精神分裂症与21号染色体上遗传标志无连锁

最近在一例慢性精神分裂症患者发现有位于21q21的APP基因17外显子的突变,导致APP713发生Ala→Val的置换,该突变发生在APP基因进化高度保守区域,紧挨与Alzheimer病有关的突变部位,提示该突变对精神分裂症发病可能有重要作用,后来Jones等在100个无亲属关系的患者中没有发现这样的突变,但这并不能排除在高发家系存     

山东半岛东部地区精神分裂症13号染色体的基因扫描研究

目的通过微卫星遗传标记对精神分裂症患者及对照者的13号染色体进行扫描,查找精神分裂症关联区域。方法在13号染色体上间隔约10cM(厘摩)遗传距离选择14个微卫星遗传标记,对119例精神分裂症患者与119例正常对照者组成的DNA混合样本分别进行了基因扫描及分型,经过卡方(χ2)检验统计学分析,比较患者组与对照组每个等位基因峰型比率的差异。结果在D13S265(13q31.3)位点患者组与对照组的等位基因频率差异存在显著性意义(P<0.01)。结论山东半岛东部人群中精神分裂症患者的13号染色体上存在与本病的关联位点。     

山东半岛东部地区精神分裂症8号染色体基因扫描研究

目的对精神分裂症患者的8号染色体进行扫描,查找精神分裂症的关联区域。方法采用DNA混合池(DNA pooling)的方法,选择8号染色体上遗传距离间隔10cM(厘摩尔)的14个微卫星遗传标记,对山东潍坊东部偏远地区人群中的119例精神分裂症患者与119名正常对照分别进行了扫描,比较两组每个等位基因峰高比率的差异。结果患者组和对照组在遗传位点D8S264的等位基因频率差异有统计学意义(P<0.05)。结论山东潍坊东部地区的精神分裂症患者中在8号染色体短臂上存在与精神分裂症的关联区域,该区域可能包含致病基因或调控因子的畸变。     

山东省某地区精神分裂症患者6号染色体的基因组扫描研究

目的在6号染色体上寻找与精神分裂症的关联区域，进而定位精神分裂症的致病基因。方法在6号染色体采用问隔10cM（厘摩）遗传距离的20个微卫星遗传标记，分别对山东省潍坊市东部地区119例精神分裂症患者和119名正常对照者的DNA混合样本进行基因组扫描，比较两组每个等位基因峰值比率的差异。结果患者组D6S289和D6S460两个遗传位点上的等位基因频率分别为0．121和0．200，高于对照组（分别为0．046和0．157，P〈0．01），而患者组D6S1610遗传位点的等位基因频率（0．087）低于对照组（0．161，P〈0．01）。结论山东省潍坊市东部地区的精神分裂症患者中存在与6号染色体的关联区域，致病因子（基因或调控因子等）可能位于其中。     

山东半岛东部地区精神分裂症21号染色体基因扫描研究

目的用DNA混合池(DNA pooling)的方法,通过微卫星遗传标记对精神分裂症患者及对照者的21号染色体进行扫描,寻找精神分裂症的关联区域。方法在21号染色体上间隔10 cM(厘摩)遗传距离选择了5个微卫星遗传标记,对119例精神分裂症患者与119例正常对照者组成的DNA混合样本分别进行了扫描。用卡方[X~2]检验的方法进行统计学分析,逐一比较患者组与对照组等位基因峰型比率的差异。结果在D21S1256遗传位点患者组和对照组的等位基因频率差异有显著性意义,P＜0．001。结论山东半岛东部地区精神分裂症患者群体在21号染色体长臂存在关联区域,可能包含致病基因或调控因子的病变。     

精神分裂症的全基因组关联分析研究

全基因组关联分析（genome-wideassociationstudy,GWAS）是指采用高通量的基因分型技术,对覆盖全基因组的遗传标志进行基因分型,通过病例对照研究或基于家系的关联分析来寻找全基因组中与疾病（性状）相关的基因。目前广泛用于复杂遗传疾病研究的GWAS已在多种疾病中取得了重大突破,精神分裂症作为复杂遗传疾病的典型代表,GWAS发现了许多新的精神分裂症候选致病基因,GWAS研究虽然有良好的应用前景,但也存在一些缺陷,如多次假设检验造成的假阳性结果。本文就GWAS的特点和存在的问题及其在精神分裂症研究中的应用进展做一综述。     

精神分裂症9号染色体基因扫描研究

目的:对山东半岛精神分裂症患者及正常对照者的9号染色体进行基因扫描,查找精神分裂症的关联位点.方法:在9号染色体上间隔10 cM(厘摩)遗传距离,选择20个微卫星遗传位点,用脱氧核糖核酸(DNA)混合池的方法对119例精神分裂症患者与119名正常对照者的DNA样本分别混合后进行基因扫描,对比患者组与对照组在差异位点的等位基因峰型比率的差异.结果:在D9S273遗传位点患者组与对照组的等位基因频率差异有统计学意义(P＜0.01).结论:山东半岛东部地区精神分裂症患者群体中存在与9号染色体关联的区域.     

精神分裂症同胞家系的6号染色体基因组扫描研究

目的：通过对6号染色体进行候选区域的基因组扫描，探索精神分裂症的遗传易感基因。方法：以分布于6号染色体的28个微卫星标记在137个精神分裂症同胞家系样本中进行候选区域的基因扫描，采用受累同胞对分析方法，结合诊断分类，量表及必要的临床资料。通过GENEHUNTER ，MAPMAKER／SIBS等软件系统进行质量性状及数量性状的非参数连锁分析。结果：结合诊断分类的质量性状连锁分析未发现阳性结果。结合阳性和阴性症状量表（PANSS）的Haseman Elston数量性状连锁分析，结合PANSS－P分析所得最大Lod值为1．39，位于D6S1960附近，结合PANSS－G和PANSS－N所得最大Lod值分别为2．50和1．56，位于D6S291附近，变异因素数量性状分析与Haseman-Elason分析结果一致，即在相应的数量性状分析中，在D6S1960和D6S291附近，位点本身的遗传效应有明显作用的趋势。结论：6号染色体短臂可能存在精神分裂症的易感基因。     

微卫星DNA vWA的多态性与精神分裂症的关联研究

目的　通过对微卫星DNAvWA多态性的分析 ,了解精神分裂症与vWA有关“等位基因”的关联情况。方法　对 32例精神分裂症患者和 12 3名随机人群采用PEProfilerplus系统进行PCR复合扩增 ,然后用ABI310型基因分析系统对扩增产物进行电泳和基因检测。结果　两组vWA“等位基因”频率符合Hardy Weinberg平衡定律 (P >0 0 5 ) ;精神分裂症组vWA 14的检出率为 17 2 % ,对照组的检出率为 33 3% ,两组有显著性差异 (P <0 0 5 ) ;精神分裂症组vWA 17的检出率为 31 2 % ,对照组检出率为 19 5 % ,两组有显著性差异 (P <0 0 5 ) ;其他各“等位基因”检出率两组无统计学显著差异 (P >0 0 5 )。结论　vWA“等位基因”vWA 14和vWA 17与精神分裂症的发病有关 ,在第 12号染色体上可能存在与精神分裂症相关的基因     

精神分裂症染色体的研究

本文对８２例精神分裂症的染色体进行了研究。结果观察到１例染色体核型４７，ＸＸＹ，其它皆为４６，ＸＹ。其染色体相对长度，臂比和着丝粒指与正常人无差异，８２例中的８１例４０５０个细胞的染色体数目畸变率和结构畸变率与正常人亦无显著差异。     

Positive association of the human STON2 gene with schizophrenia

Synaptic hypothesis of schizophrenia suggests that alterations of synaptic transmission and neuronal connectivity might be core feature of schizophrenia. STON2 participates in synaptic vesicle protein recognition and neural endocytosis. To explore the association of STON2 with schizophrenia, 11 single nucleotide polymorphisms (SNPs) were examined in 768 Chinese Han schizophrenia cases and 1347 Chinese Han controls. The results showed that three SNPs had strong association with schizophrenia, two exonic SNPs (rs2241621: allelic P=0.0005; rs3813535: allelic P=0.0078) and one intronic SNP (rs9323698: allelic P=0.0019). When haplotype analysis performed, two linkage disequilibrium blocks showed significant differences in frequency between cases and controls. Notably, our data displays an over-transmitted functional haplotype C-C (Pro307-Ala851) in schizophrenia cases. Our results suggest STON2 may be a susceptibility gene for schizophrenia.     

A study of single nucleotide polymorphisms in CD157, AIM2 and JARID2 genes in Han Chinese children with autism spectrum disorder

Purpose: Autism spectrum disorder (ASD) is a group of developmental brain disorders caused by genetic and environmental factors. The objective of this study was to investigate whether single nucleotide polymorphisms (SNPs) in genes related to immune function were associated with ASD in Chinese Han children.

Materials and methods: A total of 201 children with ASD and 200 age- and gender-matched healthy controls were recruited from September 2012 to June 2106. A TaqMan probe-based approach was used to genotype SNPs corresponding to rs28532698 and rs4301112 in CD157, rs855867 in AIM2, and rs2237126 in JARID2. Case-control and case-only studies were performed to determine the contribution of SNPs to the predisposition of disease and its severity, respectively.

Results: Our results revealed that the genotypes and allele frequencies of these SNPs were not significantly associated with childhood ASD and its severity in this population.

Conclusions: Results of our study suggest that these SNPs are not predictors of childhood ASD in the Chinese Han population. The discrepant results suggest the predictor roles of SNPs have to be determined in different ethnic populations due to genetic heterogeneity of ASD.     

Positive association between ALDH1A2 and schizophrenia in the Chinese population

Vitamin A (retinol), in the biologically active form of retinoic acid (RA), has been proposed as involved in the pathogenesis of schizophrenia. We hypothesized that genetic basis of genes encoding RA metabolism enzymes, which control the cellular RA level, might be associated with this disease. This cascade genetic association model, using markers in genes of synthesis and degradation enzymes within the retinoid cascade, would better fit the biological character of the retinoid hypothesis than the single gene strategy. In the present study we chose to investigate 7 genes involved in the synthesis, degradation and transportation of RA, ALDH1A1, ALDH1A2, ALDH1A3, CYP26A1, CYP26B1, CYP26C1 and Transthyretin (TTR), for their roles in the development of schizophrenia. We genotyped 18 single nucleotide polymorphisms (SNPs) in the regulatory and coding regions of these 7 genes using LDR technology in the 617 Chinese Han subjects. Case–control analyses were performed to detect association of these 7 genes with schizophrenia. Association analyses using both allelic and genotypic single-locus tests revealed no significant association between the risk for each of investigated gene and schizophrenia. However, analyses of multiple-locus haplotypes indicated that the overall frequency of rs4646642–rs4646580 of ALDH1A2 gene showed significant difference between patients and control subjects (p = 0.0055). We also employed multifactor dimensionality reduction method to detect multilocus effects. In summary, in this work we show multiple candidate genes involved in retinoid cascade in schizophrenics. In addition, our results suggest a positive association between ALDH1A2 and schizophrenics in the Chinese population and support the retinoid hypothesis of schizophrenia.     

TGFBR2 gene expression and genetic association with schizophrenia

TGFBR2 gene is a tumor suppressor gene located at chromosome 3p22, and the locus is reported to be linked with schizophrenia susceptibility. According to the previous studies, a reduced incidence of cancer is observed in schizophrenic patients compared with the general population and tumor suppressor genes may be associated with schizophrenia. We measured the mRNA expression of TGFBR2 gene in the peripheral leukocytes from 19 medication-free schizophrenics and 25 medication-free major depressive patients compared with age- and sex-matched control subjects using a quantitative real-time PCR method. We also followed up the TGFBR2 mRNA expression levels from 13 schizophrenics after several weeks - antipsychotic treatments. The TGFBR2 mRNA levels of medication free schizophrenics were significantly higher than those of control subjects and decreased to almost the same level as controls after antipsychotic treatment. On the other hand, the TGFBR2 mRNA levels of medication-free major depressive patients were not significantly different from controls. In genetic studies, we failed to find any association between the TGFBR2 gene and schizophrenia with 10 SNPs of TGFBR2 gene in Japanese subjects (279 subjects each) and there was no significant difference with haplotype analysis, either. Our results suggest that the TGFBR2 gene itself does not link to schizophrenia but that the TGFBR2 mRNA levels in the peripheral leukocytes may be a potential state marker for schizophrenia.     

精神分裂症患者细胞色素P450 2D6酶基因多态性与利培酮治疗效应的关系

目的研究精神分裂症患者细胞色素P450 2D6酶(CYP2D6)多态性是否与利培酮治疗效应有关.方法采用阳性和阴性症状量表(PANSS)、大体评定量表(GAS)、治疗时需处理的副反应量表(TESS)以及锥体外系副反应量表(RSESE)对52例精神分裂症[PANSS基线分(105.59±17.30)分;GAS基线分(31.75±3.32)分]患者,分别在利培酮治疗前及治疗[(5±3)mg/d]第1～8周末各进行一次药物反应评定,采用聚合酶链反应技术对CYP2D6 exon Ⅰ C/T188和CYP2D6 G/A1934两个多态性位点进行检测.根据CYP2D6 exonI C/T188基因型将患者分为三组(C/C组 13例,C/T组20例,T/T组19例);采用治疗前后PANSS 30%减分率为标准 ,将52例患者分为治疗有效组和治疗无效组,比较组间药物治疗效应的差异.结果从利培酮治疗后第5周末开始,三组之间PANSS评分的差异有显著性(P<0.01);两两比较发现,C/C组PANSS分低于T/T组(P<0.01);三组之间GAS评分的差异从第6周开始出现显著性(P<0.01),其中C/C组GAS分明显高于T/T组(P<0.01).多因素方差分析显示,三组的PANSS总分 (F=2.64, P<0.01)及GAS评分(F=1.85,P<0.05)差异有非常显著性;CYP2D6 exon Ⅰ C/T188多态性基因型频率(χ2＝6.56,P<0.05)和等位基因频率(χ2＝5.03,P<0.05,相对风险＝2.54,95%可信区间＝1.40～8.32).利培酮治疗有效组与无效组之间的差异有显著性.样本中未发现CYP2D6 G/A1934多态性.结论中国人群精神分裂症CYP2D6 exon Ⅰ C/T188多态性可能是影响利培酮临床疗效的遗传易感因素.     

强啡肽原基因和多巴胺D2受体基因与精神分裂症的关系研究

目的探讨甘肃省汉族人群强啡肽原（Prodynorphin,PDYN）基因和多巴胺D2受体（dopamine D2 receptor,DRD2）基因与精神分裂症遗传易感性的关系及其相互作用对精神分裂症的影响。方法采用聚合酶链反应-限制性片段长度多态性〈PCR—RFLP）技术检测128例精神分裂症患者和124例健康对照者PDYN基因启动子区68bp可变串联重复序列（variable number tandem repeat,VNTR）多态性及DRD2基因启动子区-141位胞嘧啶插入／缺失（-141C Ins／Del）多态性的基因型和等位基因的频率。结果精神分裂症患者PDYN等位基因和基因型频率与健康对照者没有显著不同;精神分裂症患者DRD2-141C Del等位基因的频率则显著低于健康对照者;在携带DRD2-141C Del等位基因的精神分裂症患者和健康对照者中,精神分裂症患者PDYN等位基因3的频率显著高于健康对照者。结论DRD2-141C Del等位基因的降低可能与精神分裂症的遗传易感性相关,单独的PDYN基因多态性不会改变精神分裂症的危险度,但是通过与DRD2—141C Del等位基因的上位相互作用可能与这种疾病的易感性相关。     

PLA2G6基因多态性与偏执型精神分裂症的关联

目的：探讨PLA2G6基因多态性与偏执型精神分裂症的关系.方法：采用聚合酶链反应（PCR）和限制性内切酶片段长度多态性（RFLP）方法,在109个偏执型精神分裂症患者核心家系中检测PLA2G6基因上的3个单核苷酸多态性（SNP）（rs2235346、rs2272831和rs2284060）.运用单倍型相对风险（HRR）分析和传递不平衡分析（TDT）方法进行关联分析.结果：所检测的3个SNPs的基因型在患者组和父母组中频数分布均符合Hardy-Weinberg平衡.HRR和TDT分析均表明,rs2272831位点与偏执型精神分裂症相关联（χ^2=5.590,υ=1,P=0.018;χ^2=5.333,υ=1,P=0.021）,而rs2235346和rs2284060位点与偏执型精神分裂症无关联.结论：PLA2G6基因可能是偏执型精神分裂症的易感基因.     

多巴胺D2、D3受体基因多态性与汉族人精神分裂症相关研究

目的探索多巴胺D2受体(Dopamine D2receptor,DRD2)基因第8外显子Taq I A位点多态和多巴胺D3受体(Dopamine D3receptor,DRD3)基因第5内含子Msp I位点多态与汉族人群精神分裂症是否关联及其在不同性别是否存有差异。方法使用聚合酶链反应-限制性片段长度多态性(Polymerase chain reaction-re-striction fragment length polymorphism,PCR-RFLP)及DNA测序技术,对317例精神分裂症患者及310名对照DRD2Taq I A基因多态性和DRD3Msp I位点基因多态性进行检测。结果患者组与对照组间DRD2 Taq I A位点等位基因分布差异显著(P<0.01)、两两基因型对比(A1/A2与A1/A1相比:P<0.05;A2/A2与A1/A1相比:P<0.01)及两基因型联合对比(A1/A2+A2/A2与A1/A1:P<0.01)组间差异也显著。性别分层研究DRD2Taq I A位点女性组间差异显著(P<0.01),男性组间差异无意义(P>0.05)。DRD3Msp I位点的基因型频率、等位基因分布及性别分层分析等所有数据均显示患者组与对照组之间差异无统计学意义(P>0.05)。风险因子趋势检验结果DRD2Taq I A位点等位基因A2:P<0.01;DRD3Msp I位点等位基因2:P>0.05。结论所得数据支持DRD2Taq I A位点等位基因A2可能为精神分裂发生的风险因子,特别对女性而言。数据分析不支持DRD3Msp I位点基因与精神分裂发生有关。此结果需更进一步研究证实。     

An association study between the Cys311 variant of dopamine D2 receptor gene and schizophrenia in the Okinawan population

Abstract  Neuroleptic drugs have a high affinity for the dopamine D₂ receptor (DRD2); therefore DRD2 is thought to be a candidate gene for schizophrenia. Arinami et al . have reported a positive association between schizophrenia and the Cys311 variant of the DRD2 gene. We determined the allele frequency of this polymorphism in 78 Okinawan schizophrenic patients and 112 control subjects. The patients and controls did not differ significantly in allele frequencies of Cys311.