Hypomethylation of MB-COMT promoter is a major risk factor for schizophrenia and bipolar disorder
Hypomethylation of MB-COMT promoter is a major risk factor for schizophrenia and bipolar disorder
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DOI：
10.1093/hmg/ddl253
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发表时间：
2006-11-01
影响因子：
3.5
通讯作者：
Thiagalingam, Sam
中科院分区：
文献类型：
--
作者：
Abdolmaleky, Hamid Mostafavi;Cheng, Kuang-hung;Thiagalingam, Sam
精神疾病中表型表现的变异性和遗传关联的缺乏一致性仍然是分子精神病学的一个主要挑战。最近，越来越清楚的是，改变启动子DNA甲基化可以在介导基因的差异调节和促进对环境的短期适应中发挥关键作用。在这里，我们报告的差异活动的膜结合儿茶酚-O-甲基转移酶（MB-COMT）的调查，由于改变启动子甲基化和COMT Val 158 Met多态性的贡献的性质作为精神分裂症和双相情感障碍的危险因素，通过分析115个死后大脑额叶样本。这些研究首次揭示了与对照组相比，MB-COMT启动子DNA在精神分裂症和双相情感障碍患者中经常发生低甲基化（甲基化率：分别为26和29对60%; P=0.004和0.008），特别是在左额叶（甲基化率：29和30对81%; P=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的MB-COMT转录水平相应增加（P=0.02），MB-COMT和DRD 1表达之间存在负相关。此外，有一个富集的瓦尔等位基因的COMT Val 158 Met多态性MB-COMT低甲基化的患者。这些研究结果表明，MB-COMT过度表达，由于启动子低甲基化和/或过度活跃的等位基因的COMT可能会增加额叶多巴胺的降解提供了一个分子基础的共同症状的精神分裂症和双相情感障碍。
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.