title: Altered neural signaling and immune pathways in peripheral blood mononuclear cells of schizophrenia patients with cognitive impairment: A transcriptome analysis.
abstract: 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.
authors.affiliation: 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.
authors.forename: Jing Qin
authors.initials: JQ
authors.lastname: Wu
authors.affiliation: Schizophrenia Research Institute, Sydney, Australia; School of Psychiatry, University of New South Wales, Sydney, NSW, Australia.
authors.forename: Melissa J
authors.initials: MJ
authors.lastname: Green
authors.affiliation: 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.
authors.forename: Erin J
authors.initials: EJ
authors.lastname: Gardiner
authors.affiliation: School of Biomedical Sciences and Pharmacy, Faculty of Health, The University of Newcastle, University Drive, Callaghan, NSW 2308, Australia; Schizophrenia Research Institute, Sydney, Australia.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Tooney
authors.affiliation: 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.
authors.forename: Rodney J
authors.initials: RJ
authors.lastname: Scott
authors.affiliation: Schizophrenia Research Institute, Sydney, Australia; School of Psychiatry, University of New South Wales, Sydney, NSW, Australia.
authors.forename: Vaughan J
authors.initials: VJ
authors.lastname: Carr
authors.affiliation: 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. Electronic address: Murray.Cairns@newcastle.edu.au.
authors.forename: Murray J
authors.initials: MJ
authors.lastname: Cairns
mesh_terms: D000328:Adult; D016022:Case-Control Studies; D003071:Cognition / Q000502:physiology; D060825:Cognitive Dysfunction / Q000097:blood* / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D015536:Down-Regulation; D005260:Female; D015870:Gene Expression; D020869:Gene Expression Profiling; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000276:immunology*; D008297:Male; D009474:Neurons / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D009483:Neuropsychological Tests; D012559:Schizophrenia / Q000097:blood* / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D015398:Signal Transduction; D015854:Up-Regulation; D060449:Wnt Signaling Pathway / Q000235:genetics
keywords: Cognition; Development; Gene expression; Immune; Schizophrenia