Assciation Study Of Estrogen Receptor α And MicroRNA137Gene Polymorphisms With Schizophrenia

BackgroundSchizophrenia is a severe mental disease with heterogeneity and complex symptoms. Its etiology and pathogenesis are still unknown. Genetic factors play an important role in the pathological mechanisms of schizophrenia. In the estrogen hypothesis of schizophrenia, estrogen may play a protective role, and estrogen receptor (ESR) genetic variations could affect the effect of estrogen. MicroRNA137(miR-137) is a small RNA, which could affect neurodevelopment. The genetic variations of miR-137would be related to schizophrenia. Recent studies have found that the ESRa and miR-137gene polymorphisms may be associated with susceptibility to schizophrenia.Objectives1. The relationships between the polymorphisms of ESRa and miR-137gene and schizophrenia susceptibility were clarified in Chinese Han population. Whether these two genes could be schizophrenia susceptibility genes, and provide evidence for genetics mechanisms of schizophrenia.2. The relationships between the polymorphisms of ESRa and miR-137gene and clinical characteristics of schizophrenia, including age at onset, clinical symptoms, and treatment effects were explored. Whether these polymorphisms could provide references for clinical diagnosis and prognosis of schizophrenia.Methods1.322schizophrenic patients and300healthy controls from Chinese Han population in the North of Henan province were recruited. The Positive and Negative Syndrome Scale (PANSS) was used to estimate symptoms and therapeutic effects after treatment for six weeks.2. General information of subjects were collected. Genomic DNA was extracted from5ml peripheral venous blood, and ESRa and miR-137gene were amplified by Polymerase Chain Reaction. Subsequently, genotypes of these genes were detected by the methods of restriction fragment length polymorphism or sequencing directly.3. The distribution of genotypes and allele frequencies of polymorphisms in ESRa and miR-137gene, and the associations of these polymorphisms with clinical characteristics were analyzed by SPSS18.0software. Hardy-Weinberg Equilibrium, Linkage Disequilibrium, and Haplotype analyses were performed in Haploview V4.1, SHEsis, and SNPStats software, respectively.4. Meta-analysis of the associations of ESRa with schizophrenia was performed in Review Manager5.1software.Results1. The distribution of genotypes and allele frequencies of rs2234693(T/C) and rs9340799(A/G) in ESRa gene exhibited no significant differences between patients and controls, while haplotypes consisting of these polymorphisms had significant differences (P<0.05). For2234693, T-allele carriers had an earlier age at onset (P=0.017). CC-homozygote carriers had a higher general psychopathology score in male (P=0.048). CC-homozygote carriers had a higher tension and poor impulse control score. Patients with the CC homozygote had higher reductions of G4and G14scores when treated by aripirazole (P=0.015) and risperidone (P-0.006), respectively.2. The distribution of genotypes and allele frequencies of rs2234693and rs9340799also exhibited no significant differences between patients and controls in meta-analysis.3. Genotype and allele frequencies of rs66642155and rs1625579(A/C) in miR-137gene were not significantly different between patient and control populations. In schizophrenic patients, however, age at onset was much later in wild type rs66642155carriers (no tandem repeats) than in mutation carriers (at least one tandem repeat in either allele)(P=0.045). Total positive score on the PANSS, total five-factor model positive score derived from PANSS, and the PANSS delusions symptom subscore were all significantly higher in wild type rs66642155carriers with schizophrenia (P<0.05).Conclusions1. In Chinese Han population, only haplotypes consisting of rs2234693and rs9340799polymorphisms in ESRa gene may be strongly associated with schizophrenia. ESRa gene may be a candidate gene of schizophrenia. The rs2234693was related to age at onset, general psychopathology, tension, and poor impulse control symptoms, even the therapeutic effect in different groups.2. MiR-137gene may not be a significant candidate gene of schizophrenia, but the rs66642155allelic variant of miR-137appears to influence age at onset and the severity of positive symptoms in schizophrenic patients.3. The polymorphisms in ESRa and miR-137gene may be etiologically contribute to the severity of symptoms and treatment effects in schizophrenia, but the mechanisms needs further investigation.