精神分裂症与六种候选功能基因的关联研究

目的：探讨多巴胺D2受体基因（dopamine D2 receptor,DRD2)、多巴胺D4受体基因（DRD4）、5－羟色胺2A受体基因（5－hydroxytryptamine 2A receptor,5-HT2A),5-羟色胺6受体基因（5－HT6)、儿茶酚胺氧位甲基转移酶基因（catechol-O-methyltransferase,COMT)和多巴胺转运体基因（dopamine transferase,DAT1)多态性与精神分裂症的关系。方法：应用基因扩增片段长度多态和基因扩增的限制性片段长度多态技术，对中国汉族人群中67例精神分裂症患者与上述6种候选功能和基因扩增的限制性片段长度多态技术，对中国汉族人群中67例精神分裂症患者与上述6种候选功能基因进行遗传关联分析。结果：（1）DRD2、5－HT2A、5－HT6和KCOMT的基因型和等位基因频率在患者组和对照组中差异无显著性（P＞0．05）。（2）DRD4基因中6次重复序列等位基因、DAT1基因中480bp等位基因和480／520基因型在两组中差异有显著性，Z分别为2．03、2．05和2．05；P均小于0．05。（3）经关联分析后，仅DAT1基因的480bp等位基因的比值比为0．441，95％可信区间为0．202－0．963，并有显著性意义（Z＝2．05，P＜0．05），而DAT1的480／520基因型和DRD4和6次重复序列等位基因的比值比分别为0．128和0．123，但Z均小于1．96，无显著性意义（P＞0．05）。因此，6个功能基因中仅DAT1的480bp等位基因与精神分裂症呈负关联。结论：中国汉族人群中DAT1基因的480bp等位基因与精神分裂症间存在负关联，支持精神分裂症的多巴胺假说。     

DRD3基因Ser9Gly多态性与不同性别精神分裂症患者工作记忆的关联研究

目的:探讨DRD3基因Ser9Gly多态性与汉族人群不同性别精神分裂症患者工作记忆的关联.方法:选取符合美国精神障碍诊断与统计手册第4版(DSM-Ⅳ)中精神分裂症的诊断标准的汉族患者526例和415例汉族健康对照,检测DRD3基因Ser9Gly多态性,用中国修订韦氏成人智力量表(WAIS-RC)进行智商(IQ)评定,N-back任务测量工作记忆能力.采用协方差分析等方法分析DRD3基因Ser9Gly多态性与精神分裂症工作记忆的关联.结果:在全体被试中,男性的1-back[(0.50±0.27) vs.(0.56±0.25)]和2-back[(0.25±0.22) vs.(0.28±0.22)]任务错误率小于女性(均P＜0.05).男性患者中,Ser/Ser基因型的1-back任务错误率[(0.39±0.23) vs.(0.33±0.23)]高于Gly/Ser基因型,IQ[(97.4±15.1) vs.(101.9±13.4)]低于Gly/Ser基因型(均P＜0.05);男性对照组中,不同基因型之间工作记忆及IQ得分差异无统计学意义(均P＞0.05).女性被试中,Ser9Gly多态性不同基因型的工作记忆与IQ得分差异无统计学意义(均P＞0.05).结论:精神分裂症患者的工作记忆可能存在性别差异,Ser9Gly多态性在汉族人群中与精神分裂症的工作记忆障碍有一定相关性.     

湖南地区汉族人多巴胺D4受体基因48 bp可变数目串联重复多态性分布

目的 了解湖南地区汉族人群多巴胺D4受体（dopamine D4 receptor，DRD4）基因48 bp可变数目串联重复（variable number tandem repeat,VNTR）多态性基因型及等位基因的频率分布。方法 随机抽取湖南地区304名汉族健康正常人，采用聚合酶链反应、变性聚丙烯酰胺凝胶电泳结合银染技术检测基因型和等位基因的频率。结果 （1）湖南汉族人群DRD4基因48 bp VNTR多态性共检测出7种等位基因、12种基因型。最常见的等位基因是5等位基因（DRD4＊5），频率为70．6％。（2）湖南汉族人群DRD4基因48 bp VNTR多态性各等位基因频率与中国上海、北京、四川地区人群存在明显的差异。（3）湖南汉族人群DRD4基因48 bp VNTR多态性各等位基因频率与日本、美国、墨西哥、意大利人群也存在明显差异。结论 DRD4基因48 bp VNTR多态性分布存在不同程度的地区差异和种族差异。     

多巴胺受体D2型基因启动区多态性与精神分裂症关联研究

目的探讨湖北武汉地区汉族人群中多巴胺受体D2型基因(dopamine receptor D2, DRD2)启动区-141位点胞嘧啶插入/缺失多态性与精神分裂症的关联关系.方法应用聚合酶链反应-限制性片段长度多态性方法,对120例精神分裂症患者、100名健康对照者进行基因分型.对精神分裂症患者的 DRD2 -141位点胞嘧啶插入/缺失多态性进行了相关分析.结果 DRD2型基因启动区-141位点的等位基因、基因型频率在精神分裂症组与对照组之间的分布差异有统计学意义(P<0.05).在精神分裂症组中,-141C缺失的等位基因频率为0.11,对照组为0.18(比值比为0.55,95%可信区间为0.30～0.96,P <0.05).结论 -141位点胞嘧啶插入/缺失多态性非独立性地对精神分裂症与 DRD2基因的相关性产生修饰作用.-141位点胞嘧啶缺失可能是湖北武汉汉族精神分裂症患者的保护因素之一.     

多巴胺D2受体基因启动子多态性与帕金森病的关联研究

目的 探讨中国汉族人群多巴胺D2受体基因启动子多态性在帕金森病（Parkinson's disease,PD)遗传易感性中的作用。方法 采用病例－对照关联分析，聚合酶链反应－限制性片段长度多态性方法分析了123例PD患者（PD组）与124名健康成人（对照组）多巴胺D2受体基因启动子多态性。结果 PD组－141△C等位基因频率为8．5％，对照组为11．7％；两组差异无显著性（P＞0．05）；中国汉族人PD组组和对照组－141△C等位基因频率明显高于意大利南部人群，差异有显著性（P＜0．05）。结论中国汉族人群多巴胺D2受体基因启动子多态性与PD的遗传易感性无关，该多态性有明显的种族差异。     

DRD4第3外显子48 bp可变重复序列多态性与幼儿气质的相关研究

目的　探讨多巴胺 D4受体第 3外显子 48bp可变重复序列多态性 (dopamine D4receptorexon 48bp variant number tandem repeat,DRD4exon 48bp VNTR)与幼儿气质的关系。方法　采用聚合酶链反应和 VNTR多态性分析技术 ,检测了成都地区 2 34名汉族幼儿的 DRD4基因多态性 ;用 1～3岁幼儿气质量表测查其气质 ;根据 DRD4外显子 48bp VNTR等位基因重复片段大小分为 S组 (基因型中只含等位基因 2 )和 L 组 (基因型中至少含有一个等位基因 3或 5、9) ,对各组幼儿气质类型和气质纬度进行相关分析 ,统计方法采用 χ2检验和 t检验。结果　不同基因型幼儿其气质类型没有差异 (χ2 =0 .795 9,ν=3,P>0 .0 5 ) ;DRD4外显子 48bp VNTR长重复基因 (L)组幼儿气质纬度中的注意力分散度得分较低 (t=2 .95 5 ,P=0 .0 0 3)。结论　 DRD4外显子 48bp VNTR长重复等位基因与注意力分散度有关     

多巴胺D4受体和COMT基因多态性在精神分裂症患者攻击行为中的交互作用

目的:讨论多巴胺D4受体(DRD4)基因第3外显子48bp可重复序列多态性(exon Ⅲ 48 bp VNTR)和COMT val158met基因多态性及其交互作用对精神分裂症患者攻击行为的影响.方法:采用修改版外显攻击行为量表(MOAS)对301例精神分裂症患者进行分组,分为伴攻击行为组(研究组)和不伴攻击行为组(对照组),分别进行社会人口学资料、阳性和阴性症状量表(PANSS)测定,采用多聚酶链反应-限制性片断长度多态性技术检测DRD4 exon Ⅲ 48 bp VNTR 和 COMT val158met 基因多态性.采用 logistic 逐步回归分析 DRD4 exon Ⅲ 48 bp VNTR和COMT val158met基因多态性及其交互作用的效应.结果:除既往攻击行为史(t=13.118,P＜0.01)外,两组间社会人口学资料差异无统计学意义(P＞0.05);两组DRD4 exon Ⅲ 48 bp VNTR和COMT va1158met基因的等位基因及基因型频率分布比较均有统计学意义(X2＝13.232,14.384,9.108,4.436;P＜0.05);COMT Val/Met和DRD42/2/2、2/4、3/4基因型多态性的交互作用可影响精神分裂症的攻击行为,其OR值(95％CI)为0.195(0.042～0.918).结论:①DRD4 exon Ⅲ 48 bp VNTR和COMT val158met基因多态性可能与精神分裂症患者攻击行为存在关联;②COMT Val/Met和DRD42/2/2、2/4、3/4基因型多态性对精神分裂症攻击行为存在负交互作用.     

传统抗精神病药物所致迟发性运动障碍的药理遗传学初步研究

目的：进一步探讨多巴胺D2、D3受体（dopamine D2,D3 receptor,DRD2,DRD3)功能基因多态性与迟发性运动障碍(tardive dyskinesia,TD）的相关性及各候选基因，同时包括五羟色胺2C受体（5－hydroxytryptamine 2C receptor,HTR2C）和锰超氧化物歧化酶（manganese superoxide dismutase,MnSOD）基因的相互作用对TD发生的影响。方法：使用异常不自主运动量表（abnormal involuntary movement scale,AIMS)评定精神分裂症（schizophrenia,CSH)患者有无TD及其严重程度，并采用简明精神病评定量表评定患者精神症状；应用聚合酶链反应－限制性片段长度多态性技术分析TD组和非TD组各候选基因等位基因和（或）基因型分布频率及其结合分布频率，并分析对AIMS总分值的影响。结果：各候选基因在SCH患者组以及TD和非TD组基因型分布均符合Hardy-Weinberg平衡定律；TD组HTR2C基因－697C（突变型）等位基因频率高于非TD组，差异有显著性（P＜0．05）；DRD2基因Taq I A1/A2、DRD3基因Ser9Gly和MnSOD基因Ala-9Val等位基因频率和基因型分布在TD组与非TD组之间差异均无显著性（P＞0．05）；仅DRD3突变型（Gly）和MnSOD野生型（Val）结合分布频率高于其它结合型，差异有显著性（P＜0．05）；但上述各候选基因不同等位基因和（或）基因型亚组间的临床学资料和AIMS总分值（TD值）差异均无显著性（P＞0．05）。结论：HTR2C基因启动区－697G→C单碱基置换可能是中国汉族男性SCH患者TD发生的易感因素；而SCH患者若同时携带DRD3基因9Gly突变型和MnSOD基因－9Val野生型等位基因可能增加了TD的易感性。     

AKT1基因多态性与利培酮治疗精神分裂症8周疗效的关联研究

目的:探讨AKT1基因多态性与利培酮治疗首发、未用药精神分裂症8周后疗效的关联。方法:共入组150例符合美国精神障碍诊断与统计手册第4版(DSM-IV)诊断标准的汉族精神分裂症门诊或住院患者,其中完成利培酮(治疗剂量4~6 mg/d)治疗8周者为128例。采用治疗8周后阳性与阴性症状量表(PANSS)减分率评估药物疗效;采用DNA测序方法,在128例汉族精神分裂症患者中,检测AKT1基因4个单核苷酸多态性(SNP)位点(rs1130214、rs10149779、rs1130233、rs2494732)的基因型,并采用数量性状位点分析方法(QTL)探索AKT1基因多态性与利培酮治疗精神分裂症疗效的关联。结果:AKT1基因rs1130233(GA)及rs2494732多态性(CT)与利培酮治疗精神分裂症8周后PANSS减分率关联显著(P0.05),经多重检验Bonferroni校正后仍有统计学意义。而rs1130214与rs10149779在本样本中与利培酮疗效的关联无统计学意义(P0.05)。结论:本研究提示在中国汉族人群中,AKT1基因多态性可能与利培酮治疗精神分裂症急性期疗效关联,有望对个体化药物疗效预测提供依据。     

神经丛蛋白A2(PLXNA2)基因多态性与精神分裂症的关联研究

目的:探讨神经丛蛋白(PLXNA2)基因与汉族人群精神分裂症的关联。方法:采用DNA测序检测方法,依据ICD-10诊断标准,在735例汉族精神分裂症住院患者和1316例年龄、性别匹配的正常对照者中,探索PLXNA2基因5个单核苷酸多态性(SNP)位点与精神分裂症的关联。结果:PLXNA2基因的4个SNPs位点与精神分裂症关联(均P<0.05);由rs3811383-rs841865-rs2785622组成的单体型ATT及由rs841865-rs752016组成的单体型AC与精神分裂症关联(均P<0.05)。结论:本研究结果提示PLXNA2基因多态性在中国汉族人群中与精神分裂症关联。     

Association study of dopamine D3 receptor gene and schizophrenia

Several groups have reported an association between schizophrenia and the MscI polymorphism in the first exon of the dopamine D3 receptor gene (DRD3). We studied this polymorphism using a North American sample (117 patients plus 188 controls) and an Italian sample (97 patients plus 64 controls). In the first part of the study, we compared allele frequencies of schizophrenia patients and unmatched controls and observed a significant difference in the total sample (P = 0.01). The second part of the study involved a case control approach in which each schizophrenia patient was matched to a control of the same sex, and of similar age and ethnic background. The DRD3 allele frequencies of patients and controls revealed no significant difference between the two groups in the Italian (N = 53) or the North American (N = 54) matched populations; however, when these two matched samples were combined, a significant difference was observed (P = 0.026). Our results suggest that the MscI polymorphism may be associated with schizophrenia in the populations studied. © 1995 Wiley-Liss, Inc.     

Habit learning and the genetics of the dopamine D3 receptor: evidence from patients with schizophrenia and healthy controls

In this study, the authors investigated the relationship between the Ser9Gly (SG) polymorphism of the dopamine D3 receptor (DRD3) and striatal habit learning in healthy controls and patients with schizophrenia. Participants were given the weather prediction task, during which probabilistic cue-response associations were learned for tarot cards and weather outcomes (rain or sunshine). In both healthy controls and patients with schizophrenia, participants with Ser9Ser (SS) genotype did not learn during the early phase of the task (1-50 trials), whereas participants with SG genotype did so. During the late phase of the task (51-100 trials), both participants with SS and SG genotype exhibited significant learning. Learning rate was normal in patients with schizophrenia. These results suggest that the DRD3 variant containing glycine is associated with more efficient striatal habit learning in healthy controls and patients with schizophrenia.     

No association between the Ser9Gly polymorphism of the dopamine D3 receptor gene and schizophrenia in a Spanish sample.

This study aims to further evaluate the controversial association between the Ser9Gly polymorphism in codon 9 of the D3 dopamine receptor gene (DRD3) and schizophrenia in psychiatric inpatients acutely hospitalized in two general hospitals in Madrid, Spain. The Ser9Gly polymorphism of the DRD3 was examined in 178 schizophrenic patients, 286 patients with other psychiatric diagnoses, and 132 controls recruited. Genotype frequencies were in Hardy-Weinberg equilibrium. No association was found between schizophrenia and the Ser9Gly polymorphism of the D3 dopamine receptor gene.     

Dopamine receptor DRD3 codes for trait aggression as Mendelian recessive

The dopamine receptor gene DRD3 and in particular the single nucleotide polymorphism Ser9Gly has been extensively investigated and found to have potential association with a wide variety of conditions. These include essential tremor, unipolar and bipolar depression, as well as a loose association with schizophrenia. Evaluation of (1) these known associations with DRD3, (2) the recent finding of Costas and colleagues that a haplotype containing Ser-9 is associated with protection from schizophrenia, and (3) an extant trait model of personality, leads to the hypothesis that an allele DRD3/Ser codes for trait aggression by Mendelian recessive inheritance. The implications of this hypothesis are that (1) DRD3 is a pleiotropic gene having allelic polymorphism related to both behavior and disease, and (2) models of personality based on genetic traits hold promise. In the area of schizophrenia, the hypothesis implies that schizophrenic patients can be divided into two broad classes: those having genotype DRD3/Ser/Ser and those who lack this homozygosity. The hypothesis of the association of DRD3 with trait aggression could be readily evaluated by testing groups of healthy individuals by personality inventory focused on aggression and by biochemical assay of neurotransmitter levels.     

Effect of chronic activation of 5-HT3 receptors on 5-HT3, 5-HT(1A) and 5-HT(2A) receptors functional activity and expression of key genes of the brain serotonin system

The dopamine D3 receptor gene (DRD3) is considered being one of the candidate genes contributing to the development of tardive dyskinesia (TD). In a recent meta-analysis with mixed ethnicities, only a barely positive association was found between the functional DRD3 Ser9Gly polymorphism and TD in patients with schizophrenia (OR = 1.17; 95% CI: 1.01-1.37; p = 0.041). To further evaluate the controversial association between the polymorphism and TD using only Japanese subjects, we tested the association in a case-control design. We also conducted a meta-analysis including 8 studies with 3 East Asian populations (Japanese, Chinese, and Korean). In our Japanese case-control sample (43 with TD/157 without TD), we found no association between the DRD3 Ser9Gly polymorphism in schizophrenia and TD (genotype: p = 0.92; allele: p = 1.00). Furthermore, no significant difference in the mean AIMS score among the three genotypic groups was observed in our sample. The meta-analysis comprising 1291 East Asian subjects also showed no association between the polymorphism and TD; the Mantel-Haenszel pooled OR for TD among carriers of the DRD3 Ser9Gly of the eight Asian studies was 0.94 (95% CI: 0.78-1.12). Overall, our results suggest that the DRD3 Ser9Gly polymorphism may not confer susceptibility to TD in East Asian populations. Given that the Ser9Gly variant may play a putative role in the DRD3 function, further studies on the DRD3 are warranted.     

Trend for an association between schizophrenia and D3S1310, a marker in proximity to the dopamine D3 receptor gene.

There is considerable controversy regarding a putative association between schizophrenia and a biallelic BalI polymorphism in the first exon of the dopamine D3 receptor gene (DRD3), although meta-analyses of published data suggest an association. If such an association exists, it may be detectable at markers physically close to DRD3. Accordingly, we conducted a case-control association study using D3S1310, a short tandem repeat polymorphism located approximately 700 kb telomeric to DRD3 on chromosome 3q13.3. The subjects were Swedish patients with schizophrenia (DSM III-R criteria, n = 110) and screened adult controls (n = 83). A trend for a negative association with the 141 bp allele was detected (chi2 = 7.6, d.f. = 1, P = 0.006; odds ratio 0.46, 95% confidence intervals 0.26, 0.81). However, following corrections for multiple comparisons using subgroups (n = 15) the difference was not significant. Also, due to the risk for population stratification in case-control association studies the results must be treated as tentative. If replicated the results may lend further support for the proposition of an association between schizophrenia and DRD3 or a gene in close proximity to DRD3 on chromosome 3q.     

No association between a promoter dopamine D(4) receptor gene variant and schizophrenia

The dopamine D(4) receptor has been implicated in the pathogenesis of schizophrenia. An association between a putative functional promoter polymorphism (-521C/T) in the dopamine D(4) receptor gene (DRD4) and schizophrenia was recently reported. In the present study, patients with schizophrenia (n = 132) and control subjects (n = 388) were analyzed with respect to the DRD4 - 521C/T polymorphism. No significant case control differences emerged. The present results do not support a major role for DRD4 in the etiology of schizophrenia among Caucasians from Sweden.     

Dopamine D1 receptor gene polymorphism and schizophrenia in Japan

We studied the relationship between schizophrenia and the DdeI polymorphism in the 5' untranslated region (5'UTR) of the dopamine D1 receptor (DRD1) gene. This polymorphism is an A (A1 allele) to G (A2 allele) transition in the 5' UTR of exon 2 at bp -48 (A-48G). One hundred forty-eight schizophrenics and 148 control subjects were investigated. No significant differences in genotypic counts and allele frequencies between schizophrenics and controls were found. Although a significant difference between the patients classified as disorganized type and the controls was discovered both in genotypic counts and allele frequencies, neither association proved significant when a Bonferroni correction was used. Moreover, there were no differences in scores of main symptoms of schizophrenia based on the Manchester Scale between patients with A1/A1 genotype and those with A1/A2 genotype. These findings suggest that this gene may not be involved in the pathogenesis of schizophrenia.     

Converging evidence implicates the dopamine D3 receptor gene in vulnerability to schizophrenia

The dopamine D3 receptor has been implicated in the pathophysiology of schizophrenia (SZ). A glycine‐to‐serine polymorphism at codon 9 of the dopamine D3 receptor gene (DRD3), rs6280, has been widely studied for its association with SZ, but with conflicting results. Altered levels of DRD3 mRNA have also been reported in SZ compared with normal controls. Moreover, it has been suggested that DRD3 is subject to recent positive selection in European populations. To explore the potential role of DRD3 in SZ from these various aspects, we conducted a threefold study. First, we tested the genetic association of rs6280 with SZ in 685 SZ patients and 768 normal controls. Second, we examined DRD3 mRNA levels in peripheral leukocytes in a subset of 37 patients and 37 controls. Finally, we investigated the possible recent positive selection on DRD3 in an East Asian population. Consequently, we observed that the genotypic distribution of rs6280 was nominally associated with SZ (P = 0.045), with the ancestral CC genotype being significantly over‐represented in SZ patients. DRD3 mRNA levels were significantly lower in patients than in controls (P = 5.91E?5). The derived C‐allele of rs6280 might have been subject to recent positive selection (P < 0.001) in the East Asian population. Taken together, our results suggest that DRD3, a gene possibly under natural selection, might be involved in vulnerability to SZ in the Han Chinese population. These findings may further add to the body of data implicating DRD3 as a schizophrenia risk gene. © 2011 Wiley‐Liss, Inc.