Biomarkers Discovery In Chinese Treatment Resistant Schizophrenia Patients

Schizophrenia is a highly heterogeneous and complex disorder.Approximately 20%-35% of the patients with schizophrenia do respond to treatment,classified as treatmentresistant schizophrenia(TRS).To date,the molecular mechanism of TRS is still unclear,and there is no clinically accurate biomarker for TRS precision therapy.The NRG1(neuregulin1)gene has been shown to be a susceptibility gene for schizophrenia.More importantly,some studies have confirmed that the NRG1 gene is associated with differences in antipsychotic drugs response to patients with TRS.NRG1 polymorphism in different responds of TRS therapeutic drugs deserves further study.Moreover,the number of related research,which schizophrenia was significantly inversely associated with NRG1 gene is most among common human diseases.For finding the relationship between NRG1 genetic polymorphism and TRS,420 TRS clinical samples were enrolled strictly in accordance with the entry criteria,and 40 Tag-SNP sites in NRG1 were selected.The results showed that the SNPrs77493513,rs6982890,and rs7834206 of the NRG1 gene sites were statistically significant between TRS patients and non-TRS patients(corrected P<0.05).By GCBI,we found that thesis between the NRG1 gene and TRS has a somewhat narrow focus on pathway analysis and mi RNA research.NRG1 may activate EGFR,ERB2,ERB3,ERB4 proteins,regulated by CREB,interact with CDC5 L,DLG4,EGFR,ERB2/3/4,IXZF4,LIMKI,targeting hsa-mi R-124-3p.The NRG1 gene may also be coordinated by multiple long noncoding RNAs.By genotyping,We studied 40 SNPs on the NRG1 gene.The SNP sites of rs77493513,rs6982890,and rs7834206,which were first discovered in NRG1,were significantly different between TRS patients and SCZ patients.By RNA sequencing,we found that GSTM1,NRG1,SIGLEC8,VSTM4,MTATP8,OLIG2,RHPN2,SPP1,SYCP2 L,NRXN1 expression were significantly downregulated in patients with TRS clozapine-ineffective;MAO-B,HBE2,KRC2,HIST1H4 D,CARD17,SHROOM4,BNIP3P11,AIFM3,GADD45 G,METTL7B expression were significantly up-regulated.The alcohol addiction-related pathway and PI3K/Akt signal transduction signal pathway may be relevant to TRS.Further evidence such as biological experiments are needed in the future.These results suggest that NRG1 signaling pathway,metabolic dysfunction and its oxidative stress damage and apoptosis may be the key factors affecting drug therapy to TRS and it may promote the TRS progression.We found that hsa-mi R-29c-5p up-regulated significantly,hsa-mi R-127-3p decreased significantly between patients with SCZ and TRS.These mi RNA may be new TRS biology target.In this study,NRG1 genotyping and transcriptome sequencing techniques were used to analyze the NRG1 genotyping characteristics in patients with TRS and form their major transcriptome expression profiles and non-coding mi RNA expression levels.The conclusions would be of great significance for etiology and diagnostics of TRS in the future.Our research also will play an important role in the development and precise use of anti-TRS drugs,the theory about precision medicine for TRS.