Schellenberg G D, Payami H, Wijsman E M, Orr H T, Goddard K A, Anderson L, Nemens E, White J A, Alonso M E, Ball M J
Division of Neurology, University of Washington, Seattle 98195.
Am J Hum Genet. 1993 Sep;53(3):619-28.
Familial Alzheimer disease (FAD) is genetically heterogeneous. Two loci responsible for early-onset FAD have been identified: the amyloid precursor protein gene on chromosome 21 and the as-yet-unidentified locus on chromosome 14. The genetics of late-onset FAD is unresolved. Maximum-likelihood, affected-pedigree-member (APM), and sib-pair analyses were used, in 49 families with a mean age at onset > or = 60 years, to determine whether the chromosome 14 locus is responsible for late-onset FAD. The markers used were D14S53, D14S43, and D14S52. The LOD score method was used to test for linkage of late-onset FAD to the chromosome 14 markers, under three different models: age-dependent penetrance, an affected-only analysis, and age-dependent penetrance with allowance for possible age-dependent sporadic cases. No evidence for linkage was obtained under any of these conditions for the late-onset kindreds, and strong evidence against linkage (LOD score < or = -2.0) to this region was obtained. Heterogeneity tests of the LOD score results for the combined group of families (early onset, Volga Germans, and late onset) favored the hypothesis of linkage to chromosome 14 with genetic heterogeneity. The positive results are primarily from early-onset families. APM analysis gave significant evidence for linkage of D14S43 and D14S52 to FAD in early-onset kindreds (P < .02). No evidence for linkage was found for the entire late-onset family group. Significant evidence for linkage to D14S52, however, was found for a subgroup of families of intermediate age at onset (mean age at onset > or = 60 years and < 70 years). These results indicate that the chromosome 14 locus is not responsible for Alzheimer disease in most late-onset FAD kindreds but could play a role in a subset of these kindreds.
家族性阿尔茨海默病（FAD）在遗传上具有异质性。已确定两个与早发性FAD相关的基因座：21号染色体上的淀粉样前体蛋白基因和14号染色体上尚未确定的基因座。晚发性FAD的遗传学仍未解决。在49个平均发病年龄≥60岁的家庭中，采用最大似然法、患病家系成员（APM）分析法和同胞对分析法，以确定14号染色体基因座是否与晚发性FAD有关。所使用的标记为D14S53、D14S43和D14S52。采用对数优势（LOD）分数法，在三种不同模型下测试晚发性FAD与14号染色体标记的连锁关系：年龄依赖性外显率、仅患病个体分析以及考虑可能的年龄依赖性散发病例的年龄依赖性外显率。在这些条件下，对于晚发性家系，未获得连锁的证据，并且获得了强烈的反对该区域连锁的证据（LOD分数≤ -2.0）。对合并的家庭组（早发性、伏尔加德意志人以及晚发性）的LOD分数结果进行的异质性检验支持了与14号染色体连锁且具有遗传异质性的假设。阳性结果主要来自早发性家庭。APM分析提供了显著证据，表明在早发性家系中D14S43和D14S52与FAD连锁（P < 0.02）。在整个晚发性家庭组中未发现连锁证据。然而，在发病年龄处于中间范围的一个家系亚组（平均发病年龄≥60岁且<70岁）中，发现了与D14S52连锁的显著证据。这些结果表明，在大多数晚发性FAD家系中，14号染色体基因座与阿尔茨海默病无关，但可能在这些家系的一个子集中起作用。
