Discovery by the Epistasis Project of an epistatic interaction between the GSTM3 gene and the HHEX/IDE/KIF11 locus in the risk of Alzheimer's disease
Discovery by the Epistasis Project of an epistatic interaction between the GSTM3 gene and the HHEX/IDE/KIF11 locus in the risk of Alzheimer's disease
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DOI：
10.1016/j.neurobiolaging.2012.08.010
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发表时间：
2013-04-01
影响因子：
4.2
通讯作者：
Morgan, Kevin
中科院分区：
文献类型：
--
作者：
Bullock, James M.;Medway, Christopher;Morgan, Kevin
尽管最近在散发性阿尔茨海默病的遗传学方面有了新的发现，但仍然存在大量的“隐藏遗传性”。据认为，这种遗传性缺失的部分原因可能是由于基因与基因之间的相互作用，即上位性相互作用。我们检查了 1757 例阿尔茨海默氏病病例和 6294 名上位性项目对照受试者的 110 个候选多态性之间的潜在上位性，分为发现数据集和复制数据集。我们发现 GSTM3 中的 rs7483 和 HHEX/IDE/KIF11 基因簇中的 rs1111875 之间存在上位相互作用，两个数据集中的结果非常相似且显着。组合数据集中的协同因子（SF）为1.79，95%置信区间[CI]为1.35-2.36； p = 0.00004。在我们事后检查的 8 个附加子集中，有 7 个也发现了一致的相互作用：即，在北欧和西班牙北部、男性和女性、有或没有载脂蛋白 E ε 4 等位基因的人和 75 岁以上的人中都显示出一致的相互作用（SF，2.27；95% CI，1.60-3.20；p < 0.00001），但在75 岁以下的人（SF，1.06；95% CI，0.59-1.91；p = 0.84）。与阿尔茨海默氏病的关联纯粹是上位性，两种多态性均未显示出独立效应：比值比，1.0； p >= 0.7。事实上，在没有其他因素的情况下，每个因素都与保护相关，但在其他因素存在的情况下，则与风险相关。总之，当按性别、载脂蛋白 E 基因型的 epsilon 4 等位基因和地理区域分层时，这种上位相互作用表现出高度的一致性。 (C) 2013 Elsevier Inc. 保留所有权利。
Despite recent discoveries in the genetics of sporadic Alzheimer's disease, there remains substantial "hidden heritability." It is thought that some of this missing heritability may be because of gene-gene, i.e., epistatic, interactions. We examined potential epistasis between 110 candidate polymorphisms in 1757 cases of Alzheimer's disease and 6294 control subjects of the Epistasis Project, divided between a discovery and a replication dataset. We found an epistatic interaction, between rs7483 in GSTM3 and rs1111875 in the HHEX/IDE/KIF11 gene cluster, with a closely similar, significant result in both datasets. The synergy factor (SF) in the combined dataset was 1.79, 95% confidence interval [CI], 1.35-2.36; p = 0.00004. Consistent interaction was also found in 7 out of the 8 additional subsets that we examined post hoc: i.e., it was shown in both North Europe and North Spain, in both men and women, in both those with and without the epsilon 4 allele of apolipoprotein E, and in people older than 75 years (SF, 2.27; 95% CI, 1.60-3.20; p < 0.00001), but not in those younger than 75 years (SF, 1.06; 95% CI, 0.59-1.91; p = 0.84). The association with Alzheimer's disease was purely epistatic with neither polymorphism showing an independent effect: odds ratio, 1.0; p >= 0.7. Indeed, each factor was associated with protection in the absence of the other factor, but with risk in its presence. In conclusion, this epistatic interaction showed a high degree of consistency when stratifying by sex, the epsilon 4 allele of apolipoprotein E genotype, and geographic region. (C) 2013 Elsevier Inc. All rights reserved.