Associations Between Genotype and Peripheral Complement Proteins in First-Episode Psychosis: Evidences From C3 and C4.

Zheng Lin,Weihua Yue,Fen Lin,Lifang Wang,Yu Chen,Zhenguo Zhao

doi:10.3389/fgene.2021.647246

Abstract

Schizophrenia is a common neuropsychiatric disorder with complex pathophysiology. Recent reports suggested that complement system alterations contributed to pathological synapse elimination that was associated with psychiatric symptoms in schizophrenia. Complement component 3 (C3) and complement component 4 (C4) play central roles in complement cascades. In this study, we compared peripheral C3 and C4 protein levels between first-episode psychosis (FEP) and healthy control (HC). Then we explored whether single nucleotide polymorphisms (SNPs) at C3 or C4 genes affect peripheral C3 or C4 protein levels. In total, 181 FEPs and 204 HCs were recruited after providing written informed consent. We measured serum C3 and C4 protein levels using turbidimetric inhibition immunoassay and genotyped C3 and C4 polymorphisms using the Sequenom MassArray genotyping. Our results showed that three SNPs were nominally associated with schizophrenia (rs11569562/C3: A > G, p = 0.048; rs2277983/C3: A > G, p = 0.040; rs149898426/C4: G > A, p = 0.012); one haplotype was nominally associated with schizophrenia, constructed by rs11569562–rs2277983–rs1389623 (GGG, p = 0.048); FEP had higher serum C3 and C4 (both p < 0.001) levels than HC; rs1389623 polymorphisms were associated with elevated C3 levels in our meta-analysis (standard mean difference, 0.50; 95% confidence interval, 0.30 to 0.71); the FEP with CG genotype of rs149898426 had higher C4 levels than that with GG genotypes (p = 0.005). Overall, these findings indicated that complement system altered in FEP and rs149898426 of C4 gene represented a genetic risk marker for schizophrenia likely through mediating complement system. Further studies with larger sample sizes needs to be validated.

Highlights

Schizophrenia is a severe and complicated neuropsychiatric disorder characterized by hallucinations, delusions and cognitive dysfunction (Kahn and Keefe, 2013; Kahn et al, 2015; Owen et al, 2016)
Our results showed that three single nucleotide polymorphisms (SNPs) were nominally associated with schizophrenia; one haplotype was nominally associated with schizophrenia, constructed by rs11569562– rs2277983–rs1389623 (GGG, p = 0.048); first-episode psychosis (FEP) had higher serum component 3 (C3) and component 4 (C4) levels than healthy control (HC); rs1389623 polymorphisms were associated with elevated C3 levels in our meta-analysis; the FEP with CG genotype of rs149898426 had higher C4 levels than that with GG genotypes (p = 0.005)
Given that C3 and C4 are major plasma proteins of the complement pathway and are widely measured parameters during clinical practice, we investigated whether C3 or C4 protein levels are different between FEP and HC from our clinical data

Summary

Introduction

Schizophrenia is a severe and complicated neuropsychiatric disorder characterized by hallucinations, delusions and cognitive dysfunction (Kahn and Keefe, 2013; Kahn et al, 2015; Owen et al, 2016). Several lines of evidence suggested that dysregulation of the immune system contributed to the development of schizophrenia. Epidemiological studies found that infection and autoimmune disorders were associated with schizophrenia (Brown and Derkits, 2010; Benros et al, 2011, 2014; Arias et al, 2012; Khandaker et al, 2013). Many cross-sectional studies reported that proinflammatory cytokines and C-reactive protein (CRP) were increased in schizophrenia compared with healthy control (HC) (Miller et al, 2011; Fineberg and Ellman, 2013; Fernandes et al, 2016). Immune dysregulation could represent a vulnerability factor for schizophrenia

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