Interaction between variants in CLU and MS4A4E modulates Alzheimer's disease risk.
Interaction between variants in CLU and MS4A4E modulates Alzheimer's disease risk.
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DOI：
10.1016/j.jalz.2015.08.163
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发表时间：
2016-02
期刊：
影响因子：
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通讯作者：
Kauwe JSK
中科院分区：
文献类型：
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作者：
Ebbert MTW;Boehme KL;Wadsworth ME;Staley LA;Alzheimer's Disease Neuroimaging Initiative;Alzheimer's Disease Genetics Consortium;Mukherjee S;Crane PK;Ridge PG;Kauwe JSK
Ebbert等人报告了rs 11136000-rs670139（CLU-MS 4A 4 E）和rs3865444-rs670139（CD 33-MS 4A 4 E）之间的基因-基因相互作用。我们在上位性研究的最大数据集中评估这些相互作用。我们使用来自ADGC的3837例病例和4145例对照，使用Meta分析和排列分析来测试相互作用。我们重复了按APOEε4状态分层的荟萃分析，估计了合并OR和人群归因分数（cPAF），并探讨了因果变异。结果支持CLU-MS 4A 4 E相互作用和显性效应。CLU-MS 4A 4 E和APOEε4阴性状态之间存在关联。rs 11136000-rs670139的估计协同因子、OR和cPAF分别为2.23、2.45和8.0。我们确定了潜在的因果变异。我们在一个大的病例对照系列中复制了CLU-MS 4A 4 E相互作用，APOEε4和可能的显性效应。CLU-MS 4A 4 E OR高于除APOEε4、APP和TREM 2之外的任何阿尔茨海默病基因座。我们估计，在没有CLU-MS 4A 4 E风险等位基因的情况下，阿尔茨海默病的发病率降低了8%，并确定了潜在的因果变异。
Ebbert et al. reported gene-gene interactions between rs11136000-rs670139 (CLU-MS4A4E) and rs3865444-rs670139 (CD33-MS4A4E). We evaluate these interactions in the largest dataset for an epistasis study. We tested interactions using 3837 cases and 4145 controls from ADGC using meta- and permutation analyses. We repeated meta-analyses stratified by APOEε4 status, estimated combined OR and population attributable fraction (cPAF), and explored causal variants. Results support the CLU-MS4A4E interaction and a dominant effect. An association between CLU-MS4A4E and APOEε4 negative status exists. The estimated synergy factor, OR, and cPAF for rs11136000-rs670139 are 2.23, 2.45 and 8.0, respectively. We identified potential causal variants. We replicated the CLU-MS4A4E interaction in a large case-control series, with APOEε4 and possible dominant effect. The CLU-MS4A4E OR is higher than any Alzheimer’s disease locus except APOEε4, APP, and TREM2. We estimated an 8% decrease in Alzheimer’s disease incidence without CLU-MS4A4E risk alleles and identified potential causal variants.