School of Biomedical Sciences and Pharmacy, Faculty of Health, The University of Newcastle, University Drive, Callaghan, NSW 2308, Australia; Schizophrenia Research Institute, Sydney, Australia; Centre for Translational Neuroscience and Mental Health, Hunter Medical Research Institute, Newcastle, NSW 2305, Australia.
Schizophrenia Research Institute, Sydney, Australia; School of Psychiatry, University of New South Wales, Sydney, NSW, Australia.
Brain Behav Immun. 2016 Mar;53:194-206. doi: 10.1016/j.bbi.2015.12.010. Epub 2015 Dec 14.
Cognitive deficits are a core feature of schizophrenia and contribute significantly to functional disability. We investigated the molecular pathways associated with schizophrenia (SZ; n=47) cases representing both 'cognitive deficit' (CD; n=22) and 'cognitively spared' (CS; n=25) subtypes of schizophrenia (based on latent class analysis of 9 cognitive performance indicators), compared with 49 healthy controls displaying 'normal' cognition. This was accomplished using gene-set analysis of transcriptome data derived from peripheral blood mononuclear cells (PBMCs). We detected 27 significantly altered pathways (19 pathways up-regulated and 8 down-regulated) in the combined SZ group and a further 6 pathways up-regulated in the CS group and 5 altered pathways (4 down-regulated and 1 up-regulated) in the CD group. The transcriptome profiling in SZ and cognitive subtypes were characterized by the up-regulated pathways involved in immune dysfunction (e.g., antigen presentation in SZ), energy metabolism (e.g., oxidative phosphorylation), and down-regulation of the pathways involved in neuronal signaling (e.g., WNT in SZ/CD and ERBB in SZ). When we looked for pathways that differentiated the two cognitive subtypes we found that the WNT signaling was significantly down-regulated (FDR<0.05) in the CD group in accordance with the combined SZ cohort, whereas it was unaffected in the CS group. This suggested suppression of WNT signaling was a defining feature of cognitive decline in schizophrenia. The WNT pathway plays a role in both the development/function of the central nervous system and peripheral tissues, therefore its alteration in PBMCs may be indicative of an important genomic axis relevant to cognition in the neuropathology of schizophrenia.
认知缺陷是精神分裂症的核心特征，并严重导致功能障碍。我们研究了与精神分裂症（SZ；n=47）病例相关的分子途径，这些病例代表了精神分裂症的“认知缺陷”（CD；n=22）和“认知未受损”（CS；n=25）亚型（基于 9 项认知表现指标的潜在类别分析），并与 49 名表现出“正常”认知的健康对照进行了比较。这是通过对来自外周血单核细胞（PBMCs）的转录组数据进行基因集分析来完成的。我们在合并的 SZ 组中检测到 27 个明显改变的途径（19 个途径上调和 8 个下调），在 CS 组中进一步检测到 6 个途径上调，在 CD 组中检测到 5 个改变的途径（4 个下调和 1 个上调）。SZ 和认知亚型的转录组分析特征是上调的途径涉及免疫功能障碍（例如 SZ 中的抗原呈递）、能量代谢（例如氧化磷酸化）以及下调涉及神经元信号的途径（例如 SZ/CD 中的 WNT 和 SZ 中的 ERBB）。当我们寻找区分这两种认知亚型的途径时，我们发现 WNT 信号在 CD 组中明显下调（FDR<0.05），与合并的 SZ 队列一致，而在 CS 组中则不受影响。这表明 WNT 信号的抑制是精神分裂症认知下降的一个特征。WNT 途径在中枢神经系统和外周组织的发育/功能中都起着作用，因此其在外周血单核细胞中的改变可能是与精神分裂症神经病理学中认知相关的重要基因组轴的指标。
