Linkage studies in familial Alzheimer disease: evidence for chromosome 19 linkage.
Linkage studies in familial Alzheimer disease: evidence for chromosome 19 linkage.
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DOI：
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发表时间：
1991-06
影响因子：
9.8
通讯作者：
M. Pericak-Vance;J. Bebout;P. Gaskell;L. Yamaoka;W. Hung;M. Alberts;A. Walker;R. Bartlett;
中科院分区：
文献类型：
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作者：
M. Pericak-Vance;J. Bebout;P. Gaskell;L. Yamaoka;W. Hung;M. Alberts;A. Walker;R. Bartlett;
阿尔茨海默病(AD)病因学中的遗传成分多年来一直得到间接证据的支持，常染色体显性遗传与年龄相关的外显性被认为是解释受试者家族聚集的原因。圣乔治·海斯洛普等人。报道了4个早发性家系中家族性阿尔茨海默病(FAD)的连锁(发病平均年龄[M]小于50岁)。随后的研究结果不一致；Goate等人。也报告了积极的Lod分数。然而，Pericak-Vance等人对一系列主要晚发性FAD家系(M>60岁)的S研究和Schellenberg等人的研究都未能证实与21号染色体(Ch21)的连锁。这些不同的研究表明了基因异质性的可能性，一些家庭与ch21相关，另一些家庭没有定位。最近，圣乔治·海斯洛普等人。扩展了他们的分析以包括其他族。扩展的分析支持了他们早期发现的与ch21相关的结果，同时显示出早发(男小于65岁)和晚发(男大于60岁)FAD家系之间的异质性的有力证据。因为我们的家庭没有显示出与ch21的连锁，所以我们进行了基因组搜索，寻找FAD的另一个基因座。由于FAD发病时年龄偏高的混杂因素，以及在我们的一些家庭中缺乏明确的孟德尔传播证据，我们采用了连锁分析的受影响家系成员(APM)方法作为可能的连锁的初始筛查。利用这种方法，我们确定了两个暗示连锁的区域：19号染色体的近端长臂(CH19)和St.George Hyslop等人报道的FAD连锁的ch21区域。对这些数据应用标准似然(LOD评分)分析支持FAD基因定位于CH19的可能性，特别是在晚发性FAD家族中。这些数据进一步提示了CH19的遗传异质性，并将该区域描绘为需要在FAD中进行进一步研究的区域。
A genetic component in the etiology of Alzheimer disease (AD) has been supported by indirect evidence for several years, with autosomal dominant inheritance with age-dependent penetrance being suggested to explain the familial aggregation of affecteds. St. George Hyslop et al. reported linkage of familial AD (FAD) in four early-onset families (mean age at onset [M] less than 50 years). Subsequent studies have been inconsistent in their results; Goate et al. also reported positive lod scores. However, both Pericak-Vance et al.'s study of a series of mainly late-onset FAD families (M greater than 60 years) and Schellenberg et al.'s study failed to confirm linkage to chromosome 21 (CH21). These various studies suggest the possibility of genetic heterogeneity, with some families linked to CH21 and others unlocalized. Recently, St. George Hyslop et al. extended their analysis to include additional families. The extended analyses supported their earlier finding of linkage to CH21, while showing strong evidence of heterogeneity between early-onset (M less than 65 years) and late-onset (M greater than 60 years) FAD families. Because our families did not show linkage to CH21, we undertook a genomic search for an additional locus for FAD. Because of both the confounding factor of late age at onset of FAD and the lack of clear evidence of Mendelian transmission in some of our families, we employed the affected-pedigree-member (APM) method of linkage analysis as an initial screen for possible linkage. Using this method, we identified two regions suggesting linkage: the proximal long arm of chromosome 19 (CH19) and the CH21 region of FAD linkage reported by St. George Hyslop et al. Application of standard likelihood (LOD score) analysis to these data support the possibility of an FAD gene locate on CH19, particularly in the late-onset FAD families. These data further suggest genetic heterogeneity and delineate this region of CH19 as an area needing additional investigation in FAD.