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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.

Elevated peripheral expression of neuregulin-1 (NRG1) mRNA isoforms in clozapine-treated schizophrenia patients