Epigenomic profiling reveals DNA-Methylation changes associated with major psychosis
Epigenomic profiling reveals DNA-Methylation changes associated with major psychosis
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DOI：
10.1016/j.ajhg.2008.01.008
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发表时间：
2008-03-01
影响因子：
9.8
通讯作者：
Petronis, Arturas
中科院分区：
文献类型：
--
作者：
Mill, Jonathan;Tang, Thomas;Petronis, Arturas
表观遗传失调与精神分裂症和双相情感障碍的各种非孟德尔特征一致。然而，到目前为止，很少有研究调查DNA甲基化在重大精神病中的作用，也没有一个采用全基因组表观基因组方法。在这项研究中，我们使用CpG岛微阵列来识别与精神分裂症和双相情感障碍相关的额叶皮层和生殖细胞中的DNA甲基化变化。在额叶皮层中，我们发现了许多位点与精神病相关的DNA甲基化差异的证据，包括几个参与多巴胺能和GABA能神经传递、大脑发育以及与疾病病因学功能相关的其他过程的位点。这些基因座中的显著比例的DNA甲基化变化对应于与精神病相关的稳态mRNA水平的报告变化。基因本体论分析强调了对线粒体功能、大脑发育和应激反应相关基因座的表观遗传破坏。甲基化网络分析发现，受影响个体的大脑和生殖系中的表观遗传模块性降低，表明系统性表观遗传功能障碍可能与严重精神病相关。我们还报告了MEK1基因启动子区域的DNA甲基化与精神分裂症患者终生使用抗精神病药物之间的强相关性。最后，我们观察到BDNF基因中的额叶皮质DNA甲基化与附近非同义SNP的基因型相关，该SNP以前与重大精神病相关。我们的数据与重性精神病的表观遗传学理论一致，并表明DNA甲基化改变对精神分裂症和双相情感障碍的病因学很重要。
Epigenetic misregulation is consistent with various non-Mendelian features of schizophrenia and bipolar disorder. To date, however, few studies have investigated the role of DNA methylation in major psychosis, and none have taken a genome-wide epigenomic approach. In this study we used CpG-island microarrays to identify DNA-methylation changes in the frontal cortex and germline associated with schizophrenia and bipolar disorder. In the frontal cortex we find evidence for psychosis-associated DNA-methylation differences in numerous loci, including several involved in glutamatergic and GABAergic neurotransmission, brain development, and other processes functionally linked to disease etiology. DNA-methylation changes in a significant proportion of these loci correspond to reported changes of steady-state mRNA level associated with psychosis. Gene-ontology analysis highlighted epigenetic disruption to loci involved in mitochondrial function, brain development, and stress response. Methylome network analysis uncovered decreased epigenetic modularity in both the brain and the germline of affected individuals, suggesting that systemic epigenetic dysfunction may be associated with major psychosis. We also report evidence for a strong correlation between DNA methylation in the MEK1 gene promoter region and lifetime antipsychotic use in schizophrenia patients. Finally, we observe that frontal-cortex DNA methylation in the BDNF gene is correlated with genotype at a nearby nonsynonymous SNP that has been previously associated with major psychosis. Our data are consistent with the epigenetic theory of major psychosis and suggest that DNA-methylation changes are important to the etiology of schizophrenia and bipolar disorder.