1RNA 2009 Sep 15: 1640-51
TitleSNPs in human miRNA genes affect biogenesis and function.
AbstractMicroRNAs (miRNAs) are 21-25-nucleotide-long, noncoding RNAs that are involved in translational regulation. Most miRNAs derive from a two-step sequential processing: the generation of pre-miRNA from pri-miRNA by the DROSHA/DGCR8 complex in the nucleus, and the generation of mature miRNAs from pre-miRNAs by the Dicer/TRBP complex in the cytoplasm. Sequence variation around the processing sites, and sequence variations in the mature miRNA, especially the seed sequence, may have profound affects on miRNA biogenesis and function. In the context of analyzing the roles of miRNAs in schizophrenia and Autism, we defined at least 24 human X-linked miRNA variants. Functional assays were developed and performed on these variants. In this study we investigate the affects of single nucleotide polymorphisms (SNPs) on the generation of mature miRNAs and their function, and report that naturally occurring SNPs can impair or enhance miRNA processing as well as alter the sites of processing. Since miRNAs are small functional units, single base changes in both the precursor elements as well as the mature miRNA sequence may drive the evolution of new microRNAs by altering their biological function. Finally, the miRNAs examined in this study are X-linked, suggesting that the mutant alleles could be determinants in the etiology of diseases.
SCZ Keywordsschizophrenia
2J. Mol. Neurosci. 2013 Mar 49: 594-9
TitleEvaluation of six SNPs of MicroRNA machinery genes and risk of schizophrenia.
AbstractMicroRNAs (miRNAs) are small regulatory RNAs that modulate the expression of approximately half of all human genes. Small changes in miRNA expression have been associated with several psychiatric and neurological disorders, but whether the polymorphisms in genes involved in the processing of miRNAs into maturity influence the susceptibility of a person to schizophrenia (SZ) has not yet been elucidated. In this study, we investigated the association between SZ risk and single-nucleotide polymorphisms (SNPs) in microRNA machinery genes. We assessed the associations between SZ as a risk and six potentially functional SNPs from five miRNA processing genes (DROSHA, DGCR8, DICER, AGO1, and GEMIN4) in a case-control study of 256 Chinese SZ patients and 252 frequency-matched (age, gender, and ethnicity) controls. All the SNPs (rs10719, rs3757, rs3742330, rs636832, rs7813, and rs3744741) were genotyped by high resolution melting method. We found that two SNPs in the DGCR8 and DICER gene were significantly associated with the altered SZ risk. The genotype or allele frequency of rs3742330 in DICER was significantly different in patients and controls. Moreover, the recessive model of rs3757 in DGCR8 (AA vs. GA/GG) exhibited a significantly increased risk with an odds ratio (OR) of 3.73 [95 % confidence interval (CI), 1.03-13.52, P?=?0.032]; the dominant model of rs3742330 in DICER (AA vs. AG/GG) exhibited a significantly increased risk with OR of 1.49 (95 % CI, 1.04-2.13; P?=?0.028). Other SNPs and the haplotype of GEMIN4 (rs3744741 and rs7813) did not show any association with SZ. Our results suggested that the specific genetic variants in microRNA machinery genes may affect SZ susceptibility.
SCZ Keywordsschizophrenia
3Mol. Neurobiol. 2015 Oct -1: -1
TitleDepression, Cytokine, and Cytokine by Treatment Interactions Modulate Gene Expression in Antipsychotic Nave First Episode Psychosis.
AbstractIn schizophrenia, genetic and environmental factors affect neurodevelopment and neuroprogressive trajectory. Altered expression of neuro-immune genes and increased levels of cytokines are observed, especially in patients with comorbid depression. However, it remains unclear whether circulating levels of cytokines and expression of these genes are associated, and how antipsychotic treatments impact this association. Relationships between messenger RNA (mRNA) expression of 11 schizophrenia-related genes and circulating levels of cytokines (interleukin (IL)-6, IL-10, and tumor necrosis factor (TNF)-?) were analyzed in 174 antipsychotic nave first episode psychosis (FEP) and in 77 healthy controls. A subgroup of 72 patients was reassessed after treatment with risperidone. FEP patients were divided into those with and without depression. FEP patients with depression showed increased COMT expression and decreased NDEL1 expression. Increased IL-6 was associated with lowered AKT1 and DROSHA expression, while increased IL-10 was associated with increased NDEL1, DISC1, and MBP expression. IL-6 levels significantly increased the risperidone-induced expression of AKT1, DICER1, DROSHA, and COMT mRNA. The differential mRNA gene expression in FEP is largely associated with increased cytokine levels. While increased IL-6 may downregulate AKT-mediated cellular functions and dysregulate genes involved in microRNA (miRNA) machinery, increased IL-10 has neuroprotective properties. Increased IL-6 levels may prime the expression of genes (AKT1, DICER1, DROSHA, and COMT) in response to risperidone, suggesting that cytokine??treatment??gene interactions may improve cell function profiles. FEP patients with depression show a different gene expression profile reinforcing the theory that depression in FEP is a different phenotype.
SCZ Keywordsschizophrenia