Concordance of inflammatory markers in lymphocytes and prefrontal cortex in schizophrenia

Schizophrenia is a severe neuropsychiatric disorder associated with a wide array of transcriptomic and neurobiochemical changes. Genome-wide transcriptomic profiling conducted in postmortem brain have provided novel insights into the pathophysiology of this disorder, and identified biological processes including immune/inflammatory-related responses, metabolic, endocrine and synaptic function. However, few studies have investigated whether similar changes could be found in peripheral tissue. Here, we used RNA-sequencing to characterize transcriptomic profiles of lymphocytes in 18 non-psychotic controls and 19 individuals with schizophrenia. We identified 2,819 differentially expressed transcripts (pnominal < 0.05) in the schizophrenia group when compared to controls. Bioinformatic analyses conducted on a subset of 293 genes (pnominal < 0.01 and |log2FC| > 0.5) highlighted immune/inflammatory response as key biological processes in our dataset. Differentially expressed genes in lymphocytes were highly enriched for gene expression profiles from cortex layer 5a & immune cells. Thus, we investigated whether the changes in transcripts levels we observed in lymphocytes could also be detected in the prefrontal cortex (PFC, BA10) in a second validation cohort of schizophrenia subjects. Remarkably, mRNA levels detected in the PFC and lymphocytes were in strong agreement, and measurements obtained using RNA-sequencing were positively correlated with data obtained by RT-qPCR analysis. Collectively, our work supports a role for immune dysfunction in the pathogenesis of schizophrenia and suggest that peripheral markers can be used as accessible surrogates to investigate putative central nervous system disruptions. Overall design: Investigation of gene expression profiles in lymphocytes from 18 non-psychotic controls and 19 individuals with schizophrenia.

精神分裂症（Schizophrenia）是一种严重的神经精神疾病，与广泛的转录组学和神经生物化学改变密切相关。对死后脑组织进行的全基因组转录组学分析（genome-wide transcriptomic profiling）为该疾病的病理生理学机制提供了全新视角，并鉴定出包括免疫/炎症相关反应、代谢、内分泌及突触功能在内的核心生物学过程。然而，鲜有研究探讨在外周组织中是否也存在类似的病理改变。
本研究采用RNA测序（RNA-sequencing）技术，对18名非精神病对照个体及19名精神分裂症患者的淋巴细胞转录组特征进行了系统表征。相较于对照组，精神分裂症组中共鉴定出2819个差异表达转录本（名义p值<0.05）。针对293个基因子集（名义p值<0.01且|log2FC|>0.5）开展的生物信息学分析显示，免疫/炎症反应为本数据集的关键生物学过程。淋巴细胞中的差异表达基因高度富集了大脑皮层5a层及免疫细胞的基因表达谱。
为此，我们在第二组精神分裂症验证队列中，探究了淋巴细胞中观测到的转录水平变化是否亦可在前额叶皮层（prefrontal cortex, PFC, BA10）中被检测到。值得注意的是，前额叶皮层与淋巴细胞中的信使RNA（mRNA）水平具有高度一致性，RNA测序得到的检测结果与实时定量聚合酶链反应（RT-qPCR）分析获得的数据呈显著正相关。
综上，本研究证实免疫功能异常在精神分裂症的发病机制中发挥重要作用，并提示外周生物标志物可作为便捷的替代指标，用于探究潜在的中枢神经系统功能异常。本研究整体实验设计：对18名非精神病对照个体及19名精神分裂症患者的淋巴细胞基因表达谱进行分析。