Hypomethylation of the serotonin receptor type‐2A Gene (HTR2A) at T102C polymorphic site in DNA derived from the saliva of patients with schizophrenia and bipolar disorder

Several lines of evidence indicate that dysfunction of serotonin signaling and HTR2A receptor are involved in the pathogenesis of schizophrenia (SCZ) and bipolar disorder (BD). DNA methylation of HTR2A at T102C polymorphic site influences HTR2A expression and aberrant DNA methylation of HTR2A promoter was reported in postmortem brain of patients with SCZ and BD. Hypothesizing that the brain's epigenetic alteration of HTR2A may also exist in peripheral tissues that can be used as a diagnostic/therapeutic biomarker, we analyzed HTR2A promoter DNA methylation in DNA extracted from the saliva of patients with SCZ and BD, and their first degree relatives versus normal controls. Bisulfite sequencing was used to screen DNA methylation status of the HTR2A promoter CpGs and qMSP was used to quantify the degree of cytosine methylation at differentially methylated sites. Most of the cytosines of the HTR2A promoter were unmethylated. However, CpGs of the ?1438A/G polymorphism site, ?1420 and ?1223 were >95% methylated. The CpG at T102C polymorphic site and neighboring CpGs were ～70% methylated both in the patients and controls. qMSP analysis revealed that the cytosine of the T102C polymorphic site was significantly hypo‐methylated in SCZ, BD, and their first degree relatives compared to the controls. Cytosine methylation of HTR2A at T102C polymorphic site in DNA derived from the saliva can potentially be used as a diagnostic, prognostic, and/or therapeutic biomarker in SCZ and BD. However, these preliminary observations need to be replicated in other populations with a larger sample size to be considered for clinical applications. © 2011 Wiley‐Liss, Inc.     

Association analysis of Neuregulin 1 candidate regions in schizophrenia and bipolar disorder

Schizophrenia (SCZ) and bipolar disorder (BPD) are severe heritable psychiatric disorders involving a complex genetic aetiology. Neuregulin 1 (NRG1) is a leading candidate gene for SCZ, and has recently been implicated in BPD. We previously reported association of two NRG1 haplotypes with SCZ and BPD in a Scottish case–control sample. One haplotype is located at the 5′ end of the gene (region A), and the other is located at the 3′ end (region B). Here, association to haplotypes within regions A and B was assessed in patients with SCZ and BPD in a second Scottish case–control sample and in the two Scottish samples combined. Association to region B was also assessed in patients with SCZ and BPD in a German case–control sample, and in all three samples combined. No evidence was found for association in the new samples when analysed individually; however, in the joint analysis of the two Scottish samples, a region B haplotype comprising two SNPs (rs6988339 and rs3757930) was associated with SCZ and the combined case group (SCZ: p = 0.0037, OR = 1.3, 95% CI: 1.1–1.6; BPD + SCZ: p = 0.0080, OR = 1.2, 95% CI: 1.1–1.5), with these associations withstanding multiple testing correction at the single-test level (SCZ: p_st = 0.022; BPD + SCZ: p_st = 0.044). This study supports the involvement of NRG1 variants in the less well studied 3′ region in conferring susceptibility to SCZ and BPD in the Scottish population.     

多巴胺D2受体基因与精神分裂症和双相情感障碍关联研究的荟萃分析

遗传因素是精神分裂症(schizophrenia,SCZ)和双相情感障碍(bipolar disorder,BP)的重要致病因素,已有大量基因关联研究表明多巴胺D2受体基因与两种精神疾病可能存在风险关系,然而许多研究的结果并不一致.系统的荟萃分析可以弥补单个研究样本量小可能引起的结果偏差.经过严格筛选,本文纳入8个关于BP和49个关于SCZ的独立研究,荟萃分析多巴胺D2受体3个基因多态性(141C Del/Ins、TaqI-A、SCr311Cys)与这两种精神疾病的风险关系.结果 提示Ser311Cys的G/C多态性和SCZ发病显著关联,而TaqI-A的T/C多态性和BP发病存在显著关联(P<0.05).基因型分析结果揭示了多巴胺D2受体基因Ser311Cys携带G等位基因的基因型是SCZ的风险因素,TaqI-A的TT基因型可能是BP的风险因子而对于SCZ是保护因子.     

Levels of neuregulin 1 and 3 proteins in Brodmann's area 46 from subjects with schizophrenia and bipolar disorder

Neuregulin (NRG) 1Iα and NRG3 proteins levels were measured in Brodmann's area 46 from 20 subjects with schizophrenia, 8 subjects with bipolar 1 disorder and 20 age-sex matched control subjects. Protein levels of both NRG1Iα and NRG3 were unchanged in both psychiatric illnesses. These data suggest any change in NRG1Iα and NRG3 expression in schizophrenia or bipolar 1 disorder do not result in changes levels in levels of those proteins Brodmann's area 46.     

A prospective,longitudinal study of metabolic syndrome in patients with bipolar disorder and schizophrenia

Background

Although cross sectional studies have evaluated the prevalence of metabolic syndrome (MetS) in patients with bipolar patients (BPAD), data from longitudinal studies are limited.

Aim

To assess the prevalence of MetS in patients with BPAD, to observe the change in prevalence rate over a period of 6 months, to assess the prevalence of sub-threshold MetS (i.e., patients fulfilling one or two criteria of MetS) and to compare patients with BPAD and schizophrenia on the above mentioned parameters.

Methodology

Seventy five patients with BPAD and 53 patients with schizophrenia were initially evaluated for MetS and then followed up for a period of 6 months.

Results

According to consensus definition, prevalence of MetS at baseline was 40% in BPAD group and 32% in schizophrenia group. Over 6 months of follow-up the prevalence of MetS increased by 8% and 9.4% in the BPAD and the schizophrenia groups respectively. There was no significant difference between the two groups on any of the assessments. Another 28–32% of patients in the BPAD group also fulfilled two criteria and 13–17% fulfilled at least one criterion of MetS at different points of assessment. Similarly, 19–26% of the patients with schizophrenia met at least two and 23–26% of the patients fulfilled at least one criterion of MetS.

Limitation

The study was limited by small sample size, inclusion and the relatively short follow-up period.

Conclusion

40% patients with BPAD and 32% with schizophrenia have MetS and the prevalence of MetS increases by 8–9.4% over 6 months.     

Quantitative analysis of the 4977-bp common deletion of mitochondrial DNA in postmortem frontal cortex from patients with bipolar disorder and schizophrenia

Several reports have suggested a role for mitochondrial dysfunction in the pathophysiology of bipolar disorder and schizophrenia. We have focused on the relationship between deleted mitochondrial DNA (mtDNA) and bipolar disorder. To investigate this relationship, we developed a methodology for quantification of the common 4977-bp deletion of mtDNA based on real-time polymerase chain reaction with SYBR Green. In this study, we assessed accumulation of the common deletion in postmortem frontal cortex from 147 individuals (48 controls, 49 patients with bipolar disorder, 50 patients with schizophrenia). We demonstrated age-dependent accumulation of the common deletion of mtDNA (p = 1.09E−10). Females showed significantly higher accumulation of the deletion than did males (p = 0.002). There was no significant association between accumulation and the two studied major mental disorders in the frontal cortex (p > 0.2). However, there was no statistically significant correlation between the common deletion and aging in female patients with bipolar disorder (p = 0.133), and no significant sex difference in patients with bipolar disorder (p = 0.509). These results indicate that aging and sex have effect on accumulation of the common deletion of mtDNA in the prefrontal cortex depending on the diagnosis.     

SYNGR1 is associated with schizophrenia and bipolar disorder in southern India

Chromosome 22q11–13 is one of the most consistent linkage regions for schizophrenia (SCZ) and bipolar disorder (BPAD). The SYNGR1 gene, which is associated with presynaptic vesicles in neuronal cells, is located on 22q13.1. We have previously identified a novel nonsense mutation in the SYNGR1 gene in a SCZ pedigree. In the present study, a detailed analysis of this gene was performed in a case–control cohort (198 BPAD, 193 SCZ and 107 controls from southern India) to test for association with SCZ and BPAD. Sequence analysis of all exonic and flanking intronic regions of the SYNGR1 gene in 198 BPAD and 193 SCZ cases revealed a novel mutation Lsy99Glu (in one BPAD patient) and two other novel common polymorphisms [synonymous single nucleotide polymorphism (SNP—Ser97Ser) and an Asn ins/del] in the SYNGR1 gene. We also validated 9 out of 14 dbSNPs in our population. Case–control analysis revealed allelic (P=0.028–0.00007) association of five polymorphisms with SCZ and/or BPAD cases. Further, 3-SNP (with LD block 1 SNPs) and 2-SNP (with LD block 2 SNPs) haplotype analyses did not show any association with either SCZ or BPAD. Our results support SYNGR1 as a probable susceptibility gene for SCZ and BPAD. Also, the observed association of SYNGR1 with both SCZ and BPAD suggests the likely involvement of a common pathway in the etiology of these disorders.Electronic Supplementary Material Supplementary material is available for this article at     

Positive association between a DNA sequence variant in the serotonin 2A receptor gene and schizophrenia

Sixty-two patients with schizophrenia and 96 normal controls were investigated for genetic association with restriction fragment length polymorphisms (RFLPs) in the serotonin receptor genes. A positive association between the serotonin 2A receptor gene (HTR2A) and schizophrenia was found, but not between schizophrenia and the serotonin 1A receptor gene. The positive association we report here would suggest that the DNA region with susceptibility to schizophrenia lies in the HTR2A on the long arm of chromosome 13. © 1996 Wiley-Liss, Inc.     

Serum levels of brain-derived neurotrophic factor in patients with schizophrenia and bipolar disorder

There is evidence that major psychiatric discords such as schizophrenia (SZ) and bipolar disorder (BD) are associated with dysregulation of synaptic plasticity with downstream alterations of neurotrophins. Brain-derived neurotrophic factor (BDNF) is the most widely distributed neurotrophin in the central nervous system (CNS), and performs many biological functions such as promoting the survival, differentiation, and plasticity of neurons. Variants in the BDNF gene increase the risk of SZ and bipolar disorder. Chronic administration of drugs used to treat SZ and BD, such as lithium, valproate, quetiapine, clozapine, and olanzapine, increases BDNF expression in rat brain. To examine serum BDNF, three groups of chronically medicated DSM-IV SZ patients, on treatment with clozapine (n = 27), typical (n = 14), and other atypical antipsychotics (n = 19), 30 euthymic BD patients, and 26 healthy control had 5 ml blood samples collected by venipuncture. Serum BDNF levels were significantly higher in SZ patients (p < 0.001) when compared to either controls or euthymic BD patients. Increased BDNF in SZ patients might be related to the course of illness or to treatment variables. Prospective studies are warranted.     

启动子DNA甲基化调节胃癌中PDX1基因表达

目的明确PDXl启动子DNA甲基化,探讨启动子甲基化对PDXl在胃癌中表达的调节作用。方法收集3例胃癌活检组织,免疫组化检测PDXl蛋白表达：吉西他滨处理3株胃癌细胞,RT—PCR检测不同药物剂量和作用时间下PDXlmRNA表达;构建PDXl报告基因,检测启动子活性及吉西他滨处理前后启动子活性的变化;甲基化特异性PCR（MSP）检测3株胃癌细胞和8对配对胃癌组织中PDXl启动子甲基化状态。结果免疫组化结果显示胃癌中PDXl表达低于正常胃黏膜;RT—PCR显示吉西他滨使PDXlmRNA重获表达,且随剂量和时间依赖性。F383有最强启动子活性,吉西他滨显著增加了PDXl启动子活性（P〈0．05）。F383在AGS、BCG823、SGC7901中呈DNA完全甲基化状态;87．5％的胃癌组织出现F383部分甲基化,12．5％出现完全甲基化。癌旁正常组织仅有37．5％出现F383部分甲基化,未出现完全甲基化,两者比较有显著性差异（P〈0．05）。结论PDXl启动子存在DNA高甲基化,抑制了胃癌中PDXl的表达。     

Systematic screening for mutations in the human serotonin 1F receptor gene in patients with bipolar affective disorder and schizophrenia

Using single strand conformational analysis we screened the complete coding sequence of the serotonin 1F (5-HT_1F) receptor gene for the presence of DNA sequence variation in a sample of 137 unrelated individuals including 45 schizophrenic patients, 46 bipolar patients, as well as 46 healthy controls. We detected only three rare sequence variants which are characterized by single base pair substitutions, namely a silent T→A transversion in the third position of codon 261 (encoding isoleucine), a silent C→T transition in the third position of codon 176 (encoding histidine), and a C→T transition in position −78 upstream from the start codon. The lack of significant mutations in patients suffering from schizophrenia and bipolar affective disorder indicates that the 5-HT_1F receptor is not commonly involved in the etiology of these diseases. © 1996 Wiley-Liss, Inc.     

No association of the MCP-1 promoter A-2518G polymorphism with bipolar disorder in the Korean population

It has been suggested that bipolar disorder is associated with altered immune function. Monocyte chemoattractant protien-1 (MCP-1) is a chemokine that influences both neural and immune functions. We thus hypothesized that MCP-1 may be related to the development or pathophysiology of bipolar disorder. In this case–control study, we investigated the association between the A-2518G single nucleotide polymorphism (SNP) of the MCP-1 promoter and bipolar disorder. Patients with bipolar disorder (n = 183; bipolar I = 145, bipolar II = 38) and healthy controls (350) were recruited for the study. No significant allelic or genotypic association was detected between the A-2518G polymorphism and any sample of bipolar disorder patients. When we pooled the healthy controls and the cases of bipolar I disorder from previous Korean studies and this study, we again found no significant association. No significant difference in either allele frequency or genotype distribution was observed between bipolar I and bipolar II disorders. There was no difference in the age at onset of bipolar disorder among the three genotype groups. Our data suggest that the A-2518G polymorphism of MCP-1 is not a major susceptibility factor for bipolar disorder in the Korean population. However, the physiological role of MCP-1 is highly suggestive of its being associated with bipolar disorder, and further analyses of other SNPs of MCP-1 remain to be performed.     

PTSD样行为异常大鼠中缝背核5-HT1A受体的改变

目的观察创伤后应激障碍(PTSD)样行为异常大鼠中缝背核(DRN)神经元5-HT1A受体表达变化,为探讨PTSD的发病机制提供资料。方法成年健康雄性Wistar大鼠60只,随机分为连续单一刺激(SPS)模型1d、4d、7d组及正常对照组,采用免疫组化、Western blot方法检测PTSD样行为异常大鼠中缝背核神经元5-HT1A受体表达变化。结果 SPS刺激后1d大鼠中缝背核神经元5-HT1A受体表达水平开始逐渐升高,第4天高于第1天,第7天高于第4天。结论 PTSD样大鼠中缝背核神经元5-HT1A受体呈规律性过表达。     

Association of 677C>T polymorphism of methylenetetrahydrofolate reductase (MTHFR) gene with bipolar disorder and schizophrenia

Methylenetetrahydrofolate reductase (MTHFR) gene polymorphism 677C>T has been shown to be a risk factor for psychiatric disorders. We investigated the genotype and allelic frequencies of MTHFR 677C>T polymorphism in the group of patients with bipolar disorder type I (BDI) (n = 200) and schizophrenia (n = 200), and in the control group (n = 300). Odds ratio (OR) for patients with BD and schizophrenia with 677T allele was 1.988 ((95% CI = 1.370–2.883); P = 0.0003 (P = 0.0006 after Bonferroni correction)) and 1.796 ((95% CI = 1.237–2.609); P = 0.0020 (P = 0.0040 after Bonferroni correction)), respectively. The stratification of patients based on gender revealed significant association of 677T allele with male patients with BDI and schizophrenia (OR = 2.393; 95% CI = 1.429–4.006; P = 0.0008 and OR = 2.036; 95% CI = 1.207–3.433; P = 0.0073, respectively). This finding indicates possible association of BD and schizophrenia with the 1p36.3 MTHFR locus.     

UHRF1基因在甲基化调控与血管新生中的作用

近年来大量研究证实泛素样含植物同源结构域和环指结构域1(ubiquitin-like with PHD and RING finger domains 1,UHRFl)是一种与肿瘤发生相关的核蛋白基因,在表观遗传修饰过程中具有重要的调控作用,尤其是在DNA甲基化与组蛋白甲基化的调控方面。UHRF1由于其特有的结构域,在细胞生物学功能调控中起到非常重要的作用,如细胞增殖、周期和凋亡等。另外,在多种肿瘤组织和细胞中异常高表达的UHRF1可能与肿瘤血管新生密切相关。本文主要综述UHRF1对DNA甲基化及组蛋白甲基化的调控作用,并探讨了UHRF1在血管新生过程中可能发挥的表观遗传学调控作用。     

Risk of developing diabetes mellitus and hyperlipidemia among patients with bipolar disorder,major depressive disorder,and schizophrenia: A 10-year nationwide population-based prospective cohort study

Background

The high comorbidity of metabolic side effects with severe mental disorders (SMDs), including bipolar disorder (BD), major depressive disorder (MDD), and schizophrenia, had gained much attention, because the excess mortality of these patients is mainly due to physical illness. However, most of these studies were with cross-sectional study design, the time course of metabolic side effects and SMD cannot be elucidated without a cohort study.

Method

Using a nationwide database with a large sample size and a matched control cohort study design, we enrolled patients with SMDs but without diagnoses of and medications for DM and hyperlipidemia from 1996 to 2000, and followed them to the end of 2010. We compared them with age and gender-matched controls (1:4) for the incidence of DM and hyperlipidemia.

Results

The identified cases were 367 patients with BD, 417 patients with MDD, and 1993 patients with schizophrenia, with average age of 45.3±14.0, 46.5±13.7, and 45.9±12.3, respectively. The patients with BD and schizophrenia had increased risk of initiation of anti-diabetic medications (10.1% vs. 6.3%, p=0.012; 13.3% vs. 7.2% p<0.001; respectively), and anti-hyperlipidemia medications (15.8% vs.10.5%, p=0.004; 14.2% vs.12.1%, p=0.005; respectively) than the controls. After controlling age, gender, urbanization, and income, the Cox regression model showed significantly increased risk of initiation of anti-diabetic medications among patients with BD (hazard ratio (HR) of 1.702, 95% confidence interval (CI): 1.155–2.507) and schizophrenia (HR of1.793, 95% CI: 1.532–2.098). Increased risk of initiation of anti-hyperlipidemia medications was also noted among patients with BD (HR of 1.506, 95% CI: 1.107–2.047) and schizophrenia (HR of 1.154, 95% CI: 1.002–1.329). The patients with MDD did not show increased risk of initiation of these medications than the controls.

Conclusions

This first 10-year nationwide population-based prospective matched control cohort study showed increased risks of initiation of anti-diabetic and anti-hyperlipidemia medications among patients with BD and schizophrenia. No significant increased risk was noted among the patients with MDD.