NMDA受体NR1亚单位基因与精神分裂症的连锁分析

目的了解N-甲基-D-天冬氨酸(NMDA)受体NR1亚单位基因与精神分裂症的连锁关系。方法选取NR1亚单位基因所在区域的2个微卫星标记D9s1838和D9s1826,对94个符合美国精神障碍诊断与统计手册第4版精神分裂症诊断标准(DSM-Ⅳ)的中国汉族精神分裂症受累同胞对及家系成员共376个个体作基因分型,其中男性194名,女性182名。采用美国国立精神卫生研究所(NIMH)制订的《遗传研究诊断问卷》(DIGS),对家系成员躯体和精神状况进行评定;采用NIMH制订的《遗传研究家族问卷》(FIGS)了解家系结构。选用GENEHUNTER2.1软件对分型资料进行非参数连锁分析。结果两点、多点非参数分析最大LOD值均位于D9s1826,分别为1.70(P=0.050),2.08(P=0.015),两者均大于验证性连锁阈值1.2。结论NR1基因区域微卫星标记与精神分裂症存在验证性连锁关系,提示NR1基因可能为精神分裂症的易感基因之一。     

20个精神分裂症同胞对家系N-甲基-D-天冬氨酸受体基因的连锁研究

目的：了解兴奋性氨基酸N-甲基-D-天冬氨酸（NMDA）受体基因与精神分裂症的连锁关系。方法：选取NMDA受体4个亚单位基因附近的微卫星标记，对20个精神分裂症受累同胞对家系共83个个体作基因分型，其中男43名，女40名，患病同胞对20对40例。采用受累家系成员法（ASP）对分型资料进行连锁分析。结果：NMDA受体亚单位基因NMDAB2A位点16p13.2附近的微卫星标记D16s3075的优势对数值（LOD值）为0.81，NMDAR2B位点12p12附近的标记D12s1617的LOD值为0.47，其余位点附近的10个微卫星标记与前2个标记一样，其LOD值均未达到提示性连锁的阈值（LOD=2.2）。结论：未能肯定NMDA受体基因与精神分裂症的连锁关系，但亦不能排除该基因与精神分裂症的相关性。     

DTNBP1基因与精神分裂症

目的:了解DTNBP1基因与精神分裂症的连锁关系.方法:选取DTNBP1基因附近的微卫星标志D6s 289,对81个符合美国精神障碍诊断与统计手册第4版诊断标准的精神分裂症受累同胞对及 家系成员共324个个体作基因分型,其中男166例,女158例,患病同胞对81对162例.对分型资料进行非参数连锁分析和传递不平衡分析.结果:两点非参数分析Lod值为0.697 57(P=0.264 885),传递不平衡分析无阳性发现.结论:未能肯定DTNBP1基因是否为精神分裂症的易感基因之一.     

2个精神分裂症多发家系GRM3基因多态性位点的连锁研究

目的 探讨代谢型谷氨酸受体3亚型(GRM3)基因与精神分裂症的连锁关系.方法 收集到2个精神分裂症多发家系共54个个体,其中9个受累个体,选取GRM3基因附近3对微卫星标记引物(D7S644、D7S2555、D7S2481),采用两点和多点非参数连锁(NPL)分析对这2个家系进行遗传学分析.结果 D7S644两点NPL值为0.953(P=0.095),多点NPL值为1.672(P=0.046),达到验证性连锁的阈值.D7S2555两点和多点NPL值分别为0.079(P=0.331)和0.234(P=0.286),D7S2481两点和多点NPL值分别为0.438(P=0.225)和0.629(P=0.159).结论 GRM3基因位点可能与精神分裂症存在相关.     

一个精神分裂症多发家系染色体候选区域的连锁分析

目的 探讨1q21-22，1q32-44，5q21—33，6p24—22，8p22—21，10p15—11，11q23—24，11p15，12q23—24，13q32—34，22q11—12，9q34，16p13，12q13，17q25及19q13等染色体候选区域与精神分裂症的连锁关系。方法 选择候选染色体区域的微卫星标志，对湖南省永州市一个汉族精神分裂症多发家系进行基因组扫描。用Linkage5．1软件包及Genehunter2．1软件包进行参数和非参数连锁分析，并构建最可能的单体型。结果在染色体11q23．2-24．2区域获得3个连续高的多点非参数分析LOD值，在D11s925处获得的峰值为4．33（P=0．016），超过显著性连锁的阈值。与D11s925相邻的D11s898及D11s4151在多点非参数分析中的LOD值分别为1．57和3．82。对11号染色体上的6个微卫星标志进行单体型分析，D11s902与D11s898之间存在重组，提示可能的疾病基因在D11s902远端。结论 11q22．1-24．2区域可能包含有精神分裂症的易感基因。     

3个单纯型发作性运动诱发性运动障碍家系的致病基因定位

目的 在3个中国汉族单纯型发作性运动诱发性运动障碍(paroxysmall kinesigenic dyskinesia,PKD)家系中确定其疾病基因所在区域.方法 在已知的PKD连锁区域16p12.2-q22.3选取14个微卫星遗传标记对37位家庭成员进行基因分型,用Linkage和Genehunter等软件进行连锁分析并构建疾病单倍型.结果 连锁分析及单倍型分析将致病基因定位于D16S3133～D16S3044(16p12.1-q12.1)之间11.2 cM的区域.结论 3个汉族单纯型PKD家系的致病基因被定位于D16S3133～D16S3044(16p12.1-q12.1)之间,与最初的婴儿惊厥及阵发性舞蹈手足徐动症(infantile convulsions and paroxysmal clboreoathetosis,ICCA)的位点重叠.     

同胞精神分裂症与5-羟色胺2A受体基因的关联分析

目的 探讨慢性精神分裂症患者的受累同胞和散发性精神分裂症与5-羟色胺2A受体基因(5-HT2A)T102C多态性的关联。方法 先用严格的纳入标准收集共患慢性精神分裂症的同胞60对(120例)和散发性精神分裂症120例,分别与正常同胞60对(120名)和120名正常人对照,采用聚合酶链反应(PCR)扩增及MspI内切酶酶切技术,检测各组的5-HT2A受体基因的基因型和等位基因的频率分布。结果 60对共患慢性精神分裂症的受累同胞组5-HT2A受体基因A1／A1基因型频率显著高于正常同胞组(X2=5.58,P<0.05),经配对比较,患者同胞组共有A1／A1基因型也显著多于正常同胞组(X2=3.94,P<0.05),而散发性精神分裂症与正常人对照组各基因型和等位基因的构成差异均无显著性意义。结论 共患慢性精神分裂症的同胞与5-HT2A受体基因A1／A1型关联,A1／A1纯合子易患精神分裂症,散发性精神分裂症可能与5-HT2A受体基因无关联。     

DTNBP1基因与精神分裂症的连锁分析

目的:探讨DTNBP1基因与精神分裂症的连锁关系。方法:收集到2个精神分裂症多发家系共54个个体,其中9个受累个体的血样,选取DTNBP1基因附近4对微卫星标记引物(D6S422、D6S289、D6S276、D6S309),采用两点和多点非参数连锁(NPL)分析和Genohunter 2.1软件对这2个家系进行遗传学分析。结果:D6S276两点NPL值为0.978(P=0.086),多点NPL值为1.033(P=0.069),未达到验证性连锁的阈值。D6S422两点和多点NPL值分别为0.154和0.204(P均>0.05);D6S289两点和多点NPL值分别为0.457和0.685(P均>0.05),D6S309两点和多点NPL值分别为0.221和0.324(P均>0.05)。结论:未能验证DTNBP1基因与精神分裂症的连锁关系,但亦不能排除该基因与精神分裂症的相关性。     

递质受体相关候选基因与强迫谱系障碍

目的:了解多巴胺D2受体(DRD2)基因、D3受体(DRD3)基因、D4受体(DRD4)基因、多巴胺转运体(DAT1)基因、儿茶酚胺氧位甲基转移酶(COMT)基因、5-羟色胺2A受体(5-HTR2A)基因、5-羟色胺转运体(5-HTT)基因等与强迫谱系障碍(OCSDs)的连锁关系。方法:选取一个连续3代发病的强迫谱系障碍家系,共20名,量表采用遗传研究诊断问卷(DIGS)及遗传研究家族问卷(FIGS)。采集该家系中12个正常个体,8个受累个体的血样,选取DRD2、DRD3、DRD4、DAT1、COMT、5-HTR2A、5-HTT基因附近27对微卫星标记引物,采用两点和多点非参数分析的方法对该家系进行连锁分析。结果:27对微卫星标记位点的两点和多点非参数分析LOD值(NPL值)均未达到验证性连锁的阈值(NPL=1.2)。结论:未能验证DRD2、DRD3、DRD4、DAT1、COMT、5-HTR2A、5-HTT基因与OCSDs的连锁关系,但亦不能排除这些基因与OCSDs的相关性。     

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。     

Increased prevalence of schizophrenia spectrum disorders in relatives of neuroleptic-nonresponsive schizophrenic patients

OBJECTIVE: It is suggested that schizophrenic patients who respond to neuroleptic medication and those who do not might differ with respect to their pathogenesis. In particular, it has been proposed that genetic factors may contribute to treatment response and/or outcome. In order to test this hypothesis, we compared the pattern of familial aggregation of schizophrenia related disorders in schizophrenic patients who are either responders (R) or nonresponders (NR) to typical neuroleptics. METHOD: R (n=36) or NR (n=35) patients to typical neuroleptics and healthy controls (n=63) were recruited. At least one key informant relative of each proband was interviewed blind as to the status of the proband using the Family Interview for Genetic Studies. Morbid risk for schizophrenia and cluster A personality disorders and family loading score for schizophrenia were examined in first- and second-degree relatives of these probands. RESULTS: First-degree relatives of NR patients were at a significantly higher risk for schizophrenia (MR=8.84), compared, respectively, to relatives of controls (MR=1.52) or relatives of R patients (MR=2.45). The same pattern was observed in second-degree relatives. Family loading score for schizophrenia in first- and second-degree relatives was significantly higher in NR compared to R patients. CONCLUSIONS: Schizophrenic patients who do not respond to typical neuroleptics may suffer from a more familial form of schizophrenia compared to patients who are responders.     

Morbidity risk of psychiatric disorders among the first degree relatives of schizophrenia patients in Taiwan

This study aimed to assess the boundaries of the schizophrenia spectrum and whether inclusion of such phenotypes increases power for linkage analysis of schizophrenia. Participants were 234 first degree relatives (FDRs) of 94 schizophrenia probands in Northern Taiwan who completed a direct interview using the Diagnostic Interview for Genetic Studies (DIGS). Based on best estimate diagnosis, the morbidity risk in the relatives for schizophrenia was 2.5 percent (Weinberg's shorter method) or 3.9 percent (Kaplan-Meier estimate). Depending on the stringency of diagnosis, lifetime prevalence was 2.6 percent to 4.7 percent for schizotypal personality disorder, 3.4 percent to 8.6 percent for paranoid personality disorder, and 1.3 percent to 3.4 percent for schizoid personality disorder. These figures are significantly higher than the corresponding figures in the general population. However, none of the recurrence risk ratio for any spectrum that included both schizophrenia and a personality disorder (3.0 to 5.9) was greater than that of schizophrenia alone (9.3 to 14.4). Thus, including schizophrenia-related personality disorders in the spectrum did not increase power for linkage analysis of schizophrenia.     

情感性精神障碍与5-羟色胺转运体基因的连锁不平衡研究

目的探讨情感性精神障碍与5-羟色胺转运体(5-HTT)基因之间的分子遗传学联系：方法以中国汉族人群中的72个情感性精神障碍核心家系(双相情感性精神障碍56例，重性抑郁症34例)作为研究对象，采用自编家系调查表、美国精神障碍诊断与统计手册第4版诊断标准并结合心理测评工具，应用聚合酶链反应(PCR)和限制性片段长度多态性分析方法，检测其5-HTT基因启动子区(5-HTTLPR)、第2内含子[数目可变的顺向重复(VNTR)]和3’端非编码区(3’UTRG／T)基因多态性，并进行连锁不平衡(TDT)分析。结果5-HTT基因中的VNTR与3’UTRG／T2个位点组合单体型与情感性精神障碍存在关联(TDT-x^2=4．08，经Monte Carlo逼真法1000次重复校正后的经验P值=0．04)，其他各位点5-HTTLPR、VNTR、3’UTRG／T等位基因与情感障碍未发现存在连锁不平衡，其他位点组合的单体型分析也未发现存在连锁不平衡。结论5-HTT基因在情感性精神障碍的遗传病因中可能起着一定作用。     

Project among African-Americans to explore risks for schizophrenia (PAARTNERS): recruitment and assessment methods

The Project among African-Americans to Explore Risks for Schizophrenia (PAARTNERS) is a multi-site, NIMH-funded study that seeks to identify genetic polymorphisms that confer susceptibility to schizophrenia among African-Americans by linkage mapping and targeted association analyses. Because deficits in certain dimensions of cognitive ability are thought to underlie liability to schizophrenia, the project also examines cognitive abilities in individuals affected by schizophrenia and their extended family members. This article describes PAARTNERS study design, ascertainment methods and preliminary sample characteristics. We aim to recruit a sample of 1260 African-American families, all of whom have at least one proband with schizophrenia or schizoaffective disorder. The data collection protocol includes a structured Diagnostic Interview for Genetic Studies, Family Interview for Genetic Studies, focused neurocognitive assessment, medical records review, and the collection of blood or buccal cells for genetic analyses. We have currently completed study procedures for 106 affected sib-pair, 457 case-parent trio and 23 multiplex families. A total of 289 probands have completed the best estimate final diagnosis process and 1153 probands and family members have been administered the computerized neuropsychological battery. This project lays the foundation for future analysis of cognitive and behavioral endophenotypes. This novel integration of diagnostic, neurocognitive and genetic data will also generate valuable information for future phenotypic and genetic studies of schizophrenia.     

Concurrent validation of schizotaxia: a pilot study.

BACKGROUND: Many first-degree relatives of patients with schizophrenia show deficits in clinical, neuropsychological, neurobiological and social domains, in the absence of psychosis. We recently reformulated Meehl's concept of schizotaxia to conceptualize the liability to schizophrenia, and we proposed preliminary criteria based on the presence of negative symptoms and neuropsychological deficits. Here we investigate the concurrent validity of schizotaxia by comparing a group of subjects who met criteria for schizotaxia with a group who did not on independent measures of clinical function, and on lifetime rates of selected comorbid psychiatric disorders. METHODS: Twenty-seven adults who were first-degree, biological relatives of patients with schizophrenia were evaluated for schizotaxia based on our predetermined criteria involving negative symptoms and neuropsychological deficits. Subjects also received portions of the Diagnostic Interview for Genetic Studies, the Structured Interview for Schizotypy, the Family Interview for Genetic Studies, the DSM-IV Global Assessment of Functioning, the Physical Anhedonia Scale, the Social Adjustment Scale and the Symptom Checklist-90-Revised. Subjects who met criteria for schizotaxia were compared with those who did not on each of the clinical measures, and on their rates of comorbid DSM-IV psychiatric diagnoses. RESULTS: Eight subjects met criteria for schizotaxia, and 19 did not. Subjects with schizotaxia showed significantly lower levels of function on each of the clinical scales. Differences in comorbid psychiatric diagnoses were not significant, although the rate of lifetime substance abuse diagnoses in the schizotaxic group (50%) approached levels that are often seen in schizophrenia. CONCLUSIONS: These findings provide the first evidence of concurrent validation for a proposed syndrome of schizotaxia. They are also consistent with the view that the vulnerability to schizophrenia may be defined, at least partially, although larger studies to assess both the concurrent and predictive validity of schizotaxia will be required to confirm these results.     

Handedness and schizotypy in non-psychotic relatives of patients with schizophrenia

Existing studies have found the relationship between handedness and schizotypy to be inconsistent, and had limited generalisability since only highly homogeneous groups have been investigated. This study aimed to examine the relation between handedness and the four schizotypal factors identified from a previous confirmatory factor analysis in a population of high familial loading for schizophrenia. Study participants consisted of non-psychotic first-degree relatives (850 parents and 334 siblings) of sib-pairs who were co-affected with schizophrenia. All participants were interviewed with the Diagnostic Interview for Genetic Studies, which contains a section of the modified Structured Interview for Schizotypy, and the Annett handedness questionnaire. Both categorical and continuous indicators for handedness were examined. Non-right-handed siblings of schizophrenia patients displayed more positive schizotypal features than their right-handed counterparts when the two-way Annett's handedness classification was adopted. No association was found when handedness was treated as continuous. The relationship between handedness and schizotypy was insignificant for parents probably due to the strong social pressure against left-handedness. We concluded that categorical non-right-handedness was associated with positive schizotypy in non-psychotic siblings of schizophrenia patients. The results indicate that an atypical cerebral lateralisation underlying non-right-handedness may be also a contributing factor to positive schizotypy.     

Familial aggregation of delusional proneness in schizophrenia and bipolar pedigrees

OBJECTIVE: Clinical, familial, and, more recently, genetic linkage studies suggest that overlapping genetic susceptibility might contribute to both schizophrenia and bipolar disorder. To identify a potential psychotic dimension common to families of both bipolar and schizophrenia probands, the authors tested if delusional proneness was observed among first-degree relatives of bipolar and schizophrenia probands. METHOD: The authors included 32 schizophrenia probands and 61 bipolar probands and their respective first-degree relatives (N=63 and N=59). They were all interviewed with the Diagnostic Interview for Genetic Studies, and delusional proneness was assessed with a self-report questionnaire, the Peters et al. Delusions Inventory. Schizophrenia and bipolar probands were subdivided into subgroups according to the intensity of delusional symptoms assessed by Peters et al. Delusions Inventory scores, and the authors compared delusional proneness in their respective first-degree relatives. RESULTS: Familial aggregation of delusional proneness was demonstrated, since Peters et al. Delusions Inventory scores were higher among nonschizophrenic first-degree relatives of schizophrenia probands with productive symptoms and among first-degree relatives of bipolar probands with psychotic features during their affective episodes. The authors also found an intrafamilial correlation of delusional proneness scores in nonaffected siblings of schizophrenia and bipolar probands. CONCLUSIONS: Delusional proneness appears to be an inherited predisposition common to both schizophrenia and bipolar disorder. In the future, this dimension might be valuable when used as a quantitative phenotype in linkage and association studies.