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.

Epigenetic regulation mechanisms of microRNA expression

“…This modification, mediated by the TET family of proteins (Tet1, Tet2, Tet3), is an intermediate step in the process of active demethylation of 5mCs, and as such, it is responsible for enhancing transcriptional efficiency (67) and is essential in a range of biological processes, such as embryonic development, stem cell function and cancer formation (68,69). The 5hmC marks are found at reduced levels (~1%) compared to the 5mC levels (4-5%) in the human genome.…”

Catechol-O-Methyltransferase (COMT): A Gene Contributing to Sex Differences in Brain Function, and to Sexual Dimorphism in the Predisposition to Psychiatric Disorders

“…Hence, for a given level of COMT expression, COMT activity in the male brain is higher than it is in females, and therefore the sexual dimorphism cannot be explained by transcriptional regulation. This fact also bears upon potential explanations for sexual dimorphism in COMT based upon epigenetic regulation (Kaminsky et al, 2006); in any event, there is no evidence for a sex difference in COMT methylation status (Abdolmaleky et al, 2006). Furthermore, the finding that COMT protein and activity levels rise considerably in men between the third and fifth decade of life (Tunbridge et al, 2007a), despite steady estradiol levels across this period (Bjornerem et al, 2004) emphasizes that estrogens are not the only factor responsible for regulating COMT in the brain.…”

Prospects for Epigenetic Epidemiology

“…Disruption of epigenetic profile is a feature of most cancers (61)(62)(63) and is speculated to play a role in the etiology of other complex diseases (13,64,65), including asthma (66), allergy (67), obesity, type 2 diabetes, coronary heart disease, autism spectrum disorders (68), and bipolar disorder and schizophrenia (69)(70)(71)(72)(73). The potential to identify distinct epigenetic biomarkers associated with eating disorders has also been explored (74,75).…”