河北省健康人群谷胱甘肽硫转移酶T1、M1基因多态性的研究

目的探讨河北省健康人群谷胱甘肽硫转移酶T1、M1基因多态性的分布情况。方法应用内对照聚合酶链式反应技术(PCR)和凝胶成像分析方法对210例河北石家庄地区健康个体GSTT1、GSTM1基因进行检测分析。结果河北健康人群GSTT1、GSTM1基因缺失型的检出频率分别为48.6%和59.0%。同时具有GSTT1基因缺失型和GSTM1基因缺失型个体的检出频率为31.9%。结论GSTT1、GSTM1基因多态性在不同年龄、性别、生活习惯人群中分布差异无显著性。GSTT1、GSTM1基因在人群中的分布相互独立,无明显关联。GSTT1、GSTM1基因多态性的分布在不同地区,不同人种之间存在一定的差异。     

Association of glutathione S-transferase T1 and M1 gene polymorphisms with ischemic stroke risk in the Chinese Han population

Atherosclerosis plays an important role in ischemic stroke, and oxidative stress participates in the entire process of atherosclerosis. Glutathione S-transferase (GST) acting with other antioxidant enzymes can eliminate reactive oxygen species and protect cells against oxidative damage. To assess the association of glutathione S-transferase (GSTT1 and GSTM1) gene polymorphisms with ischemic stroke in the Chinese Han population, the present study selected 315 patients with ischemic stroke and 210 healthy controls for comparison. GSTT1 and GSTM1 genotypes were determined using polymerase chain reactions, electrophoresis and imaging analysis. No obvious evidence of GSTT1-null, GSTM1-null and GSTT1/GSTM1-double null genotype distribution differences was found between case and control groups or between genders. Subgroup analysis showed that the risk of stroke was increased when hypertension was accompanied by GSTT1-null (odds ratio (OR) = 2.996, P < 0.001) and GSTM1-null (OR = 3.680, P < 0.001) genotypes; diabetes mellitus was accompanied by GSTT1-null (OR = 1.860, P = 0.031) and GSTM1-null (OR = 2.444, P = 0.002) genotypes, and smokers showed a GSTT1-null genotype (OR = 2.276, P = 0.003). GSTT1- and GSTM1-null genotypes may interact synergistically with hypertension, diabetes mellitus and smoking to increase the incidence risk of ischemic stroke.     

精神分裂症疾病诊断标志物circRNAs筛选及验证

目的研究精神分裂症(schizophrenia,SCZ)患者外周血单个核细胞中环状RNAs (circular RNAs,circRNAs)的差异表达,寻找潜在的SCZ诊断标志物。方法纳入175例SCZ患者和200名对照。将其中60例SCZ和60名对照的外周血样品分别混合为3份(每20个样品1份),采用全转录组测序技术获得SCZ患者与对照的外周血单个核细胞circRNAs表达谱。首先选择表达丰度较高,差异倍数≥2且有统计学意义的circRNAs,在这60例SCZ和60名对照的外周血样品中,使用实时荧光定量PCR(real-time PCR)进行验证,筛选得到与测序结果一致的circRNAs作为候选circRNAs。然后,在所有被试外周血样品中确证候选circRNAs的差异表达。结果与对照相比,SCZ患者外周血单个核细胞存在差异性表达的circRNAs共195个,其中表达上调的circRNAs有83个,表达下调的circRNAs有112个。在60例SCZ患者和60名对照的外周血样品中验证,SCZ患者circRNA_16588 (circbase_id:has_circ_0004669)(0.479±0.080 vs. 1.022±0.012,P=0.003)和circRNA_12825(circbase_id:has_circ_0004442)(0.387±0.050 vs. 1.372±0.230,P=0.013)表达下调具有统计学意义,可作为候选circRNAs。在所有被试的外周血样品中对候选circRNAs进行确证,发现SCZ患者组circRNA_16588(circbase_id:has_circ_0004669)(0.583±0.050 vs. 0.910±0.060,P 0.001)和circRNA_12825(circbase_id:has_circ_0004442)(0.680±0.080 vs. 1.219±0.090,P0.001)表达下调。结论 SCZ患者外周血单个核细胞中存在差异性表达的circRNAs,circRNA_16588和circRNA_12825在SCZ患者外周血单个核细胞中表达显著下调,有作为SCZ诊断标志物的潜力。     

上海地区汉族PTEN基因多态性与精神分裂症伴发2型糖尿病的关联分析

目的探讨中国上海地区汉族人群第10号染色体缺失的磷酸酶及张力蛋白同源基因(gene of phosphate and tension homology deleted on chromosometen,PTEN)的多态性与精神分裂症(schizophrenia,SCZ)伴发2型糖尿病(type 2 diabetes mellitus,T2DM)易感性的关联。方法选取上海地区长期住院的精神分裂症伴发2型糖尿病(合并组,304例)或不伴发2型糖尿病患者(单纯SCZ组,287例),上海地区单纯2型糖尿病患者(T2DM组,206例)及正常人群(对照组,205名)为研究对象,用Taqman基因分型技术对PTEN基因的SNP位点(rs1234225、rs12569998及rs1234223)进行基因分型,比较各组的等位基因、基因型及单体型分布频率。结果rs1234223基因型频率(P=0.01)、等位基因(P=0.02)分布在合并组和单纯SCZ组间有统计学差异,经Bonferroni检验校正后,基因型分布组间差异仍有统计学意义(P=0.03),等位基因分布组间差异没有统计学意义(P=0.06)。单体型分析示,TTC单体型在合并组中少于单纯SCZ组(P=0.02)。结论 PTEN基因可能是中国上海地区汉族人群精神分裂症合并2型糖尿病的易感基因,TTC单体型可能是精神分裂症合并2型糖尿病的保护因素。     

脑源性神经营养因子基因多态性与精神分裂症及其认知功能的关联研究

目的:探讨脑源性神经营养因子(BDNF)基因多态性与中国汉族精神分裂症(SCZ)发病及其认知功能的关系。方法:对354例SCZ患者(SCZ组)和416名健康对照人群(正常对照组)的BDNF基因4个多态性位点(rs7482257、rs7483883、rs1491850、rs16917234)进行基因分型;采用重复性成套神经心理状态测验(RBANS)对SCZ组及正常对照组进行认知功能评估。结果:SCZ组RBANS注意分、言语分、视觉广度分、即刻记忆分、延迟记忆分及总分明显低于正常对照组(F=1. 40,F=16. 38,F=96. 99,F=41. 12,F=114. 40,F=65. 23; P均0. 001)。两组BDNF基因4个多态性位点的等位基因(χ2=0. 37～2. 80)、基因型(χ2=1. 06～5. 77)及单体型(χ2=0. 224～2. 979)分布频率比较差异无统计学意义(P均 0. 05)。在SCZ组中,BDNF基因rs7482257不同基因型间视觉广度因子评分差异有统计学意义(F=3. 79,P=0. 024)。结论:BDNF基因多态性可能与SCZ易感性无关联; BDNF基因rs7482257位点的CC基因型可能与SCZ的视觉广度损害有关。     

帕金森病和抑郁症转录组生物信息学分析

目的抑郁症状(MDD)是帕金森病(PD)常见的非运动症状,探讨帕金森病和抑郁症可能具有的共同致病机制。方法通过文本挖掘及转录组数据分析帕金森病与抑郁症共同的致病机制。结果文本挖掘发现63. 8%的MDD基因和32%的PD基因为共有基因及438个共有的生物学过程;转录组筛选出有统计学意义的10个共同差异基因:I类肌球蛋白(MYO1F)、活化免疫球蛋白样受体(LILRA2)、垂体腺苷酸环化酶激活多肽(ADCYAP1)、骨骼肌肌球蛋白轻链激酶(MYLK2)、钙结合蛋白2(CLSTN2)、钙调蛋白依赖性蛋白激酶4(CAMK4)、前蛋白转化酶枯草杆菌蛋白酶1 (PCSK1)、瞬时受体电位阳离子通道5(TRPC5)、钠离子葡萄糖联合转运子(SLC5A1)、酪氨酸酶相关蛋白1 (TYPR1)(P 0. 01);基因功能富集分析发现PD和MDD具有相同的14个生物学过程,6个细胞组成,10个分子功能,并且有3个相同的京都基因与基因组百科全书(KEGG)信号通路(P 0. 05);通过蛋白质网络构建,筛选出4个共同的关键基因(MYO1F、CAMK4、PCSK1、TRPC5);通过对蛋白质网络模块分析后发现关键模块具有共同的生物学过程。结论帕金森病和抑郁症具有共同的致病基因及通路,这为帕金森病和抑郁症伴存现象提供了理论基础。     

运用高通量测序方法确定云南省2个家系及散发病例中的单纯型遗传性痉挛性截瘫的致病基因及发生模式

目的 运用高通量测序方法在云南省的2个家系和散发病例人群中探讨单纯型遗传性痉挛性截瘫(HSP)的发生模式,以期筛选出病理候选基因,探讨其遗传发生模式。方法 提取云南省2个家系和散发样本的全基因组DNA; 从家系样品中选择3例外送进行全外显子高通量测序; 依据筛选获得的候选突变基因,借助Sanger测序在剩余的家系样本和散发病例中进行验证,从而整合出这些样本的单纯型HSP疾病的遗传发生模式。结果 借助全外显子高通量测序分析和Sanger测序技术,在2个家系和2例散发病例中验证筛选,获得了13个候选致病突变基因。携带突变基因的异同不但是家系成员和散发病例患单纯型HSP疾病的互作成因,也使得不同家系呈现出不同的遗传模式。结论 结合高通量测序技术可以针对遗传性痉挛性截瘫这类疾病进行最大程度的广谱测序,从而获得有指导意义的突变基因,更好地确定疾病的家族遗传模式,最终作为后续疾病诊断和治疗的有效靶点服务于临床诊疗。     

应用生物信息学鉴定无功能型垂体瘤驱动基因及特效药物筛选

目的通过无功能型垂体瘤(NFPA)致病驱动基因的鉴定以及药物的筛选验证,为生物信息学在自然科学领域的应用提供思路。方法基于基因表达微阵列芯片数据进行差异表达基因的分析。采用富集度分析(GO分析)、京都基因与基因组百科全书(KEGG)分析以及蛋白质互作用网络(PPI)关系构建的方法,探究差异表达基因富集的生物学功能,鉴定出NFPA核心驱动基因。同时采用CCK-8、克隆形成、体外划痕以及流式测细胞凋亡等实验方法验证药物药效。结果 CALM1、PRDM10和RIPK4是原代人垂体无功能腺瘤(NFPA)致病驱动基因,STO-609可以作为抗NFPA的潜在治疗药物。此外,NFPA很可能多方面与帕金森病密切相关。结论基于计算机技术,应用生物信息学方法可进行肿瘤驱动基因的筛选,依据核心基因能够进行治疗靶点的设计以及药物药效的验证。将生物信息学手段应用于生命科学领域的研究意义重大,且切实可行。     

青年卒中遗传学研究进展

青年卒中的发病率呈上升趋势,发现临床前生物标志物将获益巨大。除了罕见的卒中相关单基因疾病,许多遗传易感性研究表明青年卒中是多基因遗传病。近20年来,全基因组关联分析、验证研究和meta分析研究方法被应用于青年卒中的遗传学研究。本篇综述阐述了青年卒中的遗传学证据以及相关的单基因突变和候选基因变异,为疾病诊治提供参考。     

抑郁症和双相情感障碍的共同致病基因

抑郁症和双相情感障碍属于心境障碍里的两大常见疾病,大量的证据表明抑郁症和双相情感障碍存在重叠。本篇综述回顾相关文献,探讨了5-羟色胺转运体(SLC6A4)基因、色氨酸羟化酶(TPH)基因、儿茶酚胺甲基转移酶(COMT)基因、单胺氧化酶(MAOA)基因、5-羟色胺受体基因、多巴胺系统基因、DISC1、TSNAX基因、血管紧张素转化酶(ACE)基因等作为两个疾病共同致病基因的可能性。     

Excitement and confusion on chromosome 6q: the challenges of neuropsychiatric genetics in microcosm

The search for genes that are implicated in the pathogenesis of schizophrenia (SCZ), bipolar disorder (BPD) and other complex neuropsychiatric phenotypes has yielded a plethora of positive findings, but has also engendered a substantial degree of confusion. Exciting findings include positive linkage results in a number of chromosomal regions and the identification of several genes that have been associated with SCZ and to a lesser extent with BPD. Confusing aspects include the difference between studies in localization of linkage peaks in the same chromosomal regions, raising the possibility that these regions may harbor more than one gene, the fact that positive linkage findings as well as associated genes appear in several cases to be shared by more than one disorder, and the failure to identify thus far the precise pathogenic variants in associated genes. Recent findings of linkage and association studies on chromosome 6q illustrate the current status of neuropsychiatric genetics in intriguing microcosm. Positive findings from linkage and association studies are reviewed in order to identify approaches that may help to settle apparent contradictions and allow an interpretation of the results that may prove useful in application to findings from other chromosomal regions. Not only SCZ and BPD but also other psychiatric and neurological phenotypes are considered. Taking a topographic approach, we identify five foci of positive findings on chromosome 6q and suggest that each may harbor gene(s) that confer susceptibility to SCZ or BPD or may modify their onset or clinical course. We further suggest that in searching for these genes the possibility that they may be implicated in more than one disorder should be taken into account. We also discuss the potential contribution of rare genetic variants identified in homogeneous, isolated populations to the subsequent identification of common variants in the same gene that contribute to disease susceptibility in outbred populations.     

RNA metabolism and dysmyelination in schizophrenia

Decreased expression of a subset of oligodendrocyte and myelin-related genes is the most consistent finding among gene expression studies of postmortem brain tissue from subjects with schizophrenia (SCZ), although heritable variants have yet to be found that can explain the bulk of this data. However, expression of the glial gene Quaking (QKI), encoding an RNA binding (RBP) essential for myelination, was recently found to be decreased in SCZ brain. Both oligodendrocyte/myelin related genes, and other RBPs that are known or predicted to be targets of QKI, are also decreased in SCZ. Two different quaking mutant mice share some pathological features in common with SCZ, including decreased expression of myelin-related genes and dysmyelination, without gross destruction of white matter. Therefore, although these mice are not a model of SCZ per se, understanding the similarities and differences in gene expression between brains from these mice and subjects with SCZ could help parse out distinct genetic pathways underlying SCZ.     

Association analysis of the chromosome 4p15-p16 candidate region for bipolar disorder and schizophrenia

Several independent linkage studies have identified chromosome 4p15-p16 as a putative region of susceptibility for bipolar disorder (BP), schizophrenia (SCZ) and related phenotypes. Previously, we identified two subregions (B and D) of the 4p15-p16 region that are shared by three of four 4p-linked families examined. Here, we describe a large-scale association analysis of regions B and D (3.8 and 4.5 Mb, respectively). We selected 408 haplotype-tagging single nucleotide polymorphisms (SNPs) on a block-by-block basis from the International HapMap project and tested them in 368 BP, 386 SCZ and 458 control individuals. Nominal significance thresholds were determined using principal component analysis as implemented in the program SNPSpD. In region B, overlapping SNPs and haplotypes met the region-wide threshold (P相似文献   

No association of serotonin transporter gene (SLC6A4) with schizophrenia and bipolar disorder in Japanese patients: association analysis based on linkage disequilibrium

Summary. Serotonin transporter gene (SLC6A4) is one of the most promising candidate genes for psychiatric disorders such as schizophrenia (SCZ) and bipolar disorder (BP). Two functional polymorphisms, 5HTTLPR and 5HTTVNTR, have been a focus for genetic association analyses; however, no conclusive results have been obtained. We conducted, 1) a mutation search of SLC6A4, 2) LD mapping to select ‘tagging’ markers (10 SNPs and 5HTTVNTR, while 5HTTLPR was treated as an independent marker because of its allelic form), and 3) association analysis of these ‘tagging’ markers and independent markers (5HTTLPR and Asn605Lys) with SCZ and BP in Japanese patients. In this mutation search, a nonsynonymous SNP, Asn605Lys, was detected. No associations of ‘tagging’ markers and independent markers with such conditions were found. These results indicate that SLC6A4 might not play a major role in SCZ and BP in Japanese patients, a finding that agrees with both the common disease-common variant hypothesis and common disease-rare variant hypothesis.     

A Novel <Emphasis Type="Italic">SYNJ1</Emphasis> Mutation in a Tunisian Family with Juvenile Parkinson’s Disease Associated with Epilepsy

We investigated the effect of a set of SNPs within 5 genes identified by GWASs as possible risk genes for schizophrenia (SCZ) in two independent samples, comprising 176 SCZ patients and 326 controls of Korean origin and 83 SCZ patients and 194 controls of Italian origin. The PANSS was used to assess psychopathology severity and antipsychotic response (AR). Several clinical features were assessed at recruitment. In the Korean sample, the SP4 gene haplotype rs2282888-rs2237304-rs10272006-rs12673091 (p?=?0.02) was associated with SCZ. In the Italian sample, PPP3CC rs11780915 (genotypic: p?=?0.006; allelic: p?=?0.001) and rs2249098 (genotypic: p?=?0.0004; allelic: p?=?0.00006) were associated with SCZ, as well as the PPP3CC rs11780915-rs10108011-rs2249098 and the ZNF804A rs7603001-rs1344706 haplotypes (p?=?0.03 and p?=?0.02). Several RORA variants were associated with AR in both the samples, although only the haplotype rs1020729-rs1871858 in the Korean sample survived to the statistical correction (p?=?0.01). Exploratory analyses suggested that: (1) PPP3CC, ST8SIA2, and SP4 genes may modulate psychotic symptoms, and (2) RORA and ZNF804A genes may influence AR. Our results partially support a role for these genes in SCZ and AR. Analyses in well phenotyped samples may help to refine the role of the genes identified by GWASs.     

Association between genetic variation in a region on chromosome 11 and schizophrenia in large samples from Europe

Recent molecular studies have implicated common alleles of small to moderate effect and rare alleles with larger effect sizes in the genetic architecture of schizophrenia (SCZ). It is expected that the reliable detection of risk variants with very small effect sizes can only be achieved through the recruitment of very large samples of patients and controls (that is tens of thousands), or large, potentially more homogeneous samples that have been recruited from confined geographical areas using identical diagnostic criteria. Applying the latter strategy, we performed a genome-wide association study (GWAS) of 1169 clinically well characterized and ethnically homogeneous SCZ patients from a confined area of Western Europe (464 from Germany, 705 from The Netherlands) and 3714 ethnically matched controls (1272 and 2442, respectively). In a subsequent follow-up study of our top GWAS results, we included an additional 2569 SCZ patients and 4088 controls (from Germany, The Netherlands and Denmark). Genetic variation in a region on chromosome 11 that contains the candidate genes AMBRA1, DGKZ, CHRM4 and MDK was significantly associated with SCZ in the combined sample (n=11?540; P=3.89 × 10(-9), odds ratio (OR)=1.25). This finding was replicated in 23?206 independent samples of European ancestry (P=0.0029, OR=1.11). In a subsequent imaging genetics study, healthy carriers of the risk allele exhibited altered activation in the cingulate cortex during a cognitive control task. The area of interest is a critical interface between emotion regulation and cognition that is structurally and functionally abnormal in SCZ and bipolar disorder.     

A candidate gene study of antiepileptic drug tolerability and efficacy identifies an association of CYP2C9 variants with phenytoin toxicity

Background and purpose: It is widely acknowledged that individual response to antiepileptic drugs (AEDs) is influenced by genetic factors. However, most of the underlying genes and genetic variants remain unidentified to date. The purpose of this study is to examine the role of common variants in a number of candidate genes in the response to commonly prescribed AEDs. Methods: We recruited 495 patients with epilepsy. Patients were classified according to their response to several AEDs. We genotyped 104 polymorphisms in 17 candidate genes for AED response. We looked for statistically significant associations between these polymorphisms and well‐defined AED response phenotypes. Results: We identified significant associations of CYP2C9 variant alleles with presence of phenytoin (PHT) adverse drug reactions (ADRs) and of GSTM1 copy number variation with the presence of carbamazepine ADRs. The latter association could not be confirmed in a replication study. Conclusions: Our study is the first comprehensive candidate gene association study in epilepsy pharmacogenetics. Our results confirm the role of CYP2C9 variants in PHT toxicity. No other definite associations were identified. Large‐scale efforts are needed to unravel the genetic determinants of AED response.     

Gene expression profiles of rat olfactory bulb at developmental stage

Microarray analysis may be a useful tool to identify some candidate genes related to the development of olfactory bulbs. In the present study, gene expression profiles of olfactory bulbs from postnatal day 1 (P1) rats and postnatal day 35 (P35) rats were analyzed by oligonucleotide-microarray and expression levels of some selected genes were also confirmed by RT-PCR and in situ hybridization. 9146 genes were commonly identified in six microarray chips. Among these genes, 76 were up-regulated and 130 were down-regulated three-folds or more at P1 olfactory bulbs. Out of these 76 up-regulated genes, 24 genes were annotated based on the NCBI database of reference sequences and expression levels of these 24 genes were confirmed by RT-PCR. Among them, 2 interesting genes (neurogenic differentiation 1 and retinoid acid receptor alpha) were localized in the P1 olfactory bulb by the use of in situ hybridization technique. Our results may provide basic information to identify genes associated with functional growth of olfactory bulbs.     

Genetic Variants Within Molecular Targets of Antipsychotic Treatment: Effects on Treatment Response,Schizophrenia Risk,and Psychopathological Features

Schizophrenia (SCZ) is a common and severe mental disorder. Genetic factors likely play a role in its pathophysiology as well as in treatment response. In the present study, we investigated the effects of several single nucleotide polymorphisms (SNPs) within 9 genes involved with antipsychotic (AP) mechanisms of action. Two independent samples were recruited. The Korean sample included 176 subjects diagnosed with SCZ and 326 healthy controls, while the Italian sample included 83 subjects and 194 controls. AP response as measured by the positive and negative syndrome scale (PANSS) was the primary outcome, while the secondary outcome was the SCZ risk. Exploratory analyses were performed on (1) symptom clusters response (as measured by PANSS subscales); (2) age of onset; (3) family history; and (4) suicide history. Associations evidenced in the primary analyses did not survive to the FDR correction. Concerning SCZ risk, we partially confirmed the associations among COMT and MAPK1 genetic variants and SCZ. Finally, our exploratory analysis suggested that CHRNA7 and HTR2A genes may modulate both positive and negative symptoms responses, while PLA2G4A and SIGMAR1 may modulate respectively positive and negative symptoms responses. Moreover, GSK3B, HTR2A, PLA2G4A, and S100B variants may determine an anticipation of SCZ age of onset. Our results did not support a primary role for the genes investigated in AP response as a whole. However, our exploratory findings suggested that these genes may be involved in symptom clusters response.