Meta-analysis of polymorphism rs6311 and rs6313 in the 5-HT2AR gene and schizophrenia

Background: rs6311 and rs6313 polymorphism of 5-hydroxytryptamine 2A receptor has been widely studied regarding association with susceptibility to schizophrenia, but the results remained inconsistent.

Aims: This study aimed to assess the association between rs6311 and rs6313 polymorphism and schizophrenia using a meta-analysis.

Methods: Pubmed, Web of Science, and Embase databases were searched for all articles linking rs6311 and rs6313 polymorphism and schizophrenia. All studies which met the inclusion and exclusion criteria were included in this meta-analysis. Pooled odds ratio and 95% confidence intervals were used to evaluate the association between rs6311 and rs6313 polymorphism and schizophrenia risk. Sub-group analysis was also performed by different ethnic studies (Asian and Caucasian) and different minor allelic studies (rs6311: minor allele?=?A and minor allele?=?G; rs6313: minor allele?=?T and minor allele?=?C).

Results: Forty articles, including 50 case-control studies, were included in this meta-analysis. Specifically, 12 studies with 4100 cases and 4541 controls involved rs6311, 38 studies with 8960 cases and 9729 controls involved rs6313. The results showed that rs6311 and rs6313 were not associated with schizophrenia. Moreover, no associations were found between rs6311 and schizophrenia in different sub-groups, rs6313 was found to associated with schizophrenia among studies in which C is the minor allele.

Conclusions: This meta-analysis indicates that rs6311 and rs6313 polymorphisms of 5-HT_2AR are not associated with schizophrenia. However, the rs6313 polymorphism is associated with schizophrenia in studies in which the minor allele is C.     

Association of EPHB1 rs11918092 and EFNB2 rs9520087 with psychopathological symptoms of schizophrenia in Chinese Zhuang and Han populations

Two single‐nucleotide polymorphisms (SNPs) (rs11918092 and rs9520087) were genotyped in Chinese Zhuang and Han populations. Symptoms of schizophrenic patients were assessed by the Positive and Negative Syndrome Scale. No association of any SNP with schizophrenic susceptibility was found. However, associations of rs9520087 with the total scale score (P = 0.014), positive scale score (P = 0.013), negative scale score (P = 0.032), and general psychopathology scale score (P = 0.031) were found in Zhuang patients. Additionally, rs11918092 was associated with positive scale score (P = 0.035) in Han patients. The two SNPs might influence symptoms of schizophrenia.     

IFNGR2 genetic polymorphism associated with sex-specific paranoid schizophrenia risk

Background: Considering current scientific evidence about the significant role of chronic low grade inflammation in the physiopathology of schizophrenia, it has been hypothesized that changes in pro-inflammatory cytokines such as interferon gamma may have a significant role in the predisposition to schizophrenia.

Aim: This study focuses on identifying whether the functional polymorphism of interferon gamma receptor 2 (IFNGR2) is a risk factor for the development of schizophrenia.

Methods: This study was conducted by the RFLP-PCR on a Tunisian population composed of 225 patients with different sub-types of schizophrenia and 166 controls.

Results: The IFNGR2 (Q64R) polymorphism analysis showed higher frequencies of minor homozygous genotype (RR) and allele (R) in all patients compared to controls (21.8% vs 10.2%; p?=?.006, OR?=?2.54) and (44% vs 34.9%; p?=?.01; OR?=?1.46), respectively. This correlation was confirmed only for males. This study also noted a significant increase of the mutated homozygous (RR) genotype and (R) allele frequencies of IFNGR2 in paranoid schizophrenics compared to controls (31.4% vs 10.2%; p?=?.001; OR?=?3.34 and 47.2% vs 34.9%; p?=?.009; OR?=?1.66, respectively). This increase remains significant after using binary logistic regression to eliminate confounding factors such as age and sex. Additionally, carriers of RR genotype have significant lower scores on the Scale of Assessment of Positive (SAPS) and negative (SANS) symptoms comparatively to the carrier of the QQ?+?QR genotypes, suggesting that the R recessive allele carriers could have milder symptoms.

Conclusion: The IFNGR2Q64R polymorphism is correlated with male sex and paranoid schizophrenia. It is suggested that a chronic neuroinflammation may predispose to the paranoid schizophrenia development in men.     

C957T DRD2 polymorphism is associated with schizophrenia in Spanish patients

OBJECTIVE: The objective was to confirm whether a homozygous genotype for the C957 allele of the C957T DRD2 gene single nucleotide polymorphism (SNP) is associated with schizophrenia in an independent study population. METHOD: We examined the genotypic distribution of this SNP in a set of clinically ascertained schizophrenic patients (n = 131) and age-matched control subjects (n = 364). Individuals were genotyped using automated analysis of fluorescently labeled PCR products. RESULTS: The distribution of grouped genotypes for the C957T DRD2 SNP (CC vs. CT, TT) showed that C homozygote genotype was over-represented in our patient sample when compared with control subjects. This difference reaches the statistical significance (chi(2) = 7.0; df = 1; P = 0.008; OR = 2.05; % CI 1.2-3.4). CONCLUSION: The findings of this study provide additional evidence that genetic variation at the DRD2 gene plays an important role in the vulnerability to schizophrenia.     

The coding‐synonymous polymorphism rs1045280 (Ser280Ser) in β‐arrestin 2 (ARRB2) gene is associated with tardive dyskinesia in Chinese patients with schizophrenia

Background: Tardive dyskinesia (TD) is a severe and potentially irreversible adverse effect of long‐term antipsychotic treatment. Typical antipsychotics are commonly binding to the dopamine receptor D2 (DRD2), but the occurrence of antipsychotic‐induced TD is rather delayed; therefore, the development of TD may be associated with mediators or signalling complexes behind DRD2, such as β‐arrestin 2 (ARRB2), an important mediator between DRD2 and serine–threonine protein kinase (AKT) signal cascade. Methods: A case–control study to evaluate the association between rs1045280 (Ser280Ser) and antipsychotic‐induced TD was performed amongst 381 patients (TD/non‐TD = 228/153). Results: There was a significant difference in the genotype distribution between TD and non‐TD groups (P = 0.025); furthermore, the allelic analysis indicated that patients with T allele had increased risk of TD occurrence (OR_T = 1.58, 95% CI = 1.14–2.19, P = 0.007). Conclusions: To the best of our knowledge, this is the first study reporting a positive association between the SNP rs1045280 and TD in schizophrenic patients.     

奥氮平治疗精神分裂症对照研究的Meta分析

目的：探讨奥氮平治疗精神分裂症的疗效和不良反应。方法：应用M eta分析对17篇奥氮平与其他抗精神病药治疗精神分裂症对照研究的文章进行再分析。结果：奥氮平自身对照比较的治疗效应极大（χ^2=141.00,P〈0.05）。治疗2周和治疗结束,奥氮平与对照药疗效比较差异无显著性（P〉0.05）;阳性与阴性症状量表（PANSS）评分比较差异亦无显著性（P〉0.05）。与对照药相比,奥氮平的不良反应显著少于对照药组（P〈0.05或P〈0.01）。结论：奥氮平与对照药的临床疗效相仿,但不良反应明显较少。     

中国新疆维吾尔族人群中ANK3基因rs10761482多态性与精神分裂症关联性的病例对照研究(英文)

背景:ANK3基因rs10761482多态性已被发现与精神分裂症的发生相关联。目的:评估新疆维吾尔族人群ANK3基因和精神分裂症之间的关联。方法:使用Taqman探针技术对630例新疆维吾尔族精神分裂症患者和535名新疆维吾尔族健康人群进行ANK3基因rs10761482位点的基因分型。采用SHEsis和SPSS17.0软件进行数据分析。结果:病例组和对照组之间的基因型和等位基因频率无显著差异。在病例组,性别或精神分裂症发病年龄与基因型或等位基因频率之间没有显著关联。将男性和女性单独分析,病例组与对照组之间的等位基因和基因型频率均未发现显著差异,青春期发病与成年后发病的精神分裂症患者之间的等位基因和基因型频率也无显著差异。结论:我们的研究结果不支持以往ANK3基因与精神分裂症有关联的报告。本研究招募的维吾尔族人群中,ANK3基因rs10761482多态性与精神分裂症之间没有显著关联。如果这些结果在进一步的研究中得到证实,那么研究重点将转而了解为什么在这个特定的族群中不存在上述已经被广泛认可的关联。     

Paliperidone for treatment of schizophrenia

In short-term studies, oral paliperidone is an antipsychotic that is more efficacious than placebo. We found its adverse effects to be similar to those of its parent compound, risperidone, with movement disorders, weight gain, and tachycardia all more common with paliperidone than placebo. In addition, paliperidone is associated with substantial increases in serum prolactin that may be associated with sexual dysfunction, although sexual functioning outcomes were not reported. At doses greater than 3 mg per day, oral paliperidone appears comparable in efficacy to oral olanzapine 10 mg per day. Regarding the critical comparison of oral paliperidone to risperidone, we have no information and are thus unable to determine if paliperidone has any advantages or disadvantages compared to its well-known parent compound.     

Evaluation of shared genetic susceptibility loci between autoimmune diseases and schizophrenia based on genome-wide association studies

Background: Epidemiological studies have documented higher than expected comorbidity (or, in some cases, inverse comorbidity) between schizophrenia and several autoimmune disorders. It remains unknown whether this comorbidity reflects shared genetic susceptibility loci.

Aims: The present study aimed to investigate whether verified genome wide significant variants of autoimmune disorders confer risk of schizophrenia, which could suggest a common genetic basis.

Methods: Seven hundred and fourteen genome wide significant risk variants of 25 autoimmune disorders were extracted from the NHGRI GWAS catalogue and examined for association to schizophrenia in the Psychiatric Genomics Consortium schizophrenia GWAS samples (36,989 cases and 113,075 controls).

Results: Two independent loci at 4q24 and 6p21.32–33 originally identified from GWAS of autoimmune diseases were found genome wide associated with schizophrenia (1.7?×?10^?8?≥^?p?≥?4.0?×?10^?21). While these observations confirm the existence of shared genetic susceptibility loci between schizophrenia and autoimmune diseases, the findings did not show a significant enrichment.

Conclusion: The findings do not support a genetic overlap in common SNPs between autoimmune diseases and schizophrenia that in part could explain the observed comorbidity from epidemiological studies.     

Association of rs1006737 in CACNA1C with alterations in prefrontal activation and fronto‐hippocampal connectivity

Background: Genome‐wide association studies have identified the rs1006737 single nucleotide polymorphism (SNP) in the CACNA1C gene as a susceptibility locus for schizophrenia and bipolar disorder. On the neural systems level this association is explained by altered functioning of the dorsolateral prefrontal cortex (DLPFC) and the hippocampal formation (HF), brain regions also affected by mental illness. In the present study we investigated the association of rs1006737 genotype with prefrontal activation and fronto‐hippocampal connectivity. Methods: We used functional magnetic resonance imaging to measure neural activation during an n‐back working memory task in 94 healthy subjects. All subjects were genotyped for the SNP rs1006737. We tested associations of the rs1006737 genotype with changes in working‐memory‐related DLPFC activation and functional integration using a seed region functional connectivity approach. Results: Rs1006737 genotype was associated with altered right‐hemispheric DLPFC activation. The homozygous A (risk) group showed decreased activation compared to G‐allele carriers. Further, the functional connectivity analysis revealed a positive association of fronto‐hippocampal connectivity with rs1006737 A alleles. Conclusions: We did not replicate the previous findings of increased right DLPFC activation in CACNA1C rs1006737 A homozygotes. In fact, we found the opposite effect, thus questioning prefrontal inefficiency as rs1006737 genotype‐related intermediate phenotype. On the other hand, our results indicate that alterations in the functional coupling between the prefrontal cortex and the medial temporal lobe could represent a neural system phenotype that is mediated by CACNA1C rs1006737 and other genetic susceptibility loci for schizophrenia and bipolar disorder. Hum Brain Mapp 35:1190–1200, 2014. © 2013 Wiley Periodicals, Inc.     

Causal associations of intelligence with schizophrenia and bipolar disorder: A Mendelian randomization analysis

BackgroundIntelligence is inversely associated with schizophrenia (SCZ) and bipolar disorder (BD); it remains unclear whether low intelligence is a cause or consequence. We investigated causal associations of intelligence with SCZ or BD risk and a shared risk between SCZ and BD and SCZ-specific risk.MethodsTo estimate putative causal associations, we performed multi-single nucleotide polymorphism (SNP) Mendelian randomization (MR) using generalized summary-data-based MR (GSMR). Summary-level datasets from five GWASs (intelligence, SCZ vs. control [CON], BD vs. CON, SCZ + BD vs. CON, and SCZ vs. BD; sample sizes of up to 269,867) were utilized.ResultsA strong bidirectional association between risks for SCZ and BD was observed (odds ratio; OR_SCZ → BD = 1.47, p = 2.89 × 10⁻⁴¹, OR_BD → SCZ = 1.44, p = 1.85 × 10⁻⁵²). Low intelligence was bidirectionally associated with a high risk for SCZ, with a stronger effect of intelligence on SCZ risk (OR_{lower intelligence → SCZ} = 1.62, p = 3.23 × 10⁻¹⁴) than the reverse (OR_{SCZ → lower intelligence} = 1.06, p = 3.70 × 10⁻²³). Furthermore, low intelligence affected a shared risk between SCZ and BD (OR _{lower intelligence → SCZ + BD} = 1.23, p = 3.41 × 10⁻⁵) and SCZ-specific risk (OR_{lower intelligence → SCZvsBD} = 1.64, p = 9.72 × 10⁻¹⁰); the shared risk (OR_{SCZ + BD → lower intelligence} = 1.04, p = 3.09 × 10⁻¹⁴) but not SCZ-specific risk (OR_{SCZvsBD → lower intelligence} = 1.00, p = 0.88) weakly affected low intelligence. Conversely, there was no significant causal association between intelligence and BD risk (p > 0.05).ConclusionsThese findings support observational studies showing that patients with SCZ display impairment in premorbid intelligence and intelligence decline. Moreover, a shared factor between SCZ and BD might contribute to impairment in premorbid intelligence and intelligence decline but SCZ-specific factors might be affected by impairment in premorbid intelligence. We suggest that patients with these genetic factors should be categorized as having a cognitive disorder SCZ or BD subtype.     

The human dihydropyrimidinase-related protein 2 gene on chromosome 8p21 is associated with paranoid-type schizophrenia.

BACKGROUND: The dihydropyrimidinase-related protein (DRP) family, also called the collapsin response mediator protein, is implicated in the developmental process of the nervous system. Dysfunction of DRPs may result in neurodevelopmental abnormalities, which may be a factor in the pathogenesis of schizophrenia. The expression of one member of DRP-2 in humans has been reported to be decreased in the brains of people with schizophrenia. In addition, the DRP-2 gene (Dihydropyrimidinase-like 2; DPYSL2) is located on chromosome 8p21, a region that has been implicated in schizophrenia in genetic linkage studies. METHODS: We investigated a genetic association between five polymorphisms of the DRP-2 gene and schizophrenia in the Japanese population. RESULTS: The *2236T>C polymorphism in the 3' untranslated region (3'UTR) exhibited significant differences with respect to the distribution of the genotype and allele in patients compared with control subjects. The frequency of the *2236C allele was significantly higher in control subjects than patients with schizophrenia (p =.0097) and paranoid-type schizophrenia (p =.0083). CONCLUSIONS: Our results suggest that the *2236C allele in the 3'UTR of the DRP-2 gene, or an unknown mutation in linkage disequilibrium with this allele, may reduce the susceptibility to schizophrenia, especially the paranoid subtype.     

Neurotrophin-3 gene polymorphism associated with schizophrenia

The recent possible neurodevelopmental etiology of schizophrenia makes the neurotrophin-3 (NT-3) gene an interesting candidate locus. We studied the allelic distributions of dinucleotide repeat polymorphism at the NT-3 gene locus in 70 patients with schizophrenia and in 70 controls. A highly significant difference between the two groups was observed at the allele A3. Even Bonferroni's correction was used, the difference was still significant. Individuals with homozygous or heterozygous for the allele A3 had a 2.4-fold increased risk of schizophrenia. Determination of NT-3 genotype may help to identify those at greater risk of schizophrenia. Furthermore, this finding supports evidence implicating neurodevelopmental deficit in the pathogenesis of this disorder.     

利培酮与舒必利治疗精神分裂症阴性症状Meta分析

目的：采用Meta分析方法比较利培酮与舒必利治疗精神分裂症阴性症状的临床疗效。方法：将利培酮与舒必利治疗精神分裂症阴性症状的16个中文的随机对照研究进行再分析。结果：16个研究的合并效应量（WMD）为-0．58（-1．37，0．21；P〉0．05）。阳性与阴性症状量表（PANSS）阴性因子（N）亚组的WMD为-0．84（-1．91，0．24；P〉0．05）；阴性症状评定量表（SANS）亚组的WMD为0．19，（-0．77，1．15；P〉0．05）。结论：利培酮与舒必利对精神分裂症阴性症状的疗效无显著差别。