Recently, genome-wide association studies (GWAS), meta-analyses, and replication studies focusing on bipolar disorder (BD) have implicated the α-1C subunit of the L-type voltage-dependent calcium channel (CACNA1C) and ankyrin 3 (ANK3) genes in BD. Based on the hypothesis that both schizophrenia (SZ) and BD may share some common genetic risk factors, we investigated the association of CACNA1C and ANK3 with SZ using meta-analytic techniques, combining all published data up to April 2015. Nine teams, including four European decent samples and five Asian samples, contributed 14,141 cases and 30,679 controls for the analysis of CACNA1C rs1006737 and SZ. A significant difference was identified between patients and controls for the A-allele of rs1006737 in combined studies (Z = 6.02, P = 1.74E-09), in European studies (Z = 4.08, P = 4.50E-05), and in Asian studies (Z = 4.60, P = 4.22E-06). Meanwhile, for the T-allele of ANK3 rs10761482 (1,794 cases versus 1,395 controls), a significant association was observed in combined samples (Z = 2.06, P = 0.04) and in Asian samples (Z = 3.10, P = 0.002). In summary, our study provides further evidence for the positive association of CACNA1C and ANK3 with SZ. These results support the hypothesis that both SZ and BD share common genetic risk factors. Further research is needed to examine the functions of CACNA1C and ANK3, and their interacting partners in the molecular, developmental, and pathophysiological processes in SZ.
MicroRNAs (miRNAs) are a class of endogenous and non-coding single-stranded RNAs of approximately 22 nucleotides, many of which are evolutionarily conserved. Genome-wide association studies have identified a robust statistical association between the MIR137 gene and schizophrenia in Europeans, which was replicated in the Han Chinese population in a case-control study. In the previous study, we provided evidence for a significant association between the EFNB2 gene and schizophrenia in Han Chinese subjects. In the current study, we utilized computational analysis, vector construction of point mutations, luciferase reporter assays and gene expression assays including RT-qPCR and western blotting methods to investigate miR-137 directly targeting EFNB2 gene and explore the reversal effect of a genetic variant of SNP rs550067317 in the putative seed-pair region of EFNB2 3′-UTR. We also found that miR-137 could be detected in the peripheral blood of a cohort of first-onset schizophrenia patients and healthy controls, and the area under curve was 0.795 (95% confidence interval 0.700–0.890), which is a middle diagnostic value for disease, suggesting that it might be valuable for diagnosing schizophrenia. In summary, this study would improve our understanding of the role of miR-137 in schizophrenia-associated signaling pathways and identify the genetic basis of rs550067317 for schizophrenia. Furthermore, we provided new evidence for the involvement of miR-137 in the etiology and diagnosis of schizophrenia, which might contribute to the discovery of new biomarkers and therapeutic targets for the disease.
Schizophrenia is a severe psychiatric disorder with a strong hereditary component that affects approximately 1% of the world's population. The disease is most likely caused by the altered expression of a number of genes that function at the level of biological pathways or gene networks. Transcription factors (TF) are indispensable regulators of gene expression. EGR3 is a TF associated with schizophrenia. In the current study, DNA microarray and ingenuity pathway analyses (IPA) demonstrated that EGR3 regulates Reelin signaling pathway in SH‐SY5Y cells. ChIP and luciferase reporter studies confirmed that EGR3 directly binds to the promoter region of RELN thereby activating RELN expression. The expression of both EGR3 and RELN was decreased during neuronal differentiation induced by retinoic acid (RA) in SH‐SY5Y cells, and EGR3 over‐expression reduced neurite outgrowth which could be partially reversed by the knockdown of RELN. The expression levels of EGR3 and RELN in peripheral blood of subjects with schizophrenia were found to be down‐regulated (compared with healthy controls), and were positively correlated. Furthermore, data mining from public databases revealed that the expression levels of EGR3 and RELN were presented a positive correlation in post‐mortem brain tissue of subjects with schizophrenia. Taken together, this study suggests that EGR3 is a novel TF of the RELN gene and regulates neurite outgrowth via the Reelin signaling pathway. Our findings contribute to the understanding of the regulatory role of EGR3 in the pathophysiology and molecular mechanisms of schizophrenia, and potentially to the development of new therapies and diagnostic biomarkers for the disorder.
Zinc finger protein 804a (ZNF804A) has been identified by genome-wide association studies as a robust risk gene in schizophrenia, but how ZNF804A contributes to schizophrenia and its upstream regulation remains unknown. Previous studies have indicated that micrornas (mirs) are key factors that regulate the expression levels of their target genes. The present study revealed significantly increased expression of mir-148b-3p in the peripheral blood of patients with first-onset schizophrenia compared with healthy controls, and bioinformatics analysis predicted that the ZNF804A gene is a target of mir-148b-3p. Therefore, the present study investigated the possible upstream regulation of ZNF804A by mir-148b-3p in the human neuroblastoma SH-SY5Y cell line, and assessed the implications for schizophrenia. The results revealed significantly reversed expression levels of mir-148b-3p (P=0.0051) and ZNF804A (P=0.0218) in the peripheral blood of patients with first-onset schizophrenia compared with healthy individuals. Furthermore, it was demonstrated that mir-148b-3p directly targeted ZNF804A via binding to conserved target sites in the 3'-untranslated region of ZNF804A mrna, where it inhibited the endogenous expression of ZNF804A at both the mrna (P=0.048) and protein levels (P=0.013) in SH-SY5Y cells. Furthermore, mir-148b-3p was revealed to regulate the expression levels of catechol-O-methyltransferase (COMT) and serine protease 16 (PRSS16) by targeting ZNF804A in SH-SY5Y cells. collectively, the present results indicated that there was a direct upstream regulation of the schizophrenia risk gene ZNF804A by mir-148b-3p, which contributed to the regulation of the downstream genes COMT and PRSS16. Thus, the mir-148b-3p/ZNF804A/COMT/PRSS16 pathway may play an important role in the pathophysiology of schizophrenia, and may serve as a potential target in drug discovery and gene therapy for this disorder.
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