多巴胺D4受体基因与注意缺损多动障碍

为探讨注意缺损多动障碍（ADHD）与多巴胺D4受体基因（dopamine D4 receptor gene,DRD4)间的关系,采用Amp-FLP的方法检测了上海地区汉族人群中68例ADHD患及其父母DRD4的多态性,数据采用基于单体型的单体型相对风险（HHRR）及传递不平衡检验（TDT）进行遗传关联分析。结果表明HHRR分析和复等位基因的TDT检验,均未显示出与ADHD的遗传关联性（P＞0．05）。提示上海地区人群中DRD4基因与ADHD无显性关联。     

云南汉族酒精依赖综合征与COMT遗传多态性的关联研究

目的：研究儿茶酚胺氧位甲基转移酶（COMT）的不同基因型及等位基因频率在云南汉族酒精依赖综合征患者组和健康对照组的分布差异。方法：应用聚合酶链式反应．限制性片段长度多态性分析法,对COMT基因的rs2075507、rs737865、rs4680、rsl65599四个基因位点进行特异性扩增,限制性内切酶酶切分型。结果：上述4个候选基因中,COMT基因rs737865位点C／C基因型频率在健康对照组较酒依赖组高,其基因型分布在两组中有差异,且具有统计学意义（P〈0．05）。其余3个位点统计学分析均无显著性差异（P〉0．05）。单倍型分析：上述四个候选基因构建出12种主要单倍型（每种单倍型在对照组和酒依赖组中的频率至少有一个大于1％）,单倍型A—C—A—A有可能是云南汉族酒精依赖发生的一种危险因子（OR：2．865,P=0．003347）。连锁不平衡分析显示：云南汉族人群中,COMT基因的rs2075507和rs737865之间存在着强连锁（D〉0．8）。结论：在云南汉族人群中,COMT基因rs2075507、rs4680和rs165599位点与酒依赖无关联性,rs737865C／C基因型可能是酒精依赖的保护因子,可能降低嗜酒的发生率。单倍型A-C-A-A有可能是云南汉族酒精依赖发生的一种危险因子。云南汉族人群中,COMT基因的rs2075507和rs737865之间存在着强连锁。     

多巴胺D4受体基因与注意缺损多动障碍

为探讨注意缺损多动障碍(ADHD)与多巴胺D4受体基因(dopamineD4receptorgene,DRD4)间的关系,采用Amp-FLP的方法检测了上海地区汉族人群中68例ADHD患者及其父母DRD4的多态性,数据采用基于单体型的单体型相对风险(HHRR)及传递不平衡检验(TDT)进行遗传关联分析.结果表明HHRR分析和复等位基因的TDT检验,均未显示出与ADHD的遗传关联性(P＞0.05).提示上海地区人群中DRD4基因与ADHD无显著性关联。 Abstract:The present study was designed to investigate the association between attention-deficit hyperactivity disorder (ADHD) and the dopamine D4 receptor gene (DRD4).Amp-FLP was used to test the polymorphisms of DRD4 in 68 ADHD children and their parents from Shanghai.The haplotype-based haplotype relative risk (HHRR) and transmission disequilibrium test (TDT) methods were used to analyze the association between DRD4 and ADHD.In our samples we found no significant association between DRD4 and ADHD (P>0.05).Our results do not support that ADHD is associated with DRD4 in population in Shanghai.     

注意缺损多动障碍的X染色体基因组扫描分析

摘 要：注意缺损多动障碍（ADHD）是儿童期多见行为障碍。男孩发病多于女孩。家系、双生儿和寄养子研究显示该障碍发生具有遗传基础。但是病因尚不清楚。分子遗传学和药理学研究表明ADHD涉及到多巴胺和去甲肾上腺素等神经递质系统,一系列报告发现ADHD与多巴胺D4受体（DRD4）、多巴胺转运体（DAT1）和儿茶酚-O-甲基转移酶（COMT）等基因相关联。我们以往研究表明ADHD与X染色体上DXS7位点和MAOA基因相关联,而DXS7是紧密连锁于MAO基因。依此假设,我们应用基因组扫描技术探讨ADHD在X染色体上易感位点。采用TDT方法分析X染色体上48个DNA标志的多态性与中国人群中84个ADHD核心家系间的连锁关系,ADHD诊断依据DSM-III-R标准。TDT分析结果观察到如下位点与ADHD相连锁,DXS1214(TDT:χ2=18.1,df=7, P<0.01), DXS8102(TDT: χ2=7.9, df=3, P<0.05),DXS1068(TDT: χ2=21.9, df=9, P<0.01), DXS8015(TDT:χ2=14.6, df=7, P<0.05),DXS1059(TDT: χ2=27.8, df=10, P<0.01) 和DXS8088(TDT:χ2=20.4, df=3, P<0.01).研究资料提示X染色体上Xp11.4-Xp21和Xq23区域可能存在ADHD的易感基因。     

在中国汉族人群中,以家系传递分析肿瘤坏死因子a-308A/G单核苷酸多态性与抽动秽语综合征

目的：探讨在中国汉族人群中,肿瘤坏死因子a（TNF-alpha,TNF-a）基因启动子区-308A/G单核苷酸多态性与抽动秽语综合征（Tourette syndrome,TS）的遗传易感性。方法：91例TS患者及其父母组成的核心家系成员经聚合酶链式反应-限制性片段长度多态性（polymerase chain reaction-restriction fragment lengthpolymor phism,PCR-RFLP）方法进行基因分型,评估所有研究对象的TNF-a-308A/G位点的等位基因频率和基因型频率的分布,进行传递不平衡检验（transmission disequilibrium test,TDT）,单体型相对风险（haplotype-based haplotyp erelativerisk,HHRR）,单体型风险（haplotype relative riskHRR）的研究。结果：TS患者及其父母的等位基因分布经Hardy-Weinberg（H-W）平衡检验显示符合遗传平衡法则。（x2〈3.84;P〉0.05）TDT、HHRR和HRR研究结果显示该多态性位点的等位基因频率和基因型频率均不存在传递不平衡。结论：我们的数据表明肿瘤坏死因子a启动子区-308A/G单核苷酸多态性位点不是中国汉族人群TS的易感基因位点。     

注意缺损多动障碍关联于DXS7位点 Association of Attention-Deficit Hyperactivity Disorder and the DXS7 Locus

采用单体型相对风险和传递/不平衡检验方法,在中国人群中对注意缺损多动障碍（ADHD）与DXS7位点进行了遗传关联分析。结果表明,以父母双亲为对照,DXS7位点157bp等位基因与ADHD具有显著关联(χ2=9.10, P<0.05)并连锁(χ2=9.53, P<0.05)。提示,ADHD关联和连锁于DXS7位点。 Abstract　The present study was designed to assess the genetic association between attention-deficit hyperactivity disorder(ADHD) and DXD7 locus polymorphism in Chinese population, with haplotype-based haplotype relative risk(HHRR) and the transmission/disequilibrium test(TDT) analysis. We found significant association(χ2=9.10, P<0.05) and linkage (χ2=9.53, P<0.05) between the 157bp DXS7 allele and DSM-Ⅲ-R-diagnosed ADHD(N=54) in trios composed of father, mother and affected offspring. Our results suggest that ADHD was associated and in linkage with DXS7 locus.     

云南汉族酒精依赖综合征与COMT遗传多态性的关联研究

目的:研究儿茶酚胺氧位甲基转移酶(COMT)的不同基因型及等位基因频率在云南汉族酒精依赖综合征患者组和健康对照组的分布差异。方法:应用聚合酶链式反应-限制性片段长度多态性分析法,对COMT基因的rs2075507、rs737865、rs4680、rs165599四个基因位点进行特异性扩增,限制性内切酶酶切分型。结果:上述4个候选基因中,COMT基因rs737865位点C/C基因型频率在健康对照组较酒依赖组高,其基因型分布在两组中有差异,且具有统计学意义(P<0.05)其余3个位点统计学分析均无显著性差异(P>0.05)。单倍型分析:上述四个候选基因构建出12种主要单倍型(每种单倍型在对照组和酒依赖组中的频率至少有一个大于1%),单倍型A-C-A-A有可能是云南汉族酒精依赖发生的一种危险因子(OR:2.865,P=0.003347)连锁不平衡分析显示:云南汉族人群中,COMT基因的rs2075507和rs737865之间存在着强连锁(D>0.8)结论:在云南汉族人群中,COMT基因rs2075507、rs4680和rs165599位点与酒依赖无关联性,rs737865C/C基因型可能是酒精依赖的保护因子,可能降低嗜酒的发生率。单倍型A-C-A-A有可能是云南汉族酒精依赖发生的一种危险因子云南汉族人群中,COMT基因的rs2075507和rs737865之间存在着强连锁。     

5个精神分裂症高发家系与COMT关联的分析

本研究旨在探测儿茶酚氧位甲基转移酶基因（COMT）多态性与精神分裂症（SP）的关系,搜寻中国汉族人精神分裂症易患性基因。 应用聚合酶链反应（PCR）和限制性片段长度多态性（RFLP）方法对5个精神分裂症高发家系进行初步研究。 用改进的传递/不平衡（TDT）进行统计分析,结果表明,在5个精神分裂症高发家系中,COMT基因与精神分裂症相关联（P=0.0455）。 研究结果提示,在我们研究的家系中,22号染色体长臂（22q11.2）可能存在精神分裂症易患性基因。 Abstract:This study is to explore the relationship between polymorphism of Catechol O-methyltransferase gene and schizophrenia.Search for a gene predisposing to schizophrenia in the Han nationality in China.Five pedigrees with high incidence of schizophrenia were studied by polymerize chain reaction(PCR) and restriction fragment length polymorphism(RFLP) technique.Statistics analysis of the transmission/disequilibrium test (TDT) showed that the COMT gene is associatted with schizophrenia in the five pedigree with high incidence schizophrenia(P=0.0455).The results suggest that there might have a schizophrenia liability gene on 22 chromosome (22q11.2) in our studied pedigrees.     

中国人MTHFR基因多态性与神经管畸形遗传易感性

目的：应用分子生物学方法进行遗传流行病学研究, 探讨MTHFR基因多态性在神经管畸形的遗传易感性中的作用。方法：应用PCR?RFLP方法检测MTHFR热敏感性基因型;对18个NTD核心家庭进行以父母为对照的病例对照研究,计算TDT和HHRR;另外对31例NTD胎儿和62例正常成年人进行的成组病例对照研究,计算MTHFR纯合突变对NTD的比值比。结果：核心家庭分析结果：比值比OR=3.2,95％CI=1.120～11.169;TDT（χ2）=5.762,P<0.05,HHRR（成组χ2）=6.727,P<0.05;胎儿MTHFR纯合突变对NTD的相对危险度OR=3?21,P<0?05。结论：研究结果说明,突变等位基因在神经管畸形核心家庭中存在突变基因(T)的遗传失衡现象,胎儿MTHFR基因第677位核苷酸的多态性是中国人NTD遗传易感性因素之一。 Abstract：The objective of the study is to clarify the effect of MTHFR thermolabile polymorphism on genetic susceptibility of NTD in Chinese population.MTHFR genotypes were detected using PCR-RFLP analysis; 18 NTD nuclear families were analysed as case-parental control study,from which Transmitted Disequillibrium Test(TDT) and Haplotype-based Haplotype Relative Risk (HHRR) were calculated; 31 NTD fetuses and 62 adult controls were analysed for calculation of OR of homozygotic MTHFR.The results are as follow:Nuclear family analysis: OR=3.2( 95％CI=1.120～11.169);TDT（paired χ2）=5.762,P<0.05,HHRR（χ2）=6.727,P<0.05;homozygotic MTHFR of fetus vs adult control: OR=3.21,P<0.05. The 677th allele of MTHFR is abnormally transmitted in NTD nuclear families.Homozygotic MTHFR of the fetus may be a genetic factor of NTD in China.     

在中国汉族人群中，以家系传递分析肿瘤坏死因子a-308A/G单核苷酸多 态性与抽动秽语综合征

目的:探讨在中国汉族人群中,肿瘤坏死因子a(TNF-alpha,TNF-a)基因启动子区-308A/G单核苷酸多态性与抽动秽语综合征(Tourette syndrome,TS)的遗传易感性。方法:91例TS患者及其父母组成的核心家系成员经聚合酶链式反应-限制性片段长度多态性(polymerase chain reaction-restriction fragment lengthpolymor phism,PCR-RFLP)方法进行基因分型,评估所有研究对象的TNF-a-308A/G位点的等位基因频率和基因型频率的分布,进行传递不平衡检验(transmission disequilibrium test,TDT),单体型相对风险(haplotype-based haplotyp erelativerisk,HHRR),单体型风险(haplotype relative riskHRR)的研究。结果:TS患者及其父母的等位基因分布经Hardy-Weinberg(H-W)平衡检验显示符合遗传平衡法则。(x2<3.84;P>0.05)TDT、HHRR和HRR研究结果显示该多态性位点的等位基因频率和基因型频率均不存在传递不平衡。结论:我们的数据表明肿瘤坏死因子a启动子区-308A/G单核苷酸多态性位点不是中国汉族人群TS的易感基因位点。     

Association of attention-deficit disorder and the dopamine transporter gene.

Attention-deficit hyperactivity disorder (ADHD) has been shown to be familial and heritable, in previous studies. As with most psychiatric disorders, examination of pedigrees has not revealed a consistent Mendelian mode of transmission. The response of ADHD patients to medications that inhibit the dopamine transporter, including methylphenidate, amphetamine, pemoline, and bupropion, led us to consider the dopamine transporter as a primary candidate gene for ADHD. To avoid effects of population stratification and to avoid the problem of classification of relatives with other psychiatric disorders as affected or unaffected, we used the haplotype-based haplotype relative risk (HHRR) method to test for association between a VNTR polymorphism at the dopamine transporter locus (DAT1) and DSM-III-R-diagnosed ADHD (N = 49) and undifferentiated attention-deficit disorder (UADD) (N = 8) in trios composed of father, mother, and affected offspring. HHRR analysis revealed significant association between ADHD/UADD and the 480-bp DAT1 allele (chi 2 7.51, 1 df, P = .006). When cases of UADD were dropped from the analysis, similar results were found (Chi 2 7.29, 1 df, P = .007). If these findings are replicated, molecular analysis of the dopamine transporter gene may identify mutations that increase susceptibility to ADHD/UADD. Biochemical analysis of such mutations may lead to development of more effective therapeutic interventions.     

COMT基因多态性与儿童精神发育迟滞及儿童认知能力的相关性研究

儿茶酚-O-甲基转移酶（catechol-O-methyl transferase,COMT）是儿茶酚胺类神经递质的主要代谢酶.COMT是儿茶酚-O-甲基转移酶的编码基因,其第4外显子的一个G/A转换可产生不同活性的等位基因.许多遗传学研究报道,这种功能多态性与人类精神类疾病相关.文章利用PCR扩增技术和限制性片段长度多态（Restriction fragmentlength polymorphism,RFLP）方法,研究中国秦巴山区精神发育迟滞（Mental Retardation,MR）儿童与正常对照儿童的COMT基因功能多态情况,探讨COMT基因功能多态性与儿童认知能力水平的相关性.病例-对照分析结果显示,COMT基因的不同活性等位基因型与秦巴山区儿童MR无相关性（x2=0.776,P＞0.05）,其等位基因频率与儿童MR也未呈现出相关性（x2=0.335,P＞0.05）.但是,在研究中还发现,该地区智商分（IQ）不小于55分的儿童群体中,COMT基因的多态性分布与儿童的智力呈现出相关的趋势.在智力正常组儿童中（IQ≥85）,COMT高活性等位基因纯合体（COMTHH）频率及其等位基因（COMTH）频率较高,分别为60.98%、79.28%.在智力边缘组儿童（70≤IQ＜85）中,其频率分别为46.67%、70.67%,相应地也低于正常组的频率（0.10＞P＞0.05）.结果提示,在中国秦巴山区人群中,COMT基因的功能多态性与儿童MR的形成无明显相关性,但它对正常儿童的认知能力可能有一定影响.     

Few associations of candidate genes with nonsyndromic orofacial clefts in the population of Lithuania

Nonsyndromic orofacial clefting (NS-OFC) is a common complex multifactorial trait with a considerable genetic component and a number of candidate genes suggested by various approaches. Twenty biallelic and microsatellite DNA markers in the strong candidate loci TGFA, TGFB3, GABRB3, RARA, and BCL3 were analysed for allelic association with the NS-OFC phenotype in 112 nuclear families (proband + both parents) from Lithuania by using the transmission disequilibrium test (TDT). Associations were found between the TGFA gene marker rs2166975 and nonsyndromic cleft palate only (CPO) phenotype (p = 0.045, df 1) as well as between the D2S292 marker and the cleft lip with or without cleft palate (CL/CP) phenotype in allele-wise TDT (P = 0.005, df 9) and genotype-wise TDT (P = 0.021, df 24). A weak association (P = 0.085, df 3) of the BCL3 marker (BCL3 gene) with the risk of CPO was also found. Thus our initial results support the contribution of allelic variation in the TGFA locus to the aetiology of CL/CP in the population of Lithuania but they do not point to TGFA as a major causal gene. Different roles of the TGFA and BCL3 genes in the susceptibility to NS-OFC phenotypes are suggested.     

Glutamate Receptor 6 Gene (<Emphasis Type="Italic">GluR6</Emphasis> or <Emphasis Type="Italic">GRIK2</Emphasis>) Polymorphisms in the Indian Population: A Genetic Association Study on Autism Spectrum Disorder

Autism is a neurodevelopmental disorder with early manifestation. It is a multifactorial disorder and several susceptible chromosomal regions for autism are identified through genome scan studies. The gene coding for glutamate receptor 6 (GluR6 or GRIK2) has been suggested as a candidate gene for autism based on its localization in the autism specific region on chromosome 6q21 and the involvement of receptor protein in cognitive functions like learning and memory. Despite its importance, so far no studies have been carried out on possible involvement of GluR6 with autism in the Indian population. Therefore in the present study, we have performed genetic analysis of three markers of GluR6 (SNP1: rs2227281, SNP2: rs2227283, SNP3: rs2235076) for possible association with autism through population, and family-based (TDT and HHRR) approaches. DSM-IV criteria and CARS/ADI-R have been utilized for diagnosis. Genotyping analysis for the SNPs has been carried out in 101 probands with autism spectrum disorder, 180 parents and 152 controls from different regions of India. Since the minor allele frequency of SNP3 was too low, the association studies have been carried out only for SNP1 and SNP2. Even though two earlier studies have shown association of these markers with autism, the present case–control and TDT, as well as HHRR analyses have not demonstrated any biased transmission of alleles or haplotypes to the affected offspring. Thus our results suggest that these markers of GluR6 are unlikely to be associated with autism in the Indian population.     

Association and linkage of the dopamine transporter gene and attention-deficit hyperactivity disorder in children: heterogeneity owing to diagnostic subtype and severity.

Attention-deficit hyperactivity disorder (ADHD) affects approximately 3%-5% of children in the United States. In the current psychiatric nomenclature, ADHD comprises three subtypes: inattentive, hyperactive-impulsive, and combined. In this study, we used four analytic strategies to examine the association and linkage of the dopamine transporter gene (DAT1) and ADHD. Our sample included 122 children referred to psychiatric clinics for behavioral and learning problems that included but were not limited to ADHD, as well as their parents and siblings. Within-family analyses of linkage disequilibrium, using the transmission disequilibrium test (TDT), confirmed the 480-bp allele as the high-risk allele. In between-family association analyses, levels of hyperactive-impulsive symptoms but not inattentive symptoms were related to the number of DAT1 high-risk alleles. Siblings discordant for the number of DAT1 high-risk alleles differed markedly in their levels of both hyperactive-impulsive and inattentive symptoms, such that the sibling with the higher number of high-risk alleles had much higher symptom levels. Within-family analyses of linkage disequilibrium, using the TDT, suggested association and linkage of ADHD with DAT1 and that this relation was especially strong with the combined but not the inattentive subtype. The relation of DAT1 to ADHD increased monotonically, from low to medium to high levels of symptom severity. Our results replicate and extend previous findings of the association between the DAT1 gene and childhood ADHD. This represents one of the first replicated relations of a candidate gene and a psychiatric disorder in children.     

混合家系中NOTCH4基因多态与精神分裂症、心境障碍关联研究

文章旨在探讨NOTCH4基因多态性与精神分裂症（SP）、心境障碍（MD）的关系,搜寻中国汉族人群SP与MD的共同易患基因。在中国汉族人群中收集61个SP与MD的混合家系,应用PCR-RFLP方法对NOTCH4基因多态性-1725T/G、-25T/C分型,进行传递不平衡检验（TDT）和基于单体型的单体型相对风险分析（HHRR）。结果显示-1725T/G 与SP或MD无明显关联（P>0.05）;-25T/C与SP无明显关联（P>0.05）,与女性或发病年龄≤25岁的MD相关联（P<0.05）;单体型-1725G/-25T与SP相关联（P<0.05）,与MD无明显关联（P>0.05）。本研究结果提示,在我们研究的家系中NOTCH4或邻近基因可能是精神分裂症与心境障碍的共同易患基因之一。