Full-length ArticleAltered neural signaling and immune pathways in peripheral blood mononuclear cells of schizophrenia patients with cognitive impairment: A transcriptome analysis
Introduction
Schizophrenia is a severely debilitating psychiatric disorder characterized by delusions, hallucinations, and deficits in cognitive function. Recent genome-wide association (GWA) studies have identified a growing number of genetic loci associated with schizophrenia (Purcell et al., 2009, Ripke et al., 2011, Ripke et al., 2013, Ripke et al., 2014, Shi et al., 2009, Stefansson et al., 2009) which are implicated in biological processes relating to calcium signaling, immune system function (e.g., many variants in the extended major histocompatibility complex [MHC] region), and long intergenic noncoding RNAs. We have previously shown that one recent genetic variant regulating miR-137 (Green et al., 2013) is associated with a cognitive deficit subtype of schizophrenia. However, the precise functional implication of associated variants remains to be determined, and requires investigation of gene expression regulation, at both transcriptional and post-transcriptional levels. In this study we explore the biological pathways associated with cognitive subtypes of schizophrenia using gene-set analysis of high throughput expression profiles from patient derived PBMCs.
Gene expression changes are evident in several brain regions from post-mortem tissues, and have also been reported in studies using peripheral blood mononuclear cells (PBMCs; for a recent review, see (Sequeira et al., 2012). Findings from both types of study converge on biological processes involved in cell cycle, intracellular signaling, oxidative stress and metabolism, phosphatidylinositol signaling, and ubiquitin proteasome system dysregulation (Bousman et al., 2010, Craddock et al., 2007, McCurdy et al., 2006). Briefly, transcriptome profiling of both fresh PBMCs and lymphoblastoid cell lines have demonstrated unique gene expression signatures related to these processes that discriminate schizophrenia from bipolar disorder, and healthy control groups (Tsuang et al., 2005); more recently, candidate blood biomarkers for two key psychotic symptoms in schizophrenia (hallucinations and delusions) were identified (Kurian et al., 2011), alongside the detection of blood-based gene expression signature using a supervised classifier in association with diagnosis of schizophrenia (Takahashi et al., 2010). Notably, PBMCs play important roles in the immune system, which is increasingly acknowledged in contributing to higher cognitive functions (Wolf et al., 2009). PBMCs express a number of brain associated proteins including receptors for brain derived neurotrophic factor, glucocorticoids, catecholamines, serotonin, dopamine and acetylcholine (McKenna et al., 2002), and many neurons express receptors for signaling molecules of the immune system such as cytokines (Guyon et al., 2008, Kronfol and Remick, 2000, Muller and Ackenheil, 1998).
The emerging studies of PBMCs in schizophrenia have reported dysregulated gene expression of actin assembly factor DAAM2 (Kuzman et al., 2009), a splice variant of NRG1, involved in neurological function and higher levels of sensory and motor neuron derived factor (SMDF) (Petryshen et al., 2005); other implicated genes are involved in processes of neurotransmission and presynaptic function (e.g., dopamine receptor D2 [DRD2]), the inwardly rectifying potassium channel (Kir2.3), and neuropeptide Y (NPY1R) (Middleton et al., 2005a, Vawter et al., 2004a, Zvara et al., 2005). More recently, our study using the largest PBMC cohort to date has reported differential expression of a substantial number of genes involved in the immune system (Gardiner et al., 2013), consistent with a recent mRNA sequencing study implicating a number of immune pathways in schizophrenia, such as antigen presentation and chemokine signaling (Xu et al., 2012).
In this context, there has not yet been a systematic investigation of gene expression profiles associated with putative cognitive subtypes of schizophrenia. While cognitive deficits are a core feature of schizophrenia, there remains substantial heterogeneity among schizophrenia patients in the severity of cognitive impairments. The potential to detect specific biological associations with cognitive subtypes of schizophrenia has been demonstrated in two independent cohorts (Green et al., 2013, Hallmayer et al., 2005, Morar et al., 2011), and in a similar vein, it has been recognised that better use of phenotypic information can increase the power of GWA studies considerably (van der Sluis et al., 2013). In this study we explore the biological pathways associated with cognitive subtypes of schizophrenia using gene-set analysis of high throughput expression profiles from patient derived PBMCs.
Section snippets
Participants
Participant data was obtained from the Australian Schizophrenia Research Bank (ASRB), an established register of participants and research data collected by scientific collaborators across five Australian states and territories, with written informed consent obtained from all participants (Loughland et al., 2010). Ethical approval for this project was obtained from the Hunter Area Health Services Human Research Ethics Committee. ASRB participation required that participants be fluent in English
Results
Demographic, clinical, and cognitive characteristics of the schizophrenia subtypes CS and CD along with healthy controls are presented in Table 1. CS, CD groups and healthy controls showed no differences in age, gender, and RQI (all p > 0.05). ANOVA revealed no difference between CS and CD subtypes in terms of duration of illness or antipsychotic treatment; Fisher’s exact test showed no difference in the type of antipsychotic medications being used by CS and CD subtypes (all p > 0.05). The
Discussion
In this study we investigated transcriptional variation in relation to putative cognitive subtypes in schizophrenia (SZ). In simple gene level analysis, the ‘cognitive deficit’ (CD) subtype showed 130 DEGs, 106 of which were also found to be differentially expressed in the SZ group as a whole; however, the ‘cognitively spared’ (CS) subgroup displayed very little difference to the control group (HC) with only 4 DEGs surviving multiple correction (ZNF827, HINT2, LOC653103, YWHAB). Functional
Role of funding
This research was supported by the Schizophrenia Research Institute, the Hunter Medical Research Institute and the Neurobehavioral Genetics Unit, utilizing infrastructure funding from NSW Ministry of Health. It was supported by a MC Ainsworth Research Fellowship in Epigenetics (MC); a NARSAD Young Investigator Award Samples and clinical and demographic data for this study were provided by the Australian Schizophrenia Research Bank (Chief Investigators: Carr V, Schall U, Scott R, Jablensky A,
Acknowledgments
PBMCs were processed by Melissa Tooney, Trish Collinson, Amy Martin, and Janelle Collins-Langworthy.
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2022, Psychiatry ResearchCitation Excerpt :This research provides some validation to searching for levels of gene expression in blood that may be differentially associated with clusters of impaired versus intact cognitive performance in subgroups within disorders that include people with clear cognitive impairments, such as schizophrenia. It is therefore significant that one study has reported that blood levels of RNA for genes, which act to suppress WNT signalling could be used to predict cognitive impairment in patients with the disorder (Wu et al., 2016). Another study reported levels of RNA for genes involved in immune or inflammatory mechanisms being linked to deficits in verbal working memory in schizophrenia (Ukkola-Vuoti et al., 2019).
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2020, Progress in Neuro-Psychopharmacology and Biological PsychiatryCitation Excerpt :Recent evidence indicated that schizophrenia was related to immune reactions caused by prenatal infection exert potential long-lasting immune disturbances, leading to cognitive impairments and neuroanatomical alterations (Kneeland and Fatemi, 2013). A transcriptome study found that the differentially expressed genes of SCZ patients were enriched in immune system process (GO:0002376) (Wu et al., 2016). The cell adhesion molecules (CAMs) pathway was also detected for SCZ.
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2019, Progress in Neuro-Psychopharmacology and Biological PsychiatryCitation Excerpt :Furthermore, immune pathways, including antigen processing and presentation, genes (MCH-region, e.g. HLA-G gene) showed enrichment in a study of schizophrenia patients with cognitive impairment (Wu et al., 2016). Thus there is a growing body of evidence suggesting that the aetiology of schizophrenia may involve infectious or autoimmune processes from epidemiological (Feigenson et al., 2014), genome-wide loci (Schizophrenia Working Group of the Psychiatric Genomics, 2014), genetic and proteomic (Chan et al., 2017), and gene expression (Gardiner et al., 2013; Schmitt et al., 2011; Wu et al., 2016; Xu et al., 2012) approaches. Several cognitive endophenotypes, including general intelligence, information processing speed, and memory, has been used to study cognitive performance in schizophrenia (Hubbard et al., 2016), and in healthy individuals (Ibrahim-Verbaas et al., 2016; Luciano et al., 2011; Sniekers et al., 2017).
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2018, Brain, Behavior, and ImmunityCitation Excerpt :It is possible that the repertoire of peptide antigens displayed by the same HLA variant differs between patients with schizophrenia and controls. This mechanism is supported by gene expression and SNP studies in schizophrenia that have implicated genes involved in the molecular pathway for the processing, transport or loading of peptide antigens onto MHC (Fellerhoff and Wank, 2009; Wu et al., 2016). The ubiquitin system is also involved in antigen processing in herpes virus infections (Loureiro and Ploegh, 2006), and hence the dysfunction of protein ubiquitination observed in schizophrenia might also extend to antigen presentation (Rubio et al., 2013).