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Schizophrenia is a serious neurodevelopmental disorder. Genetics is an important factor leading to schizophrenia, but its exact role is still unclear. Many studies have focused on neurotransmitters and regulators that participate in the processes mediated by these neurotransmitters. Alcohol dehydrogenase may not only catalyze the oxidation of retinol and ethanol but also be involved in a variety of neurotransmitter metabolic pathways. Therefore, our study investigated whether ADH7 gene variations in the Chinese Han population were associated with schizophrenia. Genomic DNA was extracted from a cohort of 275 schizophrenic patients (136 men and 139 women) and 313 healthy controls (160 men and 153 women) from the Northern Han Chinese population. The Hardy-Weinberg equilibrium test and linkage disequilibrium analysis were performed. Differences in genotypes, alleles, and haplotypes between the schizophrenic and control groups were determined using the chi-square test and correlation analysis. The distribution of the CC + TT genotype of rs284787 was statistically different between the case and control groups (p = 0.026, OR = 1.448); however, the difference disappeared after Bonferroni correction. Linkage analysis indicated that rs739147, rs284787, rs3805329, rs894369, rs3805331, and rs284786 were closely linked in one block. The haplotype analysis found no association between the composed haplotypes and the occurrence of schizophrenia. Our study showed that the ADH7 gene was not associated with the risk of schizophrenia. Additional studies with larger cohorts of different ethnicities are needed to validate our findings.

Background: The CACNA1C gene was defined as a risk gene for schizophrenia in a large genome-wide association study of European ancestry performed by the Psychiatric Genomics Consortium. Previous meta-analyses focused on the association between the CACNA1C gene rs1006737 and schizophrenia. The present study focused on whether there was an ancestral difference in the effect of the CACNA1C gene rs1006737 on schizophrenia. rs2007044 and rs4765905 were analyzed for their effect on the risk of schizophrenia., Methods: Pooled, subgroup, sensitivity, and publication bias analysis were conducted., Results: A total of 18 studies met the inclusion criteria, including fourteen rs1006737 studies (15,213 cases, 19,412 controls), three rs2007044 studies (6007 cases, 6518 controls), and two rs4765905 studies (2435 cases, 2639 controls). An allele model study also related rs2007044 and rs4765905 to schizophrenia. The overall meta-analysis for rs1006737, which included the allele contrast, dominant, recessive, codominance, and complete overdominance models, showed significant differences between rs1006737 and schizophrenia. However, the ancestral-based subgroup analysis for rs1006737 found that the genotypes GG and GG + GA were only protective factors for schizophrenia in Europeans. In contrast, the rs1006737 GA genotype only reduced the risk of schizophrenia in Asians., Conclusions: Rs1006737, rs2007044, and rs4765905 of the CACNA1C gene were associated with susceptibility to schizophrenia. However, the influence model for rs1006737 on schizophrenia in Asians and Europeans demonstrated both similarities and differences between the two ancestors.

Objective: Schizophrenia is a severe neurodevelopmental disorder with a complex genetic and environmental etiology. The gene encoding EF-hand domain-containing protein D2 ( EFHD2 ) may be a genetic risk locus for schizophrenia., Methods: We genotyped four EFHD2 single-nucleotide polymorphisms (281 schizophrenia cases [SCZ], 321 controls) from northern Chinese Han individuals using Sanger sequencing and polymerase chain reaction-restriction fragment length polymorphism analysis. Differences existed in genotype, allele, and haplotype frequency distributions between SCZ and control groups., Results: The rs2473357 genotype and allele frequency distributions differed between SCZ and controls; however, this difference disappeared after Bonferroni correction. Differences in rs2473357 genotype and allele frequency distributions between SCZ and controls were more pronounced in men than in women. The G allele increased schizophrenia risk (odds ratio = 1.807, 95% confidence interval = 1.164-2.803). Among six haplotypes (G-, A-, G-insC, A-C, G-C, and G-T), the G- haplotype frequency distribution differed between SCZ and controls in women; the A-C and G-C haplotype frequency distributions differed between SCZ and controls in men., Conclusions: EFHD2 may be involved in schizophrenia. Sex differences in EFHD2 genotype and allele frequency distributions existed among schizophrenia patients. Further research is needed to determine the role of EFHD2 in schizophrenia.

The dopamine transporter is coded by the SLC6A3 gene and plays an important role in regulation of the neurotransmitter dopamine. To detect the association between the SLC6A3 gene and the risk of schizophrenia, 31 case-control articles were included in this meta-analysis. There were 23 studies with 40 bp VNTR (3246 cases and 3639 controls), 4 studies with rs40184 (2020 cases and 1674 controls), rs6347 (1317 cases and 1917 controls), rs403636 (2045 cases and 1704 controls), and rs2975226 (849 cases and 904 controls); and 3 studies with rs12516948 (1920 cases and 1569 controls), rs27072 (984 cases and 1015 controls), rs6869645 (1142 cases and 1082 controls), rs37022 (1168 cases and 1091 controls), rs464049 (1169cases and 1096 controls), rs2652511 (707 cases and 714 controls), and rs3756450 (1176 cases and 1096 controls). Pooled, subgroup, and sensitivity analyses were performed, and the results were visualized by forest and funnel plots. In the dominant genetic model, the genotype AA+AT of rs2975226 in the Indian population (P z  = 0, odds ratio [OR] = 3.245, 95% confidence interval [CI] = 1.806-5.831), TT of rs464049 (P z  = 0.002, OR = 1.389, 95% CI = 1.129-1.708), and TT of rs3756450 (P z  = 0.014, OR = 1.251, 95% CI = 1.047-1.495) might be risk factors for schizophrenia. Additionally, no other single nucleotide polymorphisms were observed. These results indicate that more functional studies are warranted.

The Schizophrenia Psychiatric GWAS Consortium (PGC) has identified the rs1625579 polymorphism in the MIR137 gene, which encodes miR-137, as the strongest new association with schizophrenia in the European population. However, whether the influence of rs1625579 on schizophrenia in the Asian population is consistent with these results remains unclear. A total of 21 studies (9878 schizophrenic patients and 9447 control subjects) that met the inclusion criteria were included in our meta-analysis. Pooled analysis, subgroup analysis, sensitivity analysis and publication bias were performed. The T allele, TT genotype and TT + GG genotype were associated with schizophrenia as risk factors. Subgroup analysis shows that no heterogeneity existed in the European and Asian populations. Our meta-analysis found that the Rs1625579 polymorphism in the MIR137 gene was associated with the risk of schizophrenia. The current findings provide a reference for case-control studies of schizophrenia in the future., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: This study investigated the effects of haplotypes T-G and C-A derived from NG_012836.1:g.4160T>C and NG_012836.1:g.4326G>A on protein expression levels in vitro and identified the functional sequence in the regulatory region of the GABRB3 gene linked to possible associations with schizophrenia., Methods: Recombinant plasmids with haplotypes T-G and C-A and 10 recombinant vectors containing deletion fragments from the GABRB3 gene 5' regulatory region were transfected into HEK-293, SK-N-SH, and SH-SY5Y cells. The relative fluorescence intensity of the two haplotypes and different sequences was compared using a dual luciferase reporter assay system., Results: The relative fluorescence intensity of haplotype C-A was significantly lower than that of T-G. We shortened the core promoter sequence of the GABRB3 gene 5' regulation region from -177 bp to -18 bp (ATG+1). We also found an expression suppression region from -1,735 bp to -1,638 bp and an enhanced regulatory region from -1,638 bp to -1,335 bp. Multiple inhibitory functional elements were identified in the region from -680 bp to -177 bp., Conclusion: We demonstrated that haplotype C-A might increase the risk of schizophrenia and found multiple regulatory regions that had an effect on GABRB3 receptor expression., (© 2019 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc.)

Background: Epidemiological studies found that genetic factors are among the causes of schizophrenia, exclusively the genes involved in the dopamine system. Prior to this, the role of dopamine receptor D2 (DRD2) gene promoter polymorphisms and schizophrenia has been studied extensively, but there are still some uncertainties about these associations. The present study is focusing on the association between the DRD2 gene promoter region polymorphisms and schizophrenia in the northern Chinese Han population., Methods: We sequenced 2,111-bp fragment of DRD2 gene promoter region in 306 schizophrenic patients and 324 healthy controls to find association between DRD2 and schizophrenia. SPSS version 18 0.0 was used to calculate odds ratios (OR), 95% confidence intervals (CIs).The Hardy-Weinberg equilibrium test and the confirmation of haplotypes were calculated using Haploview version 4.1. The association of schizophrenic risk of DRD2 genotypes, alleles, and haplotypes between case and control groups was calculated using the chi-squared test. PS program was used to calculate the Power analysis., Results: The genotype frequencies of rs7116768 (p = 0.025) and rs1799732 (p = 0.042) were associated meagerly. After Bonferroni correction, there was no association found between DRD2 gene promoter region with schizophrenia risk in the northern Chinese Han population., Conclusions: In this study, we did not find any significant difference between schizophrenia and the polymorphisms of DRD2 gene promoter region. A more forceful conclusion remains to be verified by further confirmatory experiments., (© 2019 The Authors. Brain and Behavior published by Wiley Periodicals, Inc.)

Background: Schizophrenia is a severe neurodevelopmental disorder with a complex genetic and environmental etiology. Abnormal glutamate ionotropic N-methyl-D-aspartate receptor (NMDA) type subunit 1 (NR1) may be a potential cause of schizophrenia., Methods: We conducted a case-control study to investigate the association between the GRIN1 gene, which encodes the NR1 subunit, and the risk of schizophrenia in a northern Chinese Han population using Sanger DNA sequencing. The dual luciferase reporter assay was used to detect the influence of two different haplotypes on GRIN1 gene expression., Results: Seven SNPs (single nucleotide polymorphisms), including rs112421622 (- 2019 T/C), rs138961287 (- 1962--1961insT), rs117783907 (-1945G/T), rs181682830 (-1934G/A), rs7032504 (-1742C/T), rs144123109 (-1140G/A), and rs11146020 (-855G/C) were detected in the study population. Rs117783907 (-1945G/T) was associated with the occurrence of schizophrenia as a protective factor. The genotype frequencies of rs138961287 (- 1962--1961insT) and rs11146020 (-855G/C) were statistically different between cases and controls (p < 0.0083). The other four variations were not shown to be associated with the disease. Two haplotypes were composed of the seven SNPs, and distribution of T-del-G-G-C-G-G was significantly different between the case and control groups. However, the dual luciferase reporter assay showed that neither of the haplotypes affected luciferase expression in HEK-293 and SK-N-SH cell lines., Conclusions: The GRIN1 gene may be related to the occurrence of schizophrenia. Additional research will be needed to fully ascertain the role of GRIN1 in the etiology of schizophrenia.

Background: Schizophrenia is associated with multiple neurotransmitter disorders, including serotonin (5-hydroxytryptamine, 5-HT). The neuromodulatory action of serotonin on brain function largely depends on the action of specific subtypes of serotonin receptors. The serotonin receptor 1B (HTR1B) gene has been proposed to play putative roles in the development of multiple emotional and psychiatric disorders., Methods: To study the relationship of HTR1B polymorphisms and schizophrenia, gene information was drawn from a cohort of 310 schizophrenic patients (152 men and 158 women) and 313 healthy controls (153 men and 160 women) of northern Han Chinese descent. The χ2 test was used to compare allele and genotype distributions between case and control groups. The haplotype and linkage equilibrium were also assessed in two group comparisons., Results: We detected 14 SNPs. Male patients were observed to have higher frequencies of the A-allele and AA+AG genotype at rs1778258 than female patients (p = 0.012 and p = 0.015, respectively). Both the A-allele and AA+AG genotype were associated with schizophrenia risk (OR = 1.986 and OR = 2.061, respectively), although the statistical significance of the genotype was lost after Bonferroni correction. Linkage analysis showed that rs17273700, rs11568817, rs9361234 and rs58138557 polymorphisms exhibit strong linkage disequilibrium (LD). In addition, schizophrenic patients show stronger linkage between 11,568,817 and rs130058 than healthy controls., Conclusions: HTR1B polymorphisms are associated with schizophrenia in the northern Han Chinese population, which provides an etiological reference for schizophrenia.

The aim of this study was to explore whether schizophrenia occurrence is associated with polymorphisms in the 5' regulatory region of GABRB3 (gamma-aminobutyric acid type A receptor beta 3, subunit gene). The study included 324 patients with schizophrenia and 327 unaffected participants; all individuals were northern Han Chinese. Genotype and haplotype frequency distributions were compared for the 2 groups by means of PCR amplification and direct sequencing of the promoter region of GABRB3. The genotype distribution among control participants was in accordance with the Hardy-Weinberg equilibrium. Five common single-nucleotide polymorphism (SNP) sites were detected in the 5' promoter region of GABRB3: rs4243768, rs7171660, rs4363842, rs4906902, and rs8179184. Only rs8179184 and rs4906902 differed significantly in frequency between controls and cases (P < 0.05); this difference remained significant when only women in each group were compared. The 2 SNP sites showed linkage disequilibrium, resulting in 2 haplotypes: T-G and C-A. The frequency of C-A was significantly higher among patients with schizophrenia than among controls. Our findings suggest that rs4906902 and rs8179184 in the 5' promoter region of GABRB3 are associated with schizophrenia. The C-A haplotype may entail an increased risk of schizophrenia, and the onset of schizophrenia may be gender-specific.

The abnormal expression Dopamine D1 receptor (DRD1) gives rise to the dysfunction of dopaminergic neurotransmitter and may be associated with the occurrence of schizophrenia. MicroRNAs (miRNAs) can regulate the DRD1 expression by binding 3'UTR and be involved in the post-transcriptional regulation. We first constructed the pmirGLO-recombined vectors of series of DRD1 gene 3′UTR-truncated fragments and performed the luciferase receptor assay to screen the underlying 3′UTR sequence targeted by miRNAs. Then, we predicted the potential miRNAs binding the target sequence and confirmed their effects using luciferase receptor assay after transfection of the miRNA mimics/inhibitors. We also examined the effects of the miRNA on the endogenous DRD1 expression. We found that the DRD1 3′UTR ranging from –12 to +1135 bp was essential for the post-transcriptional regulation of miRNAs. The deletion of –12 to +154 bp fragment significantly increased the luciferase expression but not the mRNA expression. The miRNA-15a, miRNA-15b and miRNA 16 affected DRD1 expression in HEK293, U87, SK-N-SH and SH-SY5Y cell lines. The miRNA-15a, miRNA-15b and miRNA-16 inhibit the human dopamine D1 receptor expression by targeting 3′UTR –12 to +154 bp. DRD1 3′UTR ranging from –12 to +1135 bp was essential for the post-transcriptional regulation of miRNAs. The deletion of –12 to +154 bp fragment significantly increased the luciferase expression but not the mRNA expression. The miRNA-15a, miRNA-15b and miRNA 16 affected DRD1 expression in different cell lines, respectively. [ABSTRACT FROM AUTHOR]

Background: Epidemiological studies have shown that genetic factors are among the causes of schizophrenia. Galanin receptor 1 is an inhibitory receptor of galanin that is widely distributed in the central nervous system. This study mainly explored the relationship between polymorphisms of the 5′ region of the GALR1 gene and schizophrenia in the northern Chinese Han population. Methods: A 1545 bp fragment of the 5′ regulatory region of the GALR1 gene was amplified and sequenced in 289 schizophrenia patients and 347 healthy controls. Results: Among the haplotypes composed of the 16 detected SNPs, the haplotype H3 was identified as conferring a risk of schizophrenia (p=0.011, OR=1.430, 95% CI=1.084– 1.886). In addition, the haplotypes H4 and H7 were both protective against schizophrenia (p=0.024, OR=0.526, 95% CI=0.298– 0.927; p=0.037, OR=0.197, 95% CI=0.044– 0.885, respectively). In the subgroup analysis by sex, it was found that seven SNP alleles (rs72978691, rs11662010, rs11151014, rs11151015, rs13306374, rs5373, rs13306375) conferred a risk of schizophrenia in females (p< 0.05), while allele G of rs7242919 (p=0.007) was protective against schizophrenia in females. Moreover, the rs72978691 AA+AC genotype (p=0.006, OR=1.874, 95% CI=1.196– 2.937, power=0.780), rs7242919 CC+CG genotype (p=0.002, OR=2.027, 95% CI=1.292– 3.180, power=0.861), rs11151014 GG+GT genotype (p=0.008, OR=1.834, 95% CI=1.168– 2.879, power=0.735), rs11151015 GG+AG genotype (p=0.002, OR=2.013, 95% CI =1.291– 3.137, power=0.843), rs13306374 CC+AC genotype (p=0.006, OR=1.881, 95% CI=1.198– 2.953, power=0.788), and rs13306375 GG+AG genotype (p=0.006, OR=1.868, 95% CI=1.194– 2.921, power=0.770) increased the risk of schizophrenia in females. The haplotype FH2 consisting of rs72978691, rs11662010, rs7242919, rs11151014, rs11151015, rs13306374, rs5373, and rs13306375 may also be associated with the risk of schizophrenia in females (p=0.024). Conclusion: This study identified an association between polymorphisms in the 5′ region of the GALR1 gene and schizophrenia, especially in females. [ABSTRACT FROM AUTHOR]

Abnormal expression of the 5-HT1A receptor, which is encoded by the HTR1A gene, leads to susceptibilities to neuropsychiatric disorders such as depression, anxiety, and schizophrenia. miRNAs regulate gene expression by recognizing the 3′-UTR region of mRNA. This study evaluated the miRNAs that might identify and subsequently determine the regulatory mechanism of HTR1A gene. Using the HEK-293, U87, SK-N-SH and SH-SY5Y cell lines, we determined the functional sequence of the 3′-UTR region of the HTR1A gene and predicted miRNA binding. Dual luciferase reporter assay and Western Blot were used to confirm the effect of miRNA mimics and inhibitors on endogenous 5-HT1A receptors. In all cell lines, gene expression of the −17 bp to +443 bp fragment containing the complete sequence of the 3′-UTR region was significantly decreased, although mRNA quantification was not different. The +375 bp to +443 bp sequence, which exhibited the most significant change in relative chemiluminescence intensity, was recognized by hsa-miR-3177-5p and hsa-miR-3178. In HEK-293 and U87 cells, hsa-miR-3177-5p significantly inhibited the 5-HT1A receptor expression, while a hsa-miR-3178 inhibitor up-regulated HTR1A gene expression in SK-N-SH and SH-SY5Y cells. By constructing the pmirGLO-vector with the mutated HTR1A gene, we further confirmed that hsa-miR-3177-5p recognized the HTR1A gene tgtacaca at +377 bp to +384 bp, and the +392 bp to +399 bp fragment cgcgccca was identified by hsa-miR-3178. hsa-miR-3177-5p and hsa-miR-3178 had significant inhibitory effects on expression of the HTR1A gene and 5-HT1A receptor and may directly participate in the development of neuropsychiatric diseases. [ABSTRACT FROM AUTHOR]