Abstract
Differential expression of neuregulin-1 (NRG1) mRNA isoforms and proteins has been reported in schizophrenia, primarily in post-mortem brain tissue. In this study, we examined 12 NRG1 SNPs, eight NRG1 mRNA isoforms (type I, type I(Ig2), type II, type III, type IV, EGFα, EGFβ, pan-NRG1) in whole blood, and NRG1-β1 protein in serum of clozapine-treated schizophrenia patients (N = 71) and healthy controls (N = 57). In addition, using cultured peripheral blood mononuclear cells (PBMC) from 15 healthy individuals, we examined the effect of clozapine on NRG1 mRNA isoform and protein expression. We found elevated levels of NRG1 mRNA, specifically the EGFα (P = 0.0175), EGFβ (P = 0.002) and type I(Ig2) (P = 0.023) containing transcripts, but lower NRG1-β1 serum protein levels (P = 0.019) in schizophrenia patients compared to healthy controls. However, adjusting for smoking status attenuated the difference in NRG1-β1 serum levels (P = 0.050). Examination of clinical factors showed NRG1 EGFα (P = 0.02) and EGFβ (P = 0.02) isoform expression was negatively correlated with age of onset. However, we found limited evidence that NRG1 mRNA isoform or protein expression was associated with current chlorpromazine equivalent dose or clozapine plasma levels, the latter corroborated by our PBMC clozapine exposure experiment. Our SNP analysis found no robust expression quantitative trait loci. Our results represent the first comprehensive investigation of NRG1 isoforms and protein expression in the blood of clozapine-treated schizophrenia patients and suggest levels of some NRG1 transcripts are upregulated in those with schizophrenia.
Highlights
Neuregulin-1 (NRG1) is vital for neurodevelopment and plasticity[1], making it an appealing gene to examine in schizophrenia
Among the remaining four NRG1 isoforms, levels of EGFα, EGFβ, and type I(Ig2) mRNA were significantly elevated and type III did not differ in schizophrenia patients compared to healthy controls after adjustment for covariates and correction for multiple testing (Fig. 1)
Gene expression levels of NRG1 isoforms were not correlated with clozapine plasma levels or chlorpromazine equivalent antipsychotic exposure (Supplementary Table S5), which was further corroborated by our in vitro analysis that showed no difference in mRNA levels of detectable isoforms (EGFα, EGFβ, and type II) in clozapine exposed compared to unexposed peripheral blood mononuclear cells (PBMC) (Supplementary Fig. S7)
Summary
Neuregulin-1 (NRG1) is vital for neurodevelopment and plasticity[1], making it an appealing gene to examine in schizophrenia. This appeal has been weakened by genome-wide association study results that have failed to identify it as a top schizophrenia ‘‘risk’’ gene[2]; questioning the relevance of NRG1 in schizophrenia[3]. The relevance of any gene to schizophrenia should not be determined exclusively on whether sequence variations within the gene meet genome-wide significance but rather mRNA and protein levels associated with schizophrenia in specific populations or in certain contexts, which could, in part, be attributed to the complex and highly interactive nature of the NRG-ErbB signaling pathway[1,5]. Similar evidence of differential gene and protein expression in the peripheral tissue of schizophrenia patients is Mostaid et al Translational Psychiatry (2017)7:1280 Post-mortem human brain studies in schizophrenia have shown differential expression of NRG1 mRNA and protein in various brain regions, most notably in dorsolateral prefrontal cortex and hippocampus[6,7,8,9], other studies of both regions have been negative[10,11,12,13,14].
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
