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Human Molecular Genetics Advance Access originally published online on September 19, 2006
Human Molecular Genetics 2006 15(21):3132-3145; doi:10.1093/hmg/ddl253
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© The Author 2006. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Hypomethylation of MB-COMT promoter is a major risk factor for schizophrenia and bipolar disorder

Hamid Mostafavi Abdolmaleky1,2,3,4,5,6,*, Kuang-hung Cheng2,3,4, Stephen V. Faraone7, Marsha Wilcox1,2,8,9, Stephen J. Glatt10, Fangming Gao2,3,4, Cassandra L. Smith6, Rahim Shafa11, Batol Aeali6, Julie Carnevale2, Hongjie Pan2,3, Panagiotis Papageorgis2,3, Jose F. Ponte2,3,4, Vadivelu Sivaraman12, Ming T. Tsuang1,10,{dagger} and Sam Thiagalingam2,3,4,{dagger}

1 Department of Psychiatry at Massachusetts Mental Health Center and Harvard Institute of Psychiatric Epidemiology and Genetics, Harvard Medical School, Boston, MA, USA, 2 Department of Medicine (Genetics Program), 3 Department of Genetics and Genomics, 4 Department of Pathology and Laboratory Medicine, Boston University School of Medicine, Boston, MA, USA, 5 Department of Psychiatry, Tehran Psychiatric Institute and Mental Health Research Center, Iran University of Medical Sciences, Tehran, Iran, 6 Molecular Biotechnology Research Laboratory and Department of Biomedical Engineering, Boston University, Boston, MA, USA, 7 Medical Genetics Research Center and Department of Psychiatry, SUNY Upstate Medical University, Syracuse, NY, USA, 8 Department of Biostatistics, 9 Department of Epidemiology, Boston University Schools of Public Health, Boston, MA, USA, 10 Center for Behavioral Genomics, Department of Psychiatry, University of California, San Diego, La Jolla, CA, USA, 11 Metrowest CNS Research Center, Tenet Metrowest Medical Center, Natick, MA, USA, 12 Critical Care Medicine, Department of Anesthesiology, University of Maryland School of Medicine, Baltimore, MD, USA

* To whom correspondence should be addressed at: Department of Medicine, Genetic Program, Boston University School of Medicine, 715 Albany Street, L-320 Boston, MA 02118, USA. Tel: +1 6176386022; Fax: +1 6176384275; Email: hamostafavi{at}yahoo.com

Received June 26, 2006; Revised August 21, 2006; Accepted September 8, 2006

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.

{dagger} These authors contributed equally and co-directed this work.


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