Hidden Risk Genes with High-Order Intragenic Epistasis in Alzheimer's Disease
Hidden Risk Genes with High-Order Intragenic Epistasis in Alzheimer's Disease
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DOI：
10.3233/jad-140054
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发表时间：
2014-01-01
影响因子：
4
通讯作者：
Lei, Hongxing
中科院分区：
文献类型：
--
作者：
Sun, Jiya;Song, Fuhai;Lei, Hongxing
对阿尔茨海默病（AD）全基因组关联研究（GWAS）数据的荟萃分析证实了APOE的高风险，并确定了其他20个具有中等效应大小的风险基因/位点。然而，更多的风险基因/位点仍有待发现，以解释缺失的遗传力。单个单核苷酸多态性（SNP）的贡献在传统的GWAS数据分析中已经得到了彻底的研究，而SNP-SNP相互作用可以通过各种替代方法进行探索。在这里，我们应用广义多因素降维对四个公开可用的AD GWAS数据集进行重新分析。当考虑4阶基因内SNP相互作用时，我们观察到在四个独立的GWAS数据集中发现的潜在风险基因的高度一致性。在所有四个数据集中观察到十个潜在风险基因，包括PDE 1A、RYR 3、TEK、SLC 25 A21、LOC 729852、KIRK 3、PTPN 5、FSHR、PARK 2和NR 3C 2。广义多因素降维发现的这些潜在风险基因与AD发病机制高度相关，基于多层次的证据。这些基因的遗传贡献需要在其他独立的AD GWAS数据集中进一步确认。
Meta-analysis of data from genome-wide association studies (GWAS) of Alzheimer's disease (AD) has confirmed the high risk of APOE and identified twenty other risk genes/loci with moderate effect size. However, many more risk genes/loci remain to be discovered to account for the missing heritability. The contributions from individual singe-nucleotide polymorphisms (SNPs) have been thoroughly examined in traditional GWAS data analysis, while SNP-SNP interactions can be explored by a variety of alternative approaches. Here we applied generalized multifactor dimensionality reduction to the re-analysis of four publicly available GWAS datasets for AD. When considering 4-order intragenic SNP interactions, we observed high consistency of discovered potential risk genes among the four independent GWAS datasets. Ten potential risk genes were observed across all four datasets, including PDE1A, RYR3, TEK, SLC25A21, LOC729852, KIRREL3, PTPN5, FSHR, PARK2, and NR3C2. These potential risk genes discovered by generalized multifactor dimensionality reduction are highly relevant to AD pathogenesis based on multiple layers of evidence. The genetic contributions of these genes warrant further confirmation in other independent GWAS datasets for AD.