Deregulation of complement components C4A and CSMD1 peripheral expression in first-episode psychosis and links to cognitive ability

Abstract

Up-regulation of the complement component 4A (C4A) in the brain has been associated with excessive synaptic pruning and increased schizophrenia (SZ) susceptibility. Over-expression of C4A has been observed in SZ postmortem brain tissue, and the gene encoding for a protein inhibitor of C4A activity, CUB and Sushi multiple domains 1 (CSMD1) gene, has been implicated in SZ risk and cognitive ability. Herein, we examined C4A and CSMD1 mRNA expression in peripheral blood from antipsychotic-naive individuals with first-episode psychosis (FEP; n = 73) and mentally healthy volunteers (n = 48). Imputed C4 locus structural alleles and C4A serum protein levels were investigated. Associations with symptom severity and cognitive domains performance were explored. A significant decrease in CSMD1 expression levels was noted among FEP patients compared to healthy volunteers, further indicating a positive correlation between C4A and CSMD1 mRNA levels in healthy volunteers but not in FEP cases. In addition, C4 copy number variants previously associated with SZ risk correlated with higher C4A mRNA levels in FEP cases, which confirms the regulatory effect of C4 structural variants on gene expression. Evidence also emerged for markedly elevated C4A serum concentrations in FEP cases. Within the FEP patient group, higher C4A mRNA levels correlated with more severe general psychopathology symptoms and lower CSMD1 mRNA levels predicted worse working memory performance. Overall, these findings suggest C4A complement pathway perturbations in individuals with FEP and corroborate the involvement of CSMD1 in prefrontal-mediated cognitive functioning.

Keywords: C4A; CSMD1; Cognition; First-episode psychosis; Gene expression; Schizophrenia.

Fig. 1

Relative mRNA expression levels for A C4A and B CSMD1 between healthy volunteers and FEP cases. Horizontal black lines indicate the median value for each group. P values were derived by a one-sided non-parametric Mann–Whitney test

Fig. 2

Correlation between C4 locus structural alleles (C4 haplotype groups) and mRNA expression levels in peripheral blood from FEP cases. Mean expression level (± standard error) is shown for each haplotype group

Fig. 3

Serum C4A protein levels measurements. Error bars represent standard deviation and statistical significance was derived by a non-parametric Mann–Whitney test

Fig. 4

Association between C4A, CSMD1 peripheral gene expression levels and PANSS subscale severity scores at admission among patients with FEP (*two-sided p < 0.05)

Fig. 5

Association between C4A, CSMD1 peripheral gene expression levels and WAIS-IV assessed neuropsychological indexes in patients with FEP (*two-sided p < 0.05)