Evidence for an Alzheimer disease susceptibility locus on chromosome 12 and for further locus heterogeneity
Evidence for an Alzheimer disease susceptibility locus on chromosome 12 and for further locus heterogeneity
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DOI：
10.1001/jama.280.7.614
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发表时间：
1998-08-19
影响因子：
120.7
通讯作者：
St George-Hyslop, PH
中科院分区：
文献类型：
--
作者：
Rogaeva, E;Premkumar, S;St George-Hyslop, PH
上下文。-阿尔茨海默病(AD)的易感基因已被发现位于第1、14、19和21号染色体上，最近的一项研究表明在第12号染色体上有一个基因座。-在家族性AD病例的独立样本中，证实或否认在12号染色体上存在熟悉的AD易感基因。设计。-回溯性队列研究。对6个12号染色体遗传标记的DNA数据进行了参数Lod评分、非参数连锁分析和连锁异质性检验。后者包括在整个家系群体中进行的同质性混合检验和在受影响成员中有无载脂蛋白E(APOE)epsilon 4等位基因的家庭中进行预先划分的样本检验。重复参数分析，假设AD的常染色体显性遗传，以及年龄和性别相关的外显或零外显用于分析未受影响的亲属。-美国大陆、加拿大、阿根廷和意大利的临床人口。患者。-53个白人家庭，由多名受AD影响的成员组成，从173名AD患者和146名非痴呆亲属中提取DNA样本，这些患者的病情已根据既定标准进行诊断。-在受影响的家庭成员中存在apoE epsilon 4等位基因。-使用参数方法，如果假设家族性阿尔茨海默病发生在所有53个家庭中，则无法检测到与12号染色体标记所跨越的区域相关联的证据。然而，使用混合检验(优势比，15,135：1)，在存在基因异质性的情况下，检测到了显著的连锁证据。根据假设的遗传模式和载脂蛋白E状态的不同，所调查的53个家庭中有关联的家庭的估计比例在0.40到0.65之间。AD基因的确切位置无法确定，但包括了之前提出的整个区域。非参数连锁分析证实了与12号染色体的连锁，其中以D12S96(P<；.001)的连锁最为明显。-我们的数据独立地证实了12号染色体上存在AD易感基因，并提示在其他染色体上存在AD易感基因。为了确定12号染色体AD基因，有必要用额外的染色体标记筛选更大的一组家系。
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 familiar 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) epsilon 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 epsilon 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.