An Association Study of Common Variation at the MAPT Locus With Late-Onset Alzheimer's Disease
An Association Study of Common Variation at the MAPT Locus With Late-Onset Alzheimer's Disease
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DOI：
10.1002/ajmg.b.30951
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发表时间：
2009-12-05
影响因子：
2.8
通讯作者：
Owen, Michael J.
中科院分区：
文献类型：
--
作者：
Abraham, Richard;Sims, Rebecca;Owen, Michael J.
编码Tau的MAPT基因位于染色体17q21上，该区域已经进化成两种主要的单倍型H1和H2。有强有力的证据表明，H1单倍型和一个亚单倍型(H1c)被过度表达，并与散发性互补性疾病、进行性核上性麻痹(PSP)和皮质基底性变性(CBD)的风险增加相关。PSP和CBD病例的Tau病理表现与晚发性阿尔茨海默病(LOAD)相似。然而，许多研究MAPT在LOAD中的遗传参与的关联研究产生了相互矛盾的结果。在这里，我们使用了大量病例对照样本来对已被证明定义H1/H2状态和H1内变异性的SNP进行基因分型。单标记关联分析没有发现任何SNP与负荷风险相关的证据。当考虑到性别和载脂蛋白4状态时，我们观察到与SNP rs242557有关联(P=0.02)。样本分层显示仅在APOE4阳性个体中与rs242557相关(P=0.01隐性模型)，然而这一结果不能经受多次校正。病例组和对照组的H1/H2单倍型分布差异无统计学意义。我们还测试了H1背景上特定亚单倍型的关联性，同样的结果是否定的。没有观察到任何被研究的标记物对发病年龄的影响。总之，我们没有发现等位基因或单倍型与MAPT基因和LOAD中的SNPs相关的证据。在APOE4阳性个体中，SNP rs242557在名义上显著。在所研究的SNP中，没有一个是为了负载而修饰AAO的。(C)2009年Wiley-Liss，Inc.
The MAPT gene that encodes Tau is located on chromosome 17q21, in a region, which has evolved to form two major haplotypes, H1 and H2. There is strong evidence that the H1 haplotype, and a sub-haplotype (H1C), are overrepresented and associated with increased risk for the sporadic tauopathies, progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). Both PSP and CBD cases display Tau pathology similar to Late-Onset Alzheimer's Disease (LOAD). However, numerous association studies investigating the genetic involvement of MAPT in LOAD have generated conflicting results. Here we have used a large LOAD case-control sample to genotype SNPs that have been shown to define H1/H2 status and intra-H1 variability. Single marker association analyses found no evidence that any of the SNPs are associated with risk of LOAD. When gender and APOE4 status were taken into account we observed suggestive association for SNP rs242557 (P=0.02). Stratification of the sample revealed association with rs242557 only in APOE4 positive individuals (P=0.01 recessive model), however this result would not survive multiple correction. There was no significant difference in H1/H2 haplotype distribution between cases and controls. We also tested the association of specific sub-haplotypes on the H1 background and likewise results were negative. No effect was observed on disease age of onset for any of the markers studied. In summary, we find no evidence for allelic or haplotypic association, with SNPs in the MAPT gene and LOAD. SNP rs242557 is nominally significant in the APOE4 positive individuals. None of the SNPs studied modified AAO for LOAD. (C) 2009 Wiley-Liss, Inc.