Gene expression profiles of human prefrontal cortex brain tissues

Dissecting the shared etiology of different diseases could benefit from a systematic search for associated molecules and their interactions. We investigated genome-wide disruptions in the co-regulation of genes in two neurodegenerative diseases, Alzheimer's or Huntington's disease (AD or HD), using expression profiles from postmortem prefrontal cortex samples of 624 demented patients and non-demented control individuals with matched genotype and clinical data. A meta-analysis based screen for changes in coordinate expression patterns revealed differentially co-expressed (DC) gene pairs that either gained or lost correlation in disease cases relative to the control group, with the former being dominant for both AD and HD. Integration of disruptions common to AD and HD with large-scale data on protein-protein and protein-DNA interactions yielded a 242-gene sub-network that was enriched for proteins involved in neuronal differentiation and genetic associations to brain structural changes and dementia in subjects aged over 70 years. Replication of the AD DC network in independent human and mouse cohorts lends confidence to the comprehensive view we offer on dysregulated brain molecular pathways in AD and HD. DLPFC (BA9) brain tissues of AD patients, HD patients and non-demented controls samples were obtained from Harvard Brain tissue resource center (HBTRC). The HBTRC samples were primarily of Caucasian ancestry, as only eight non-Caucasian outliers were identified, and therefore excluded for further analysis. Post-mortem interval (PMI) was 17.8+8.3 hours (mean ± standard deviation), sample pH was 6.4±0.3 and RNA integrity number (RIN) was 6.8±0.8 for the average sample in the overall cohort. Tissues were profiled on a custom-made Agilent 44K array (GPL4372). 624 individual DLPFC samples were profiled against a common DLPFC pool constructed from the same set of samples.

剖析不同疾病共有的致病机制，可借助系统性搜寻相关分子及其相互作用提供助力。本研究针对阿尔茨海默病（Alzheimer's disease, AD）与亨廷顿病（Huntington's disease, HD）这两种神经退行性疾病，利用624名痴呆患者及匹配基因型与临床数据的非痴呆对照个体的死后前额叶皮层样本表达谱，探究了全基因组水平上的基因共调控紊乱情况。基于元分析的共表达模式变化筛查，鉴定出差异共表达（differentially co-expressed, DC）基因对：相较于对照组，疾病组中这些基因对的相关性或增强或减弱，且相关性增强的情况在AD与HD中均占主导。将AD与HD共有的调控紊乱数据与大规模蛋白质-蛋白质、蛋白质-DNA相互作用数据集整合后，得到了一个包含242个基因的子网络，该网络显著富集于神经元分化相关蛋白，以及70岁以上人群脑结构改变与痴呆的遗传关联相关蛋白。在独立人类与小鼠队列中对AD差异共表达网络进行验证，进一步证实了本研究提出的AD与HD脑内分子通路失调的全面图景。本研究使用的阿尔茨海默病患者、亨廷顿病患者及非痴呆对照个体的背外侧前额叶皮层（DLPFC, BA9）组织，均取自哈佛大学脑组织资源中心（Harvard Brain Tissue Resource Center, HBTRC）。该中心的样本主要为高加索血统，仅识别出8名非高加索血统的异常个体，故将其排除于后续分析。整体队列的平均死后间隔时间（post-mortem interval, PMI）为17.8±8.3小时，样本平均pH值为6.4±0.3，RNA完整性指数（RNA integrity number, RIN）为6.8±0.8。所有组织均通过定制安捷伦44K芯片（GPL4372）进行表达谱分析。624份独立DLPFC样本，均与由相同样本集合构建的通用DLPFC混合样本进行杂交比对。