Human Molecular Genetics Advance Access published online on September 19, 2006
Human Molecular Genetics, doi:10.1093/hmg/ddl253
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1 Department of Psychiatry at Massachusetts Mental Health Center, Harvard Institute of Psychiatric Epidemiology and Genetics, Harvard Medical School, Boston, MA; Departments of Medicine (Genetics Program) (L-320), Genetics & Genomics, and Pathology & Laboratory Medicine, Boston University School of Medicine, 715 Albany Street, Boston, MA, 02118, USA; Department of Psychiatry, Tehran Psychiatric Institute and Mental Health Research Center, Iran University of Medical Sciences, Tehran, Iran; Molecular Biotechnology Research Laboratory, Center for Advanced Biotechnology, and Departments of Biomedical Engineering, Biology, and Pharmacology, Boston University, Boston, MA
* To whom correspondence should be addressed. 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 to 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 to 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.
Received June 26, 2006
Revised August 21, 2006
Accepted September 8, 2006
Article
Hypomethylation of MB-COMT Promoter is a Major Risk Factor for Schizophrenia and Bipolar Disorder
Hamid Mostafavi Abdolmaleky 1 *, Kuang-hung Cheng 2, Stephen V. Faraone 3, Marsha Wilcox 4, Stephen J. Glatt 5, Fangming Gao 2, Cassandra L. Smith 6, Rahim Shafa 7, Batol Aeali 6, Julie Carnevale 2, Hongjie Pan 2, Panagiotis Papageorgis 2, Jose F. Ponte 2, Vadivelu Sivaraman 8, Ming T. Tsuang 9, and Sam Thiagalingam 2
2 Departments of Medicine (Genetics Program), Genetics & Genomics, and Pathology & Laboratory Medicine, Boston University School of Medicine, Boston, MA
3 Medical Genetics Research Center and Department of Psychiatry, SUNY Upstate Medical University, Syracuse, NY
4 Department of Psychiatry at Massachusetts Mental Health Center, Harvard Institute of Psychiatric Epidemiology and Genetics, Harvard Medical School, Boston, MA; Departments of Medicine (Genetics Program), Biostatistics, and Epidemiology, Boston University Schools of Medicine and Public Health, Boston, MA
5 Center for Behavioral Genomics, Department of Psychiatry, University of California, San Diego, La Jolla, CA
6 Molecular Biotechnology Research Laboratory, Center for Advanced Biotechnology, and Departments of Biomedical Engineering, Biology, and Pharmacology, Boston University, Boston, MA
7 Metrowest CNS Research Center, Tenet Metrowest Medical Center, Natick, MA
8 Critical Care Medicine, Department of Anesthesiology, University of Maryland School of Medicine, Baltimore, MD
9 Department of Psychiatry at Massachusetts Mental Health Center, Harvard Institute of Psychiatric Epidemiology and Genetics, Harvard Medical School, Boston, MA; Center for Behavioral Genomics, Department of Psychiatry, University of California, San Diego, La Jolla, CA
Hamid Mostafavi Abdolmaleky, E-mail: hamostafavi{at}yahoo.com
Abstract 
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  J. S. Brown Jr Effects of Bisphenol-A and Other Endocrine Disruptors Compared With Abnormalities of Schizophrenia: An Endocrine-Disruption Theory of Schizophrenia Schizophr Bull, January 31, 2008; (2008) sbm147v1. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. HILLEMACHER, H. FRIELING, M. A.N. MUSCHLER, and S. BLEICH Homocysteine and Epigenetic DNA Methylation: A Biological Model for Depression? Am J Psychiatry, October 1, 2007; 164(10): 1610 - 1610. [Full Text] [PDF]
|
|
|
|
 |
|
 S. Bleich, H. Frieling, and T. Hillemacher Elevated Prenatal Homocysteine Levels and the Risk of Schizophrenia Arch Gen Psychiatry, August 1, 2007; 64(8): 980 - 981. [Full Text] [PDF]
|
|