Epistatic genetic effects among Alzheimer's candidate genes.
Epistatic genetic effects among Alzheimer's candidate genes.
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DOI：
10.1371/journal.pone.0080839
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Alzheimer's Neuroimaging Initiative
中科院分区：
文献类型：
--
作者：
Hohman TJ;Koran ME;Thornton-Wells T;Alzheimer's Neuroimaging Initiative
晚发性阿尔茨海默病（AD）的新风险变体已在全基因组关联研究中被鉴定和复制。最近的工作已经开始解决这些风险变体与AD生物标志物之间的关系，尽管结果好坏参半。本研究的目的是描述与淀粉样蛋白沉积相关的最佳候选单核苷酸多态性（SNP）之间的单标记和上位遗传效应。我们使用了ADNI-1和ADNI-2的组合数据集，并分别在每个数据集内进行查看，以验证已识别的遗传效应。使用通过正电子发射断层扫描（PET）用18F-AV-45获得的数据定量淀粉样蛋白。 当校正多重比较时，两个SNP-SNP相互作用达到显著性，BIN 1（rs7561528，rs744373）x PICALM（rs7851179）。携带BIN 1中的次要等位基因与较高水平的淀粉样蛋白沉积相关，但仅在保护性PICALM次要等位基因的非携带者中。 我们的研究结果支持了先前的研究，表明这些候选SNP与淀粉样蛋白病理学没有表现出单一标记关联。然而，我们提供的证据PICALM和BIN 1之间的一种新的相互作用，淀粉样蛋白沉积。与BIN 1次要等位基因相关的风险似乎在PICALM保护性变体的存在下减轻。通过这种方式，淀粉样斑块负荷的变化可以在复杂的遗传背景下更好地分类。AD累积风险模型的建立应明确说明这种上位效应，未来的研究应在统计学上可行时明确测试这种效应。
Novel risk variants for late-onset Alzheimer’s disease (AD) have been identified and replicated in genome-wide association studies. Recent work has begun to address the relationship between these risk variants and biomarkers of AD, though results have been mixed. The aim of the current study was to characterize single marker and epistatic genetic effects between the top candidate Single Nucleotide Polymorphisms (SNPs) in relation to amyloid deposition. We used a combined dataset across ADNI-1 and ADNI-2, and looked within each dataset separately to validate identified genetic effects. Amyloid was quantified using data acquired by Positron Emission Tomography (PET) with 18F-AV-45. Two SNP-SNP interactions reached significance when correcting for multiple comparisons, BIN1 (rs7561528, rs744373) x PICALM (rs7851179). Carrying the minor allele in BIN1 was related to higher levels of amyloid deposition, however only in non-carriers of the protective PICALM minor allele. Our results support previous research suggesting these candidate SNPs do not show single marker associations with amyloid pathology. However, we provide evidence for a novel interaction between PICALM and BIN1 in relation to amyloid deposition. Risk related to the BIN1 minor allele appears to be mitigated in the presence of the PICALM protective variant. In that way, variance in amyloid plaque burden can be better classified within the context of a complex genetic background. Efforts to model cumulative risk for AD should explicitly account for this epistatic effect, and future studies should explicitly test for such effects whenever statistically feasible.
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影响因子：
30.8
作者：
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通讯作者：
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通讯作者：
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影响因子：
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作者：
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通讯作者：
Fischl, Bruce