糖及脂代谢调节基因与高血压病的连锁分析

目的 观察糖、脂代谢调节基因的微卫星位点与高血压病间是否连锁,以识别高血压易感基因位点。方法 以18个糖、脂代谢调节基因附近的微卫生为标记,采用微卫生光标记－基因扫描及分型技术,对95个EH家系477名成员进行标记位点与EH表型连锁分析。统计采用GENEHUNTER软件包两点非参数连锁（NPL）分析、计算优势对数记分（Lod）值及传递不平衡检验（TDT）。结果 NPL分析及Lod值均不支持所测微卫星位点与高血压病连锁,但TDT则提示D8S261、D11S1347位点与高血压病间存在连锁不平衡（P＜0.01）。两位点附近分别有脂蛋白酶（LPL）基因和（aplA1-C3-A4）基因簇。结论 TDT提示D8S261、D11S1347两位点与高血压病间存在连锁,其位点附近基因（LPL基因及载脂蛋白基因簇）是否为高血压病相关基基值得进一步研究。     

Association of the GLI gene with ventricular septal defect after the susceptibility gene being narrowed to 3.56 cM in 12q13

Background Our previous research has suggested that genes around D12S1056 in 12q13 may confer susceptibility to ventricular septal defect （VSD） in humans. The present study was to define the chromosome region assignment by transmission disequilibrium test （TDT）, and to identify the important candidate gene by family-based association study and haplotype analysis. Methods Surrounding D12S1056, ten microsatellite markers including D12S329, D12S305, D12S1662, D12S1056, D12S1293, D12S334, D12S102, D12S83, D12S1655 and D12S1691 were chosen, and TDT was performed in 62 nuclear family trios each consisting of an affected child and two healty parents. Subsequently, the GLI gene, a positional candidate gene that maps to the target region, was selected for further analysis. Three single nucleotide polymorphisms （SNPs）, G11888C, G11388A, and G11625T, were selected for family-based association study and haplotype analysis. Results VSD was significantly associated with all selected markers except D12S1691 [72.2 centi morgen （cM）] and D12S1700 （75.76 cM）. VSD was also significantly associated with G11888C （X^2 = 5.918, P = 0.015）, G11388A （X^2 = 8.067, P = 0.005）, and G11625T （X^2 = 11.842, P = 0.001）. Haplotype analysis showed a strong linkage disequilibrium between G11888C and G11388A （D＇=0.999）, but in significant （X^2 = 1.035, df = 2, P 〉 0.05）. Conclusions The susceptibility gene of VSD was mapped to 3.56 cM in 12q13 by TDT, and the GLI gene, an important candidate in the target region, was associated with VSD.     

Linkage analysis of chromosome 14 and essential hypertension in Chinese population

Background Hypertension is a complex biological trait that influenced by multiple factors. The encouraging results for hypertension research showed that the linkage analysis can be used to replicate other studies and discover new genetic risk factors. Previous studies linked human chromosome 14 to essential hypertension or blood pressure traits. With a Chinese population, we tried to replicate these findings.Methods A linkage scan was performed on chromosome 14 with 14-microsatellite markers with a density of about 10 centi Morgen (cM) in 147 Chinese hypertensive nuclear families. Multipoint non-parametric linkage analysis and exclusion mapping were performed with the GENEHUNTER software, whereas quantitative analysis was performed with the variance component method integrated in the SOLAR package.Results In the qualitative analysis, the highest non-parametric linkage score is 1.0 (P=0.14) at D14S261 in the single point analysis, and no loci achieved non-parametric linkage score more than 1.0 in the multipoint analysis. Maximum-likelihood mapping showed no significant results, either. Subsequently the traditional exclusion criteria of the log-of-the-odds score-2 were adopted, and the chromosome 14 with λs≥2.4 was excluded. In the quantitative analysis of blood pressure with the SOLAR software, two-point analysis and multipoint analysis suggested no evidence for linkage occurred on chromosome 14 for systolic and diastolic blood pressure. Conclusion There was no substantial evidence to support the linkage of chromosome 14 and essential hypertension or blood pressure trait in Chinese hypertensive subjects in this study. Chin Med J 2005; 118(23):1939-1944     

家族性热性惊厥与人染色体19p13.3连锁

目的 初步明确家族性热性惊厥（FC）相关基因在染色体上的定位。方法 对63个FC家系共248名成员地行染色体19p上四核苷酸微卫星标记D19S253、D19S395、D19S591和染色体8q上二核苷酸微卫星标记D8S84和D8S85的基因分型,进行传递不平衡（TDT）检验。对其中10人三肛家系共81名成员用PPAP软件计算优良对数记分（Lod）值。结果 FC家诲成员和正常对照人群（103名）在3个位点上各等位基因分布均符合Hardy-Weinburg平衡。FC家系在D8S84、D19S395和D19S591位点都存在传递不平衡,γ^2值分别为4.0、5.124和7.364,均P＜0.05,差异有显著意义。D19S253、D19S395和D19S591与FC表型的两点Lod值分别为0.58、1.53和1.42,而多点Lod值达到2.78.D8S84和D8S85与FC表型的两点Lod值分别为0.00002和0.0000017,8q上引2标记与FC多点Lod值为0.88。非参数分析（TDT法）和参数分析（Lod值法）的结果基本一致。结论 FC与人染色体19p13.3连锁,而不与染色体9q连锁。     

全基因组扫描定位毛囊闭锁三联征致病基因

目的在1例4代毛囊闭锁三联征大家系中定位其致病基因所在区域。方法用覆盖全基因组的微卫星标记对1例毛囊闭锁三联征大家系进行致病基因定位研究,用AB I3730测序仪进行微卫星标记的基因分型,利用L inkage软件(5.10version)和Cyrillic软件(2.01 version)进行连锁和单倍型分析。结果该家系符合常染色体显性遗传模式,当外显率为99.9%时,在1号染色体上的微卫星标记D1S2624处获得最大LOD值为3.26(重组率θ=0.00)。单倍型分析将该家系致病基因定位在微卫星标记D1S248和D1S2711之间的染色体1p21.1 1q25.3区域,遗传距离61.8 cM。结论染色体1p21.1 1q25.3区域存在毛囊闭锁三联征的致病基因。     

中国北方汉族格雷夫斯病主要易感位点的检测及意义

目的　探讨和确定位于染色体 6p2 1区的人类主要组织相容性复合体 (MHC)区是否为中国北方汉族Graves病 (GD)的主要易感位点。方法　采用 4个高度多态且覆盖整个染色体 6p2 1区的微卫星标记筛查 5 4个 (32 2人 )中国北方汉族GD多发家系。分别计算疾病在呈显性及隐性遗传的外显率下 ,各微卫星的两点及多点Lod值 ,并计算多点非参数连锁值。结果　在每种遗传模式下 ,各微卫星的两点 (θ =0 )及多点Lod值均小于 - 2。无任何家系在所设定的遗传模式下两点或多点Lod值达到或超过 1.0。在设定存在遗传异质性的情况下 ,最大多点Lod值为 0 .5 5 ,阳性连锁家系占 2 9%。多点非参数连锁值差异均无显著意义 (P >0 .0 5 )。结论　染色体 6p2 1区不存在与中国北方汉族GD相连锁的基因位点。MHC区不是中国北方汉族GD的主要易感位点。     

银屑病易感基因位点的检测

目的：寻找中国人群银屑病的易感基因位点。方法：选取19个多态性微卫星标记,采用由荧光标记PCR、MegaBACE测序仪和与之配套的Genetic Profiler分析软件建立的荧光标记的自动基因分型体系对38个银屑病家系中的银屑病患者与亲属的外周血白细胞中提取的DNA进行 基因扫描,并用参数和非参数分析方法进行连锁分析。结果：在参数连 锁分析中,D6S1610的最大两点连锁（LOD值）为1．18（θ＝0．2）,D17S944的两大两点LOD值为1．60（θ＝0．1）;在非参数单点和多点连锁分析中,D6S1610、D17S944和D17S785的单点非参数（NPL）值均大于1．6,相应P值也小于0．05。结论：位点D6S1610、D17S944和D17785可能与中国人群银屑病相连锁。     

全面性癫痫伴热性惊厥附加症家系致病基因的连锁定位和突变分析

目的 筛查中国全面性癫痫伴热性惊厥附加症(GEFS+)家系的致病基因.方法 采集2个GEFS+家系所有成员的外周静脉血提取基因组DNA,选取GEFS+的候选基因(SCN1B、SCN1A、SCN2A和GABRG2)附近10个微卫星位点用于遗传连锁分析,连锁分析所用的软件为LINKAGE软件包5.1版,根据两点间的LOD值判断连锁关系,以确定两家系致病基因的大致位置.限定性定位后筛选候选致病基因,并对家系所有成员进行候选基因突变分析.结果 标记SCN1A、SCN2A和SCN1B基因的多个微卫星位点在两家系患者中均没有共享等位基因,基本排除两家系与上述3个基因连锁可能.田氏家系在标记GABRG2基因的微卫星位点D5S820、D5S422和D5S1403均有共享等位基因.经两点间连锁分析,在外显率为70%,重组率为0时,D5S820、D5S422和D5S1403处的LOD值分别为0.67,1.00和0.79,提示可能有连锁关系.邸氏家系仅在标记GABRG2基因的微卫星位点D5S1403有共享等位基因.对两家系GABRG2基因9个外显子测序结果 显示,第5号外显子出现一个单核苷酸同义多态位点(c.588C>T),第3号外显子出现一个单核苷酸多态位点(c.604C>T),第7号外显子的非编码区出现一个单核苷酸多态位点,为G/A杂合性改变,未发现GABRG2基因致病突变.结论 我国新发现的两个GEFS+家系的致病基因与目前已知候选基因SCN1B、SCN1A、SCN2A和GABRG2无关.GEFS+家系的常见致病基因仍不清楚.     

陕西省汉族人群2号染色体8个STR基因座的遗传多态性研究

目的 分析陕西汉族人群中2号染色体上8个短串联重复序列(short tandem repeat,STR)基因座的多态性.方法 采用荧光标记基因扫描对2号染色体上的D2S112、D2S162、D2S2330、D2S2216、D2S347、D2S259、D2S319和D2S168基因座的遗传多态性进行分析.结果 D2S112、D2S162、D2S2330、D2S2216、D2S347、D2S259、D2S319和D2S168基因座分别检出7、11、9、8、9、9、8和13个等位基因,15、33、23、18、13、12、25和33个基因型,等位基因型分布符合Hardy-Weinberg平衡(P＞0.05).其杂合度分别为0.6985、0.8274、0.8042、0.6816、0.6541、0.5213、0.8432和0.8091:多态信息含量分别为0.6911、0.8199、0.7891、0.6809、0.6388、0.5187、0.8372和0.8049.结论 2号染色体上的这8个STR基因座在汉族人群中有高的杂合度和多态信息量,是理想的遗传标记物.     

中国汉族人群Ⅱ型糖尿病家系1号染色体易感基因的精细定位

目的 通过增加微卫星位点密度、扩大样本量、对以前定位到1号染色体上的中国北方汉族人群2型糖尿病相关易感基因研究结果进行验证。方法 运用基因组扫描的方法,经多重PCR、电泳、GeneScan及Genotyper程序分析获取位点信息,最后经参数及非参数连锁分析,得到相关的P值、NPL值（Z值）。结果 共扫描了5个区域34个位点,检出约12000个基因型。经GENEHUNTER 2.0软件分析,其中的8个位点可能与糖尿病相连锁（P＜0.05,NPL值最大为2.17),它们分布于3个区域,尤其是第1个区域（1 p36.3-1p36.23),其每一个位点都显示与糖尿病相连锁,前后分布于1个长达16.9cM的范围内。另外2个区域未检出阳性结果。结论 证实了全基因组扫描所获得的结果。尤其是,在所研究的1P末端区域,所有研究位点都显示与疾病连锁,这些位点分布在一个很宽的范围内,提示该区域可能蛰伏着多个糖尿病易感基因。     

精神分裂症高发家系13q的连锁分析

目的在中国人群中验证精神分裂症易感基因是否与13q连锁。方法收集4个精神分裂症高发家系,采集家系成员外周血,提取DNA。在13q14-13q33选取7个微卫星标记,进行部分基因组扫描,采用GENEHUNTER2.1软件进行单点和多点的参数、非参数连锁分析。结果单点非参数连锁分析D13S156、D13S170、D13S265、D13S159、D13S158位点NPL值分别为1.40、2.25、2.06、1.71和1.39。多点非参数连锁分析得到约50cM的阳性区域。单点和多点参数连锁分析也在一些位点得到阳性结果。结论13q22.1-13q33.1染色体区域可能存在精神分裂症的易感基因。     

Linkage of familial amyotrophic lateral sclerosis with frontotemporal dementia to chromosome 9q21-q22

CONTEXT: Occasionally, 2 or more major neurodegenerative diseases arise simultaneously. An understanding of the genetic bases of combined disorders, such as amyotrophic lateral sclerosis (ALS) with frontotemporal dementia (FTD), will likely provide insight into mechanisms of these and related neurodegenerative diseases. OBJECTIVE: To identify loci that contain genes whose defects cause ALS. DESIGN: A genome-wide linkage analysis of 2 data sets from an ongoing study begun in the mid-1980s at 4 university research centers. SUBJECTS: An initial subset of 16 families (549 people) potentially informative for genetic analysis, in which 2 or more individuals were diagnosed as having ALS, identified from a Boston data set of 400 families and 4 families potentially informative (244 people) subsequently identified from a Chicago data set of more than 300 families to test a hypothesis based on findings from the Boston families. MAIN OUTCOME MEASURES: Linkage calculations assuming autosomal dominant inheritance with age-dependent penetrance (a parametric logarithm-of-odds [lod] score of 1.0 or greater required for further study of a potential locus); crossover analysis involving the ALS-FTD locus. RESULTS: In a set of families in which persons develop both ALS and FTD or either ALS or FTD alone, a genetic locus that is linked to ALS with FTD located between markers D9S301 and D9S167 was identified on human chromosome 9q21-q22. Families with ALS alone did not show linkage to this locus. Crossover analysis indicates this region covers approximately 17 cM. CONCLUSION: These data suggest that a defective gene located in the chromosome 9q21-q22 region may be linked to ALS with FTD. JAMA. 2000;284:1664-1669.     

全身性癫痫伴热性惊厥附加症家系GABRA1基因测序分析

目的对全身性癫痫伴热性惊厥附加症（GEFS＋）2家系进行基因定位，并对侯选基因GABRA1进行测序分析。方法用连锁分析的方法对GEFS＋家系进行研究；设计GABRA1外显子一内含子交界处全部11对内含子引物，采用Sanger双脱氧链终止法，对GABRA1PCR测序。结果在5q34区域最大LOD值3．815。GABRA1基因测序显示外显子；有-T／C多态性。结论GEFS＋致病基因在5q34区域取得了肯定的连锁关系。在该研究的2家系未发现GABRA1基因的突变；所显示的单个碱基多态性对其他癫痫家系的连锁分析及其他癫痫综合征分子遗传学机制的研究均有意义。     

Mapping of a gene for severe pediatric gastroesophageal reflux to chromosome 13q14

CONTEXT: Gastroesophageal reflux (GER) has not previously been widely regarded as a hereditary disease. A few reports have suggested, however, that a genetic component may contribute to the incidence of GER, especially in its severe or chronic forms. OBJECTIVE: To identify a genetic locus that cosegregates with a severe pediatric GER phenotype in families with multiple affected members. DESIGN: A genome-wide scan of families affected by severe pediatric GER using polymorphic microsatellite markers spaced at an average of 8 centimorgans (cM), followed by haplotyping and by pairwise and multipoint linkage analyses. SETTING: General US community, with research performed in a university tertiary care hospital. SUBJECTS: Affected and unaffected family members from 5 families having multiple individuals affected by severe pediatric GER, identified through a patient support group. MAIN OUTCOME MEASURES: Determination of inheritance patterns and linkage of a genetic locus with the severe pediatric GER phenotype by logarithm-of-odds (lod) score analysis, considering a lod score of 3 or greater as evidence of linkage. RESULTS: In these families, severe pediatric GER followed an autosomal dominant hereditary pattern with high penetrance. A gene for severe pediatric GER was mapped to a 13-cM region on chromosome 13q between microsatellite markers D13S171 and D13S263. A maximum multifamily 2-point lod score of 5.58 and a maximum multifamily multipoint lod score of 7.15 were obtained for marker D13S1253 at map position 35 cM when presumptively affected persons were modeled as unknown (a maximum multipoint score of 4.88 was obtained when presumptively affected persons were modeled as unaffected). CONCLUSION: These data suggest that a gene for severe pediatric GER maps to chromosome 13q14. JAMA. 2000;284:325-334     

一个新的染色体8q24.1带特异性微卫星DNA的筛选和分析

运用人类高分辨染色体显微切割，ＰＣＲ和微克隆技术构建８ｑ２４．１带特异性ｐＵＣ１９文库，筛选出一个含ＣＡ重复的新的多态微卫星ＤＮＡ（（ＣＡ）ｎ）经ＰＣＲ检测人鼠杂种细胞板，证实其来源于人８类染色体，在正常人群检出１１个等位片段，杂合度为０．８４；在１１个家系中进行连锁分析。结果显示，此多态标记与三个已知的位于８ｑ２３－２４．１区域的微卫星ＤＮＡ（Ｄ８Ｓ８５，Ｄ８Ｓ１９９，Ｄ８Ｓ２８１）紧密连锁，其     

A novel candidate locus on chromosome 11p14.1-p11.2 for autosomal dominant hereditary spastic paraplegia

Background Hereditary spastic paraplegia （HSP） is a group of inherited neurodegenerative disorders with the shared characteristics of slowly progressive spasticity and weakness of the lower limbs. Thirteen loci for autosomal dominant HSP have been mapped. Methods A Chinese family with HSP was found in the Shandong province and Inner Mongolia Autonomous Region of China and genomic DNA of all 19 family members was isolated. After exclusion of known autosomal dominant loci, a genome wide scan and linkage analysis were performed. Results The known autosomal dominant loci of SPG3A, SPG4, SPG6, SPG8, SPG9, SPG10, SPG12, SPG13, SPG17, SPG19, SPG29, SPG31 and SPG33 were excluded by linkage analysis. The results of a genome wide scan demonstrated candidate linkage to a locus on chromosome 11 p14.1-p11.2, over an 18.88 cM interval between markers D11 S1324 and D11 S1933. A maximal, two point LOD score of 2.36 for marker D11S935 at a recombination fraction （e） of 0 and a multipoint LOD score of 2.36 for markers D11S1776, D11S1751, D11S1392, D11S4203, D11S935, D11S4083, and D11S4148 at θ=0, suggest linkage to this locus. Conclusion The HSP neuropathy in this family may represent a novel genetic entity, which will facilitate discovery of this causative gene.     

Evidence for an Alzheimer Disease Susceptibility Locus on Chromosome 12 and for Further Locus Heterogeneity

Context.— Alzheimer disease (AD) susceptibility genes have been identified on chromosomes 1, 14, 19, and 21, and a recent study has suggested a locus on chromosome 12. Objective.— To confirm or refute the existence of a familial AD susceptibility locus on chromosome 12 in an independent sample of familial AD cases. Design.— Retrospective cohort study. DNA data for 6 chromosome 12 genetic markers were evaluated using parametric lod score and nonparametric linkage methods and linkage heterogeneity tests. The latter include the admixture test of homogeneity in the total group of families and the predivided sample test in families stratified by the presence or absence of an apolipoprotein E (APOE) 4 allele among affected members. Parametric analyses were repeated assuming autosomal dominant inheritance of AD and either age- and sex-dependent penetrance or zero penetrance for the analysis of unaffected relatives. Setting.— Clinical populations in the continental United States, Canada, Argentina, and Italy. Patients.— Fifty-three white families composed of multiple members affected with AD, from whom DNA samples were obtained from 173 patients with AD whose conditions were diagnosed using established criteria and from 146 nondemented relatives. Main Outcome Measure.— Presence of an APOE 4 allele among affected family members. Results.— Using parametric methods, no evidence for linkage to the region spanned by the chromosome 12 markers could be detected if familial AD is assumed to arise from the same genetic locus in all 53 families. However, significant evidence for linkage was detected in the presence of locus heterogeneity using the admixture test (odds ratio, 15, 135:1). The estimated proportion of linked families within the 53 families examined varied between 0.40 and 0.65, depending on the genetic model assumed and APOE status. The precise location of the AD gene could not be determined, but includes the entire region suggested previously. Nonparametric linkage analysis confirmed linkage to chromosome 12 with the strongest evidence at D12S96 (P<.001). Conclusions.— Our data provide independent confirmation of the existence of an AD susceptibility locus on chromosome 12 and suggest the existence of AD susceptibility genes on other chromosomes. Screening a larger set of families with additional chromosome markers will be necessary for identifying the chromosome 12 AD gene.      

肝豆状核变性基因连锁图谱的研究

为寻找适于中国人Ｗｉｌｓｏｎ氏病（ＷＤ）基因连锁分析的遗传标记及制定ＷＤ基因所在区域的遗传图谱，我们应用Ｄ１３ｑ１４－２１区域４个ＤＮＡ标记对７５名无亲缘关系个体及９个ＷＤ家系成品进行连锁分析。结果发现４个ＤＮＡ标记中３个标记等位片段与白种人相同而杂合率相异，其中２个ＤＮＡ标记Ｄ１３Ｓ３１，Ｐ１２３Ｍ１．８与ＷＤ基因存在紧密连锁关系。其遗传顺序为：着丝点－Ｒｂ－Ｄ１３Ｓ３１－ＷＮＤ。     

Tightly linked DNA probe for presymptomatic diagnosis and carrier detection of Wilson disease]

Haplotype analysis of the polymorphic loci, D13S26 and retinoblastoma (RB) gene which were closely linked to the gene responsible for Wilson disease (WD), was carried out to predict the presymptomatic stage or to detect carrier status in phenotypically normal sibs in 9 Chinese families with WD syndrome. By analysis of D13S26/HphI and RB/XbaI sites, 72% parents in these families were haplotypically heterozygote and therefore informative for linkage study. In 9 phenotypically normal sibs in these families, presymptomatic status was predicted with 99.2% confidence in 1 and excluded in 4. In the other 4 cases, 2 were unpredictable and 2 were at least heterozygote and had 50% chance of being WD homozygote, depending on which chromosome they have got from their fathers.     

6号染色体微卫星标记与哮喘表型的连锁不平衡研究

目的 探索6号染色体的有关微卫星标记与哮喘表型的关系。方法 对加个哮喘同胞及核心家系成员分别测定支气管反应性、总IgE、皮肤挑刺试验和外周血嗜酸性粒细胞的测定，并以此为哮喘的表型，与分布于6号染色体的16个微卫星标记进行连锁不平衡分析。用ETDT软件软件系统完成所有连锁不平衡分析。结果 在4种不同表型下，只有D6S1610位点与特应症的皮肤挑刺试验的连锁不平衡关系具有显著性意义。结论 6号染色体短臂D6S1610附近可能存在特应症的易感基因。