DTNBP1基因与精神分裂症

本文就DTNBP1基因与精神分裂症的关联作一综述。     

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.     

DTNBP1基因多态性与精神分裂症的研究进展

精神分裂症是以严重的精神障碍为特征的复杂疾病之一,发病机制尚未明确.研究表明该病由多个微效基因与环境因素共同作用导致,遗传因素发挥更至关重要的作用.DTNBP1基因作为精神分裂症的易感基因之一,对谷氨酸、多巴胺等神经递质具有调控作用,与神经递质假说密切相关.目前,国内外已广泛研究DTNBP1基因单核苷酸多态性与精神分裂...     

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。     

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。     

Neuregulin-1基因与精神分裂症

nrg-1基因定位于8p2．1-p1．2,它编码的NRG-1蛋白属于表皮生长因子相关蛋白家族,通过与体内受体型酪氨酸蛋白激酶（ErbB）结合,对神经元存活、发育、迁移及髓鞘形成、突触可塑性及功能行使有重要作用,且与谷氨酸能神经元、多巴胺能神经元及GABA能神经元功能密切联系,成为研究精神分裂症重要且有希望的候选基因。     

精神分裂症患病同胞基因型配对分析研究

为验证精神分裂症基因位于性染色体假常染色体区域的假说，选取了７３组精神分裂症患病同胞和其父母为试验对象，以位于性染色体假常染色体区域ＤＸＹＳ１４基因座的探针ｐ２９Ｃ１进行了限制性片断长度多态性的探测，并以该探针划分的单体型进行了患病同胞基因型配对分析。在ＤＸＹＳ１４基因座附近，父母的等位基因在精神分裂症患病同胞中的分离与假设无连锁前提下的理论预计有明显的差异（Ｐ＝０．００８７）。此试验结果在一定程度上支持精神分裂症基因位于性染色体假常染色体区域的假说     

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.     

精神分裂症候选易感基因分子遗传学进展

本文从连锁分析、相关分析、染色体及其它相关的研究途径,综述了近年来手边文献报道的精神分裂症候选易感基因的分子遗传学进展.     

精神分裂症的遗传学及基因定位

精神分裂症的发生与生物、社会及心理等因素有关。在生物因素中，遗传起着尤为重要的作用；其遗传形式有多种，如显性遗传、隐性遗传及多基因遗传模式等。在对精神分裂症的家系调查、双生子及寄养子研究中显示，精神分裂症的患病率在不同人种及种族之间无明显差异(约为1％)，但在患者亲属中的患病率却比一般人群高得多；并且与患者的血     

Untranslated region haplotype in dysbindin gene: analysis in schizophrenia

Summary. Genome-scans performed in schizophrenia families have provided evidence for region 6p24-21 where variability may confer susceptibility to schizophrenia. Recent studies have implicated that gene DTNBP1 (dysbindin) in this region is strongly associated with schizophrenia. In a family based association study we investigated three markers located in the untranslated region of the DTNBP1 gene: rs909706, rs1047631 and rs742106. The sample size of our study is 117 families. No biased transmission towards the disorder was detected by haplotype analysis using TRANSMIT.     

Strong evidence for association between the dystrobrevin binding protein 1 gene (DTNBP1) and schizophrenia in 488 parent-offspring trios from Bulgaria.

BACKGROUND: The gene encoding the dystrobrevin binding protein (DTNBP1) has been implicated in the pathogenesis of schizophrenia by several association studies. We tried to replicate these findings in a sample of 488 parent-proband trios recruited in Bulgaria. Probands had a diagnosis of schizophrenia (n = 441) or schizoaffective disorder (n = 47). METHODS: We genotyped eight single nucleotide polymorphisms within the gene, four of which had been reported in previous studies, and four identified as informative by our group through direct screening of the gene and genotyping in a sample of cases and control subjects. RESULTS: A significant excess of transmissions was observed for two of the markers, p1635 and p1757, (p =.0009 and.0013, respectively). Analysis of two-, three-, and four-marker haplotypes produced numerous positive results, with six (4% of the total combinations) at p <.001. CONCLUSIONS: These results provide strong support for DTNBP1 as a susceptibility gene for schizophrenia; however, different haplotypes seem to be associated in different studies.     

Association between the dysbindin gene (DTNBP1) and cognitive functions in Japanese subjects

Aim:  The dysbindin gene (dystrobrevin binding protein 1: DTNBP1 ) is a susceptibility gene for schizophrenia. Susceptibility genes for schizophrenia have been hypothesized to mediate liability for the disorder at least partly by influencing cognitive performance. This report investigated the relationship between cognitive function and the dysbindin gene.
Methods:  The possible association between a single nucleotide polymorphism (SNP) of DTNBP1 (rs2619539: P1655), which is a risk-independent SNP for schizophrenia in Japanese populations, and memory and IQ was investigated in 70 schizophrenia patients and 165 healthy volunteers in a Japanese population.
Results:  This SNP was associated with two memory scales, verbal memory and general memory, on the Wechsler Memory Scale–Revised (WMS-R), and three subcategories of the Wechsler Adult Intelligence Scale–Revised (WAIS-R), vocabulary, similarities and picture completion in healthy subjects. The SNP, however, did not influence either the indices of WMS-R, IQ or subcategories of WAIS-R in schizophrenia patients.
Conclusion:  A risk-independent SNP in DTNBP1 may have an impact on cognitive functions such as memory and IQ in healthy subjects.     

Association between schizophrenia and the syntaxin 1A gene.

BACKGROUND: Both microarray and candidate molecule studies have demonstrated that protein and mRNA expression of syntaxin and other genes involved in synaptic function are altered in the cerebral cortex of patients with schizophrenia. METHODS: Genetic association between polymorphic markers in the syntaxin 1A gene and schizophrenia was assessed in a matched case-control sample of 192 pairs, and in an independent sample of 238 nuclear families. RESULTS: In the family-based sample, a significant genetic association was found between schizophrenia and one of the four single nucleotide polymorphisms (SNPs) tested: an intron 7 SNP (transmission disequilibrium test [TDT] chi(2) = 5.898; df = 1; p =.015, family-based association test [FBAT] z = 2.280, p =.023). When the results for the TDT and case-control analyses were combined, the association was stronger (n = 430; z(c) = 2.859; p =.004). Haplotype analysis supported the association with several significant values that appear to be driven by the intron 7 SNP. Conclusions: The results should be treated with caution until replicated, but this is the first report of a genetic association between syntaxin 1A and schizophrenia.     

A linkage study of schizophrenia to markers within Xp11 near the MAOB gene

A sex chromosome locus for psychosis has been considered on the basis of some sex differences in genetic risk and expression of illness, and an association with X-chromosome anomalies. Previous molecular genetic studies produced weak evidence for linkage of schizophrenia to the proximal short arm of the X-chromosome, while some other regions were not ruled out. Here we report an attempt to expand the Xp findings in: (i) a multicenter collaboration focusing on 92 families with a maternal pattern of inheritance (Study I.); and (ii) an independent sample of 34 families unselected for parental mode of transmission (Study II.). In the multicenter study, a parametric analysis resulted in positive lod scores (highest of 1.97 for dominant and 1.19 for recessive inheritance at a theta of 0.20) for locus DXS7, with scores below 0.50 for other markers in this region (MAOB, DXS228, and ARAF1). Significant allele sharing among affected sibling pairs was present at DXS7. In the second study, positive lod scores were observed at MAOB (highest of 2.16 at a theta of 0.05 for dominant and 1.64 at a theta of 0.00 for recessive models) and ALAS2 (the highest of 1.36 at a theta of 0.05 for a recessive model), with significant allele sharing (P=0.003 and 0.01, respectively) at these two loci. These five markers are mapped within a small region of Xp11. Thus, although substantial regions of the X-chromosome have been investigated without evidence for linkage being found, a locus predisposing to schizophrenia in the proximal short arm of the X-chromosome is not excluded. © 1997 Elsevier Science Ireland Ltd.     

多巴胺D3受体基因多态性与精神分裂症

目的:探讨沈阳地区汉族人群中多巴胺D3受体基因(DRD3)第一外显子第9密码子A→G单核苷酸置换多态性(Ser9Gly多态)与精神分裂症的关联。方法:采用聚合酶链反应-限制性内切酶片断长度多态性(PCR-RFLP)技术对70例精神分裂症患者、94名健康对照者进行基因分型鉴定。比较患者组与对照组DRD3多态性分布频率、精神分裂症早发组与非早发组基因分布频率差异,并与其他国家人群进行比较。结果:患者组与对照组之间等位基因分布无明显差异,早发组与非早发组亦未发现明显差异,而该位点等位基因分布频率与巴西、英国人群有明显差异。结论:研究人群中未发现DRD3基因Ser9Gly多态与精神分裂症存在明显关联。     

Interleukin-1 beta gene polymorphism and its interactions with neuregulin-1 gene polymorphism are associated with schizophrenia

Interleukin-1β (IL-1β) and neuregulin-1 (NRG-1) have an important role in development of the central nervous system. Several recent studies suggest that their genetic polymorphisms are associated with schizophrenia. We studied the effects of the IL-1β gene (IL-1B) -511 and NRG-1 SNP8NRG221533 polymorphisms and their interactions on the risk and age of onset of schizophrenia in 113 Finnish schizophrenic patients and 393 healthy controls. The allele and genotype frequencies of IL-1B and NRG-1 did not differ between schizophrenic patients and healthy controls, but the risk of schizophrenia was more than 10 times higher (odds ratio 10.20, 95% CI 2.53–41.09, p = 0.001) among subjects with the IL-1B 2.2, NRG-1 CC genotypes compared to subjects with the IL-1B 2.2, NRG-1 T-allele carriage. There was also a trend for an association between the interaction between IL-1B and NRG-1 polymorphisms and the age at onset of schizophrenia (χ² = 2.80; df = 1; p = 0.09, log rank test). IL-1B-511 allele 1 homozygotes had a significantly higher age of onset than allele 2 carriers (mean age of onset 25.9 ± 7.7 and 22.7 ± 5.4 years, t-test: t = 2.46; p = 0.032). Our results suggest that there is an interaction between the IL-1B and NRG-1 genes in schizophrenia. In addition, the IL-1B-511 polymorphism seems to be associated with the age at onset of schizophrenia.     

精神分裂症与G72基因多态性的关联分析

目的:探讨精神分裂症与G72基因多态性的关系,是否有混合家族史精神分裂症在G72基因多态性的区别。方法:采用聚合酶链反应技术分别检测162例无混合家族史精神分裂症、62例有混合家族史精神分裂症、88名正常对照的G72基因单核苷酸多态性rs947267、rs2181953,进行关联分析。结果:不同性别及发病年龄的无混合家族史精神分裂症组与对照组rs947267、rs2181953基因型及等位基因分布差异均无显著性(P均>0.05);不同性别及发病年龄的有混合家族史精神分裂症组与对照组rs947267基因型及等位基因分布差异无显著性(P>0.05);不同性别及早发型(发病年龄≤25岁)有混合家族史精神分裂症组与对照组rs2181953基因型及等位基因分布差异无显著性(P>0.05);晚发型(发病年龄>25岁)有混合家族史精神分裂症与对照组rs2181953基因型及等位基因分布差异显著(χ2=9.121,P=0.01与χ2=6.804,P=0.01),基因型A/A、T/T及等位基因A、T的OR值分别为7.083(P=0.007)、0.357(P=0.049)、2.531(P=0.009)、0.395(P=0.009)。结论:G72基因多态性可能与晚发型有混合家族史精神分裂症存在关联,其中rs2181953的A/A基因型与A等位基因是危险因子。