Abdolmaleky Hamid Mostafavi, Cheng Kuang-Hung, Faraone Stephen V, Wilcox Marsha, Glatt Stephen J, Gao Fangming, Smith Cassandra L, Shafa Rahim, Aeali Batol, Carnevale Julie, Pan Hongjie, Papageorgis Panagiotis, Ponte Jose F, Sivaraman Vadivelu, Tsuang Ming T, Thiagalingam Sam
Department of Psychiatry at Massachusetts Mental Health Center and Harvard Institute of Psychiatric Epidemiology and Genetics, Harvard Medical School, Boston, MA, USA.
Hum Mol Genet. 2006 Nov 1;15(21):3132-45. doi: 10.1093/hmg/ddl253. Epub 2006 Sep 19.
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.
精神疾病表型表现的变异性以及基因关联的不一致性仍是分子精神病学面临的主要挑战。最近，越来越清楚的是，启动子DNA甲基化改变可能在介导基因的差异调控以及促进对环境的短期适应中起关键作用。在此，我们通过分析115份额叶尸检脑样本，报告了由于启动子甲基化改变导致的膜结合儿茶酚-O-甲基转移酶（MB-COMT）差异活性的研究，以及COMT Val158Met多态性作为精神分裂症和双相情感障碍风险因素的贡献性质。这些研究首次揭示，与对照组相比，精神分裂症和双相情感障碍患者的MB-COMT启动子DNA经常发生低甲基化（甲基化率：分别为26%和29%，而对照组为60%；P分别为0.004和0.008），特别是在左额叶（甲基化率：分别为29%和30%，而对照组为81%；P分别为0.003和0.002）。定量基因表达分析显示，与对照组相比，精神分裂症和双相情感障碍患者中MB-COMT的转录水平相应增加（P=0.02），且MB-COMT与DRD1表达呈负相关。此外，患者中COMT Val158Met多态性的Val等位基因有随着MB-COMT低甲基化而富集的趋势。这些发现表明，由于启动子低甲基化和/或COMT的高活性等位基因导致的MB-COMT过表达可能会增加额叶中的多巴胺降解，为精神分裂症和双相情感障碍的共同症状提供分子基础。
