Hypomethylation of MB-COMT promoter is a major risk factor for schizophrenia and bipolar disorder.
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.
Abdolmaleky
Hamid Mostafavi
HM
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
Cheng
Kuang-Hung
KH
Faraone
Stephen V
SV
Wilcox
Marsha
M
Glatt
Stephen J
SJ
Gao
Fangming
F
Smith
Cassandra L
CL
Shafa
Rahim
R
Aeali
Batol
B
Carnevale
Julie
J
Pan
Hongjie
H
Papageorgis
Panagiotis
P
Ponte
Jose F
JF
Sivaraman
Vadivelu
V
Tsuang
Ming T
MT
Thiagalingam
Sam
S
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
D014150:Antipsychotic Agents; D017447:Receptors, Dopamine D1; D002394:Catechol O-Methyltransferase