Malki K, Pain O, Tosto M G, Du Rietz E, Carboni L, Schalkwyk L C
MRC Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, King's College London, London, UK.
1] MRC Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, King's College London, London, UK [2] Laboratory for Cognitive Investigations and Behavioural Genetics, Tomsk State University, Tomsk, Russia.
Transl Psychiatry. 2015 Mar 3;5(3):e519. doi: 10.1038/tp.2015.15.
Despite moderate heritability estimates, progress in uncovering the molecular substrate underpinning major depressive disorder (MDD) has been slow. In this study, we used prefrontal cortex (PFC) gene expression from a genetic rat model of MDD to inform probe set prioritization in PFC in a human post-mortem study to uncover genes and gene pathways associated with MDD. Gene expression differences between Flinders sensitive (FSL) and Flinders resistant (FRL) rat lines were statistically evaluated using the RankProd, non-parametric algorithm. Top ranking probe sets in the rat study were subsequently used to prioritize orthologous selection in a human PFC in a case-control post-mortem study on MDD from the Stanley Brain Consortium. Candidate genes in the human post-mortem study were then tested against a matched control sample using the RankProd method. A total of 1767 probe sets were differentially expressed in the PFC between FSL and FRL rat lines at (q⩽0.001). A total of 898 orthologous probe sets was found on Affymetrix's HG-U95A chip used in the human study. Correcting for the number of multiple, non-independent tests, 20 probe sets were found to be significantly dysregulated between human cases and controls at q⩽0.05. These probe sets tagged the expression profile of 18 human genes (11 upregulated and seven downregulated). Using an integrative rat-human study, a number of convergent genes that may have a role in pathogenesis of MDD were uncovered. Eighty percent of these genes were functionally associated with a key stress response signalling cascade, involving NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells), AP-1 (activator protein 1) and ERK/MAPK, which has been systematically associated with MDD, neuroplasticity and neurogenesis.
尽管有中等程度的遗传率估计，但在揭示重度抑郁症（MDD）潜在分子基础方面的进展一直缓慢。在本研究中，我们利用MDD遗传大鼠模型的前额叶皮质（PFC）基因表达，为一项人类尸检研究中的PFC探针集优先级提供信息，以揭示与MDD相关的基因和基因通路。使用RankProd非参数算法对弗林德斯敏感（FSL）和弗林德斯抗性（FRL）大鼠品系之间的基因表达差异进行统计学评估。大鼠研究中排名靠前的探针集随后被用于在斯坦利脑库的MDD病例对照尸检研究中对人类PFC中的直系同源选择进行优先级排序。然后使用RankProd方法在人类尸检研究中的候选基因与匹配的对照样本进行测试。在FSL和FRL大鼠品系之间，共有1767个探针集在PFC中差异表达（q⩽0.001）。在人类研究中使用的Affymetrix公司的HG-U95A芯片上发现了总共898个直系同源探针集。校正多个非独立测试的数量后，发现在q⩽0.05时，有20个探针集在人类病例和对照之间显著失调。这些探针集标记了18个人类基因的表达谱（11个上调和7个下调）。通过一项整合大鼠-人类的研究，发现了一些可能在MDD发病机制中起作用的趋同基因。这些基因中有80%在功能上与一个关键的应激反应信号级联相关，该级联涉及NF-κB（核因子κB）、AP-1（激活蛋白1）和ERK/MAPK，它们已被系统地与MDD、神经可塑性和神经发生联系起来。
