DVL2基因多态性与中国汉族人群先天性脊柱侧凸遗传易感性的关联研究*☆◇

背景：近20年来小鼠的分子胚胎学研究进展获得了大量关于脊椎发育的分子信息,用同线性分析法确立先天性脊柱侧凸的候选基因已成为可能。 目的：通过候选基因DVL2上关键单核苷酸多态性位点的筛查,探索DVL2与中国汉族人群先天性脊柱侧凸及其不同临床表型之间的关联。 方法：采用病例-对照研究,入选127例中国汉族先天性脊柱侧凸患者和127例对照组。根据国际人类基因组单体型图计划提供的基因型数据,应用Haploview 4.1软件选取DVL2的标签和功能单核苷酸多态性。根据椎体畸形特点、畸形部位、畸形受累程度、有无合并肋骨畸形和椎管内畸形将病例组进一步分为不同临床表型。对所有样本应用SNPstream UHT Genotyping系统对所选单核苷酸多态性位点进行基因型鉴定;进一步进行基于基因型/等位基因频率的关联分析,并用Haploview 4.1软件分析对照组单核苷酸多态性位点间是否存在连锁不平衡。 结果与结论：共筛选5个位点：单核苷酸多态性1(rs2074222)、单核苷酸多态性2(rs222837)、单核苷酸多态性3(rs222835)、单核苷酸多态性4(rs10671352)和单核苷酸多态性5(rs222836),其基因型分布在病例和对照组中均符合Hardy-Weinberg平衡;5个位点处于完全连锁不平衡状态;5个位点的基因型/等位基因/单倍体型与先天性脊柱侧凸的发生风险之间不存在相关性。在进一步与先天性脊柱侧凸临床表型的关联分析中没有发现阳性位点。提示在中国汉族人群中DVL2基因可能不是引起先天性脊柱侧凸及其不同临床表型的主要因素,有待于进一步深入研究。     

广西汉族人群NINJ2基因单核苷酸多态性位点rs12425791与缺血性脑卒中的关系

目的 探讨广西汉族人群NINJ2基因单核苷酸多态性(SNP)位点rs12425791与缺血性脑卒中(IS)的关系.方法 采用TaqMan MGB探针等位基因分型技术,对166例IS患者(IS组)和192名健康对照者(正常对照组)NINJ2基因SNP位点rs12425791进行基因分型,对两组基因型和等位基因频率进行比较.结果 IS组NINJ2基因SNP位点rs12425791基因型分布[G/G型103例(62.05％),G/A型54例(32.53％),A/A型9例(5.42％)]与正常对照组[G/G型112例(58.33％)、G/A型65例(33.85％)、A/A型15例(7.81％)]比较差异无统计学意义(x2=1.011,P=0.603).IS组NINJ2基因SNP位点rs12425791等位基因频率(G等位基因78.31％,A等位基因21.69％)与正常对照组(G等位基因75.26％,A等位基因24.74％)比较差异亦无统计学意义(x2=0.928,P=0.335).结论 广西汉族人群NINJ2基因SNP位点rs12425791可能与IS的发病无关.     

ABCB1基因多态性与中国汉族人群动脉粥样硬化性血栓性脑梗死的相关性研究

目的探讨ATP结合盒B亚家族成员1转运蛋白(ABCB1)基因多态性与中国汉族人群动脉粥样硬化性血栓性脑梗死(ATCI)患者的关系。方法选取392例ATCI患者(脑梗死组)和429例健康对照者(对照组),通过SNa Pshot方法对ABCB1基因的rs1128503和rs1045642位点进行SNP检测。比较两组的基因型和等位基因分布频率,分析基因型与临床表型的关系。结果脑梗死组rs1128503和rs1045642位点的基因型及等位基因分布频率与对照组比较,无统计学意义(P0.05)。女性ATCI患者的rs1128503位点TT基因型和CC基因型体重指数高于TC基因型(P=0.007,P=0.011)。女性ATCI患者的rs1045642位点CC基因型低密度脂蛋白-胆固醇水平高于CT基因型(P=0.030)。结论 ABCB1基因多态性与中国汉族人群ATCI的发病无明显相关性。rs1128503位点多态性可能与女性ATCI患者的体重指数有关,rs1045642位点多态性可能与女性ATCI患者的低密度脂蛋白-胆固醇水平有关。     

DISC1基因多态性与中国上海汉族人群阿尔茨海默病的关联研究

目的：探讨精神分裂症断裂基因(DISC1)rs821633,rs1000731单核苷酸多态性(SNP)与阿尔茨海默病(AD)的关系.方法提取中国上海汉族441例 AD 患者和749名健康对照组的 DNA,采用 Taqman 探针 SNP 基因分型技术测定 DISC1基因 SNP rs821633和 rs1000731位点的等位基因及基因型,检测两组受试者等位基因及基因型的频率分布差异.结果两组受试者中 rs821633不符合Hardy－Weinberg 平衡定律给予舍弃,rs1000731符合 Hardy－ Weinberg 平衡定律纳入,rs1000731位点的等位基因及基因型在两组受试者中分布比较,差异无统计学意义(P ＞0．05).结论 DISC1基因SNP rs1000731与 AD 无明显关联.     

SLC25A12基因多态性与孤独性障碍的关联

目的：探讨SLC25A12基因单核苷酸多态性（SNP）与孤独性障碍的遗传关联性。方法：采用聚合酶链式反应和DNA芯片杂交技术，在124个汉族孤独性障碍患儿核心家系中，检测了SLC25A12基因的2个SNP位点（rs2056202，rs2292813），采用传递不平衡检验（TDT）和单倍型的方法进行关联分析。结果：在124个患儿核心家系中，所测得的2个SNP位点的等位基因和基因型的频数分布均符合Hardy-Weinberg平衡检验（χ^2=0.009，P=0.92;χ^2=0.006，P=0.94）。而且这2个SNP处于一个强连锁不平衡区域（D’=0.842，r2=0.566）。对124个核心家系TDT检验，发现带有杂合子基因的父代优先传递给子代的等位基因的传递率和此传递率的置信区间差异无显著性（P〉0.05）;所有样本的2个SNP位点，未发现与孤独性障碍的显著关联。结论：SLC25A12基因可能不是这些汉族家庭儿童孤独性障碍的主要易感基因。     

凝血因子Ⅱ、Ⅴ基因多态性与脑梗死的关联研究

目的探讨中国湖南长沙地区汉族人群中凝血因子Ⅱ(FⅡ)、凝血因子Ⅴ(FⅤ)基因单核苷酸多态性与脑梗死之间的关联。方法采用PCR及飞行时间质谱技术对351例确诊为脑梗死的汉族患者(病例组)及417例对照组FⅡ基因rs1799963位点、FⅤ基因rs6025位点进行基因分型。结果病例组FⅡ基因rs1799963位点基因型均为G/G,对照组中基因型为G/G和A/G。病例组与对照组中FⅤ基因rs6025位点基因型均为G/G。对基因型及等位基因频率进行χ2检验示,病例组FⅡ基因rs1799963位点的基因型分布与对照组相比较差异无统计学意义(P0.05);病例组等位基因频率与对照组相比较差异无统计学意义(P0.05)。Logistic回归分析示,FⅡ基因rs1799963位点多态性与脑梗死不相关(P0.05)。结论 FⅡ基因rs1799963位点多态性和FⅤ基因rs6025位点多态性均可能与中国长沙汉族人群脑梗死之间不存在关联。     

RELN基因rs12705169位点与女性偏执型精神分裂症关联

目的以中国汉族偏执型精神分裂症患者为研究对象,重复验证RELN(Reelin)基因单核苷酸多态性与精神分裂症的关联性。方法以美国精神障碍诊断与统计手册第四版为诊断标准(Diagnostic and StatisticalManual of Mental Disorders-Fourth Edition,DSM-Ⅳ)在河南省北部地区收集326例偏执型精神分裂症患者(男女各半),在同一地域招募健康体检者334名(男女各半)作为对照,检测RELN基因rs12705169、rs11764507和rs17157643单核苷酸多态性位点。结果仅发现患者组和对照组之间rs12705169位点的基因型和等位基因频率差异有统计学意义(P<0.01)。按性别分层后进一步分析,rs12705169在女性患者和对照之间基因型和基因频率分布差异具有统计学意义(CC:OR=0.27,95%CI=0.18～0.45;AC:OR=0.43,95%CI=0.29～0.63,P<0.01)。结论RELN基因多态性与中国女性偏执型汉族精神分裂症存在关联,RELN基因可能是精神分裂症的易感基因。     

5-羟色胺2C受体基因多态性与特发性癫痫关联研究

目的研究5-羟色胺(5-hydroxytryptamin)2C受体基因多态性与特发性癫痫(epilepsy)的关联性。方法采用PCR-SSCP(polymerase chain reaction-single-strand conformation polymorphism)结合测序方法检测癫痫患者(病例组,n=220)与正常人(对照组n=200)5-HTR2C基因单核苷酸多态性(SNP),并利用统计学方法分析其多态性与特发性癫痫的相关性。结果 5-HTR2C基因在染色体rs113961355、rs114141491,没有发现单核苷酸多态性位点,rs113817908位发生A/C变异,其多态性位点的基因型频率差异显著(P0.025),且分布不符合Hardy-Weinberg遗传平衡。结论 5-HTR2C基因rs113817908位点SNP多态性与特发性癫痫具有关联性。     

微卫星位点D7S2421 SNP rs6465976 G/A多态现象与散发颅内破裂动脉瘤的相关性研究

目的探讨微卫星位点D7S2421单核苷酸多态性(SNP)rs6465976 G/A多态现象在散发颅内破裂动脉瘤中的作用。方法应用聚合酶链反应-限制性酶切片段长度多态性(PCR-RFLP)方法,从100例颅内动脉瘤病人和116例对照组病人的外周血中提取微卫星位点D7S2421 SNP rs6465976 G/A的基因型,并应用SPSS13.0统计学软件进行统计学分析。结果微卫星位点D7S2421 SNP rs6465976G/A基因型与颅内动脉瘤无相关性(P=0.938,OR=0.979,95%CI0.567～1.689);在血压≥140/90mmHg的病人中,微卫星位点D7S2421 SNP rs6465976 GA+AA的基因型频率显著性高于GG的频率(P=0.026,OR=2.513,95%CI1.105～5.712);在Hunt-Hess分级>Ⅲ级者中,微卫星位点D7S2421 SNP rs6465976 GA+AA的基因型频率亦显著性高于GG的频率(P=0.008,OR=4.333,95%CI1.401～13.401)。结论微卫星位点D7S2421 SNP rs6465976 G/A的等位基因A可能在...     

PLAU基因单体型与晚发性阿尔茨海默病的相关性研究

目的 探讨PLAU(plasminogen activator urinary)基因单体型与晚发性阿尔茨海默病(Ahheimer,sdisease,AD)的相关性.方法应用基因测序的方法对PLAU基因rs2227562、rs2227563、rs2227564和rs12255769位点进行单核苷酸多态性的筛查,结果 rs2227563和rs12255769位点未发现单核苷酸的多态性,rs2227564和rs2227562位点分别具有C/T及A/G单核苷酸的多态性.应用聚合酶链式反应.限制性片段长度多态性(PCR-RFLP)方法对实验及对照组人群进行rs2227564和rs2227562两个位点基因型的检测,并对这两个多态性位点进行连锁不平衡检验,用SHEsis软件进行单体型分析.结果经病例-对照相关性分析表明PLAU基因rs2227564和rs2227562位点存在连锁不平衡(D'=0.827),研究对象中有C-A、C-G、T-A和T-G 4种单体型,其中AD组T-A单体型频率明显低于对照组,两组比较差异有统计学意义(P=0.033,OR=0.189).C-A、C-G和T-G 3种单体型频率在两组人群中分布的差异无统计学意义.结论由PLAU基因rs2227564位点和rs2227562位点组成的T-A单体型可能降低晚发性阿尔茨海默病的发病风险.     

Partial replication of a DRD4 association in ADHD individuals using a statistically derived quantitative trait for ADHD in a family-based association test.

BACKGROUND: Previous research found an association between single nucleotide polymorphisms (SNPs) in the promoter region of DRD4 and statistically derived phenotypes generated from attention-deficit/hyperactivity disorder (ADHD) symptoms. We sought to replicate this finding by using the same methodology in an independent sample of ADHD individuals. METHODS: Four SNPs were genotyped in and around DRD4 in 2631 individuals in 642 families. We developed a quantitative phenotype at each SNP by weighting nine inattentive and nine hyperactive-impulsive symptoms. The weights were selected to maximize the heritability at each SNP. Once a quantitative phenotype was generated at each SNP, the screening procedure implemented in PBAT was used to select and test the five SNPs/genetic model combinations with the greatest power to detect an association for DRD4. RESULTS: One of the four SNPs was associated with the quantitative phenotypes generated from the ADHD symptoms (corrected p-values = .02). A rank ordering of the correlation between each of the ADHD symptoms and the quantitative phenotype suggested that hyperactive-impulsive symptoms were more strongly correlated with the phenotype; however, including inattentive symptoms was necessary to achieve a significant result. CONCLUSIONS: This study partially replicated a previous finding by identifying an association between rs7124601 and a quantitative trait generated from ADHD symptoms. The rs7124601 is in linkage disequilibrium (LD) with the SNPs identified previously. In contrast to the previous study, this finding suggests that both hyperactive-impulsive and inattentive symptoms are important in the association.     

Novel, replicated associations between dopamine D3 receptor gene polymorphisms and schizophrenia in two independent samples.

BACKGROUND: Meta-analyses have suggested an association between schizophrenia (SZ) and a coding polymorphism (rs6280/Ser9Gly) at the dopamine D3 receptor gene (DRD3), but results have been inconsistent. Because most studies have evaluated only rs6280, the inconsistencies might reflect associations with other variants. METHODS: We analyzed polymorphisms spanning 109kb in two independent samples (United States: 13 single nucleotide polymorphisms (SNPs), 331 cases, 151 trios, 274 control subjects; India: 11 SNPs, 141 trios). RESULTS: In the U.S. samples, significant associations were detected with eight SNPs, including rs6280 (p = .001, odds ratio: 1.5). Consistent associations in the case-control and family-based analyses were detected with a common haplotype spanning intron 1 to the 3' region of the gene (rs324029-rs7625282-rs324030-rs2134655-rs10934254; case-control, p = .002; transmission disequilibrium test [TDT], p = .0009; global p-values = .002 and .007, respectively). In the Indian sample, one SNP was associated (rs10934254, p = .03). Moreover, over-transmission of the same common haplotype as the U.S. sample was observed in this cohort (TDT, p = .005; global test, p = .009). Ser9Gly (rs6280) was associated with SZ against this haplotype background but not other haplotypes. CONCLUSIONS: These data suggest previous inconsistencies might have resulted from associations with other DRD3 variants. A liability locus might be in linkage disequilibrium (LD) with or carried against, an associated haplotype 3' to rs6280. Comprehensive SNP evaluation in larger samples is needed.     

A single nucleotide polymorphism at DBH, possibly associated with attention-deficit/hyperactivity disorder, associates with lower plasma dopamine beta-hydroxylase activity and is in linkage disequilibrium with two putative functional single nucleotide polymorphisms.

BACKGROUND: The DBH gene regulates plasma dopamine beta-hydroxylase activity (pDbetaH). Two single nucleotide polymorphisms (SNPs), -1021C-->T (rs1611115; SNP1) and +1603C-->T (rs6271; SNP3), independently influence pDbetaH. Another SNP, commonly known as DBH Taq1A (rs2519152; SNP2) is associated with attention-deficit/hyperactivity disorder (ADHD) in some (but not all) studies. We tested whether 1) SNP2 associates with pDbetaH; and 2) whether linkage disequilibrium (LD) between SNP2 and the other SNPs explains that association. METHODS: Plasma dopamine beta-hydroxylase activity and genotypes at the SNPs were determined in Caucasian subjects (n = 418). Associations to pDbetaH were examined using analyses of variance (ANOVAs) and LD among the SNPs using estimation maximization. RESULTS: 1) Each polymorphism analyzed alone associated with pDbetaH; 2) SNP2 was in strong LD with SNP1 and SNP3, respectively, but there was no significant LD between SNP1 and SNP3; and 3) analyzed jointly, each SNP contributed significantly and uniquely to plasma DbetaH activity. CONCLUSIONS: 1) SNP2 associates with pDbetaH; 2) SNP2 shows LD with SNP1 and SNP3; 3) most of the association between SNP2 and pDbetaH simply reflects that LD; however, 4) SNP2 also appears to exert a small independent effect on pDbetaH, suggesting that SNP2, or another variant in LD with it, uniquely influences pDbetaH.     

Association Study of Fibroblast Growth Factor 2 and Fibroblast Growth Factor Receptors Gene Polymorphism in Korean Ossification of the Posterior Longitudinal Ligament Patients

Objective

The aim of this study was to determine whether single nucleotide polymorphisms (SNPs) of fibroblast growth factor (FGF) 2 gene and fibroblast growth factor receptor (FGFR) genes are associated with ossification of the posterior longitudinal ligament (OPLL).

Methods

A total of 157 patients with OPLL and 222 controls were recruited for a case control association study investigating the relationship between SNPs of FGF2, FGFR1, FGFR2 and OPLL. To identify the association among polymorphisms of FGF2 gene, FGFR1, FGFR2 genes and OPLL, the authors genotyped 9 SNPs of the genes (FGF2 : rs1476217, rs308395, rs308397, and rs3747676; FGFR1 : rs13317 and rs2467531; FGFR2 : rs755793, rs1047100, and rs3135831) using direct sequencing method. SNPs data were analyzed using the SNPStats, SNPAnalyzer, Haploview, and Helixtree programs.

Results

Of the SNPs, a SNP (rs13317) in FGFR1 was significantly associated with the susceptibility of OPLL in the codominant (odds ratio=1.35, 95% confidence interval=1.01-1.81, p=0.048) and recessive model (odds ratio=2.00, 95% confidence interval=1.11-3.59, p=0.020). The analysis adjusted for associated condition showed that the SNP of rs1476217 (p=0.03), rs3747676 (p=0.01) polymorphisms in the FGF2 were associated with diffuse idiopathic skeletal hyperostosis (DISH) and rs1476217 (p=0.01) in the FGF2 was associated with ossification of the ligament flavum (OLF).

Conclusion

The results of the present study revealed that an FGFR1 SNP was significantly associated with OPLL and that a SNP in FGF2 was associated with conditions that were comorbid with OPLL (DISH and OLF).     

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.     

Association analysis of heat shock protein 70 gene polymorphisms in schizophrenia

OBJECTIVES: Heat shock proteins (HSPs) are a promising candidate gene in schizophrenia as they are believed to play a protective role in the central nervous system. An alteration in the titers of antibodies to the HSPs in schizophrenia patients has been suggested. Association between the three polymorphisms of HSP70-1 (HSPA1A), HSP70-hom (HSPA1L) and HSP70-2 (HSPA1B) and schizophrenia has been reported. Therefore, this study investigated the association between an enlarged set of SNPs at HSP70 gene and schizophrenia. METHODS: Two hundred and ninety-four patients with schizophrenia and 287 controls were enrolled in the study. Genotypings of 5 SNPs of HSP70 were performed using pyrosequencing method. Haploview 3.2 was used to generate a linkage disequilibrium map and to test for Hardy-Weinberg equilibrium. Single locus and haplotype-based associations were tested. Tests for associations using and multi-marker haplotypes were performed by using a COCAPHASE v2.403. Association of SNP markers and clinical variables were analyzed by analysis of variance. RESULTS: Significant association was detected at rs2075799 (allele A, X2 = 8.03, df = 1, P = 0.0046), but not at rs2227956 (P = 0.28), rs1043618 (P = 0.88), rs562047 (P = 0.47) or rs539689 (P = 0.32). In fact, the rs2075799*G/A genotype was more represented in patients with schizophrenia than in controls (X2 = 8.23, df= 1, P = 0.0041). Haplotype based associations were also detected (global P value 0.000003); the T-A-C-C-G haplotype was more prevalent among the patients (odds ratio, OR 5.95). Sliding windows analysis revealed a major contribution from rs2227956 and rs2075799 (global-P value 0.0075), with T-A haplotype significantly associated with schizophrenia. There was no evidence of an association between the clinical variables and schizophrenia across the genotypes. CONCLUSION: Our results raise the possibility that HSP70 gene (i.e., haplotypes of rs2075799) might be implicated in the development of schizophrenia, although limited by rare haplotypic association with the disease. Hence further studies from different ethnics should be performed to confirm these results.     

GABRB2 association with schizophrenia: commonalities and differences between ethnic groups and clinical subtypes.

BACKGROUND: Single nucleotide polymorphisms (SNPs) and haplotypes in intron 8 of type A gamma-aminobutyric acid (GABA(A)) receptor beta2 subunit gene (GABRB2) were initially found to be associated with schizophrenia in Chinese. This finding was subjected to cross-validation in this study with Japanese (JP) and German Caucasian (GE) subjects. METHODS: Single nucleotide polymorphisms discovery and genotyping were carried out through resequencing of a 1839 base pair (bp) region in GABRB2. Tagging SNPs (tSNPs) were selected based on linkage disequilibrium (LD), combinations of which were analyzed with Bonferroni correction and permutation for disease association. Random resampling was applied to generate size- and gender-balanced cases and control subjects. RESULTS: Out of the 17 SNPs (9.2/kilobase [kb]) revealed, 6 were population-specific. Population variations in LD were observable, and at least two low LD points were identified in both populations. Although disease association at single SNP level was only shown in GE, strong association was demonstrated in both JP (p = .0002 - .0191) and GE (p = .0033 - .0410) subjects, centering on haplotypes containing rs1816072 and rs1816071. Among different clinical subtypes, the most significant association was exhibited by systematic schizophrenia. CONCLUSIONS: Cross-population validation of GABRB2 association with schizophrenia has been obtained with JP and GE subjects, with the genotype-disease correlations being strongest in systematic schizophrenia, the most severe subtype of the disease.     

Genetic association study of CSNK1E gene in bipolar disorder and circadian characteristics

Abstract

Background: A circadian rhythm disturbance is one of the essential components of the phenotype of bipolar disorder. It has been reported that casein kinase 1 epsilon (CSNK1E), a member of the clock gene family, is associated with psychiatric phenotypes.

Objectives: We performed a genetic association study to determine the genetic role of CSNK1E in bipolar disorder and circadian rhythm disturbances in the Korean population.

Methods: The present study included 215 patients with bipolar disorder and 773 controls. Circadian characteristics were measured by the Korean version of the Composite Scale of Morningness (CS). Single-nucleotide polymorphisms (SNPs) of CSNK1E, rs1534891 and rs2075984, were genotyped. Chi-square analyses were performed to evaluate associations involving alleles and genotypes. Haplotype analysis was also performed, and the permutation p value was calculated. We also tested further associations involving these SNPs and scores on the CS.

Results: We found a positive association between SNP rs2075984 and bipolar disorder in both the allelic (p?=?.003) and genotypic (p?=?.006) distributions. No allelic or genotypic association between SNP rs1534891 and bipolar disorder was observed. A significant association of haplotype with bipolar disorder was found (p?=?.033). However, no association between the CS and the genotype of either SNP was found in the total sample.

Conclusion: CSNK1E SNP rs2075984 seemed to play a significant role in the development of bipolar disorder in this Korean sample. This association does not seem to relate to the phase preference measured by the CS. Further studies on CSNK1E with larger samples and more SNPs are necessary.