Preliminary evidence of ubiquitin proteasome system dysregulation in schizophrenia and bipolar disorder: Convergent pathway analysis findings from two independent samples

Abstract

Schizophrenia (SCZ) and bipolar disorder (BPD) are polygenic disorders with many genes contributing to their etiologies. The aim of this investigation was to search for dysregulated molecular and cellular pathways for these disorders as well as psychosis. We conducted a blood-based microarray investigation in two independent samples with SCZ and BPD from San Diego (SCZ = 13, BPD = 9, control = 8) and Taiwan (SCZ = 11, BPD = 14, control = 16). Diagnostic groups were compared to controls, and subjects with a history of psychosis [PSYCH(+): San Diego (n = 6), Taiwan (n = 14)] were compared to subjects without such history [PSYCH(−): San Diego (n = 11), Taiwan (n = 14)]. Analyses of covariance comparing mean expression levels on a gene-by-gene basis were conducted to generate the top 100 significantly dysregulated gene lists for both samples by each diagnostic group. Gene lists were imported into Ingenuity Pathway Analysis (IPA) software. Results showed the ubiquitin proteasome pathway (UPS) was listed in the top ten canonical pathways for BPD and psychosis diagnostic groups across both samples with a considerably low likelihood of a chance occurrence (P = 0.001). No overlap in dysregulated genes populating these pathways was observed between the two independent samples. Findings provide preliminary evidence of UPS dysregulation in BPD and psychosis as well as support further investigation of the UPS and other molecular and cellular pathways for potential biomarkers for SCZ, BPD, and/or psychosis.

RETRACTED: Identification of gene ontologies linked to prefrontal–hippocampal functional coupling in the human brain

“…Abnormalities of ubiquitin gene expression have been reported in blood cells and the HC, PFC, and temporal gyrus of patients with schizophrenia (77)(78)(79). Gene sets related to the ubiquitin proteasome system have also been identified in two pathway analytical studies of schizophrenia, providing further evidence for the involvement of the ubiquitination processes in disease etiology (80). This is consistent with a growing number of studies suggesting that ubiquitin genes may function as upstream factors impacting the disturbed synaptic plasticity process reported in schizophrenia (81).…”

Genomic predictors of combat stress vulnerability and resilience in U.S. Marines: A genome-wide association study across multiple ancestries implicates PRTFDC1 as a potential PTSD gene

“…Interesting genes with suggestive evidence for association include CSMD1, a gene previously implicated in large GWAS of other psychiatric disorders (Schizophrenia Psychiatric Genome-Wide Association Study, 2011), genes (JAK1, FASLG) related to immune response, a pathway that has previously been implicated for PTSD by GWAS (Guffanti et al, 2013) as well as gene expression studies (Glatt et al, 2013), and genes (UBE2E3, UBE2U) from the ubiquitin system, which has been implicated in the etiology of schizophrenia and bipolar disorder (Bousman et al, 2010). Before conclusions can be drawn however these genes must be replicated in larger GWASs and meta-analyses currently planned by the PGC PTSD working group (Koenen et al, 2013).…”

Investigation of genetic variants in ubiquitin enzyme genes involved in the modulation of neurodevelopmental processes: a role in schizophrenia susceptibility?

“…The etiology of this disorder remains unclear, although research strongly points towards the interaction between genetic and environmental influences (Tsuang, 2000;Aukes et al, 2008). Recent gene expression and protein studies have reported an alteration of ubiquitin pathways in the brains from schizophrenia sufferers compared to controls (Bousman et al, 2010;Rubio et al, 2013).…”