastname: Smith
authors.forename: Rahim
authors.initials: R
authors.lastname: Shafa
authors.forename: Batol
authors.initials: B
authors.lastname: Aeali
authors.forename: Julie
authors.initials: J
authors.lastname: Carnevale
authors.forename: Hongjie
authors.initials: H
authors.lastname: Pan
authors.forename: Panagiotis
authors.initials: P
authors.lastname: Papageorgis
authors.forename: Jose F
authors.initials: JF
authors.lastname: Ponte
authors.forename: Vadivelu
authors.initials: V
authors.lastname: Sivaraman
authors.forename: Ming T
authors.initials: MT
authors.lastname: Tsuang
authors.forename: Sam
authors.initials: S
authors.lastname: Thiagalingam
mesh_terms: D000437:Alcoholism / Q000235:genetics; D019943:Amino Acid Substitution; D014150:Antipsychotic Agents / Q000627:therapeutic use; D001714:Bipolar Disorder / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D016022:Case-Control Studies; D002394:Catechol O-Methyltransferase / Q000235:genetics*; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005625:Frontal Lobe / Q000378:metabolism*; D020022:Genetic Predisposition to Disease; D006331:Heart Diseases / Q000235:genetics; D006801:Humans; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic; D017447:Receptors, Dopamine D1 / Q000235:genetics; D012307:Risk Factors; D012559:Schizophrenia / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism
chemical_list: D014150:Antipsychotic Agents; D017447:Receptors, Dopamine D1; D002394:Catechol O-Methyltransferase