Ho Ada M-C, Winham Stacey J, Armasu Sebastian M, Blacker Caren J, Millischer Vincent, Lavebratt Catharina, Overholser James C, Jurjus George J, Dieter Lesa, Mahajan Gouri, Rajkowska Grazyna, Vallender Eric J, Stockmeier Craig A, Robertson Keith D, Frye Mark A, Choi Doo-Sup, Veldic Marin
Department of Psychiatry and Psychology, Mayo Clinic, Rochester, MN, USA; Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA.
Department of Health Science Research, Mayo Clinic, Rochester, MN, USA.
J Psychiatr Res. 2019 Oct;117:45-54. doi: 10.1016/j.jpsychires.2019.05.030. Epub 2019 Jun 26.
Dorsolateral prefrontal cortex (DLPFC) and temporal pole (TP) are brain regions that display abnormalities in bipolar disorder (BD) patients. DNA methylation - an epigenetic mechanism both heritable and sensitive to the environment - may be involved in the pathophysiology of BD. To study BD-associated DNA methylomic differences in these brain regions, we extracted genomic DNA from the postmortem tissues of Brodmann Area (BA) 9 (DLPFC) and BA38 (TP) gray matter from 20 BD, ten major depression (MDD), and ten control age-and-sex-matched subjects. Genome-wide methylation levels were measured using the 850 K Illumina MethylationEPIC BeadChip. We detected striking differences between cortical regions, with greater numbers of between-brain-region differentially methylated positions (DMPs; i.e., CpG sites) in all groups, most pronounced in the BD group, and with substantial overlap across groups. The genes of DMPs common to both BD and MDD (hypothetically associated with their common features such as depression) and those distinct to BD (hypothetically associated with BD-specific features such as mania) were enriched in pathways involved in neurodevelopment including axon guidance. Pathways enriched only in the BD-MDD shared list pointed to GABAergic dysregulation, while those enriched in the BD-only list suggested glutamatergic dysregulation and greater impact on synaptogenesis and synaptic plasticity. We further detected group-specific between-brain-region gene expression differences in ODC1, CALY, GALNT2, and GABRD, which contained significant between-brain-region DMPs. In each brain region, no significant DMPs or differentially methylated regions (DMRs) were found between diagnostic groups. In summary, the methylation differences between DLPFC and TP may provide molecular targets for further investigations of genetic and environmental vulnerabilities associated with both unique and common features of various mood disorders and suggest directions of future development of individualized treatment strategies.
背外侧前额叶皮层（DLPFC）和颞极（TP）是双相情感障碍（BD）患者中表现出异常的脑区。DNA甲基化——一种既具有遗传性又对环境敏感的表观遗传机制——可能参与了BD的病理生理过程。为了研究这些脑区中与BD相关的DNA甲基化组差异，我们从20例BD患者、10例重度抑郁症（MDD）患者以及10例年龄和性别匹配的对照受试者的布罗德曼区（BA）9（DLPFC）和BA38（TP）灰质的死后组织中提取了基因组DNA。使用850K Illumina甲基化EPIC芯片测量全基因组甲基化水平。我们检测到皮质区域之间存在显著差异，所有组中脑区之间差异甲基化位点（DMPs，即CpG位点）的数量更多，在BD组中最为明显，并且各组之间存在大量重叠。BD和MDD共有的DMPs基因（假设与它们的共同特征如抑郁相关）以及BD特有的基因（假设与BD特异性特征如躁狂相关）在包括轴突导向在内的神经发育相关通路中富集。仅在BD-MDD共享列表中富集的通路指向GABA能失调，而仅在BD列表中富集的通路提示谷氨酸能失调以及对突触发生和突触可塑性的更大影响。我们进一步检测了ODC1、CALY、GALNT2和GABRD中脑区之间的组特异性基因表达差异，这些基因包含显著的脑区之间DMPs。在每个脑区中，诊断组之间未发现显著的DMPs或差异甲基化区域（DMRs）。总之，DLPFC和TP之间的甲基化差异可能为进一步研究与各种情绪障碍的独特和共同特征相关的遗传和环境易感性提供分子靶点，并为个性化治疗策略的未来发展指明方向。
