Trees Assembling Mann-Whitney approach for detecting genome-wide joint association among low-marginal-effect loci.
Trees Assembling Mann-Whitney approach for detecting genome-wide joint association among low-marginal-effect loci.
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DOI：
10.1002/gepi.21693
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发表时间：
2013-01
影响因子：
2.1
通讯作者：
Lu, Qing
中科院分区：
文献类型：
--
作者：
Wei, Changshuai;Schaid, Daniel J.;Lu, Qing
常见的复杂疾病可能受到数百甚至数千个遗传变异相互作用的影响。综合证据表明，低边际效应（LME）的遗传变异在疾病发展中发挥着重要作用。尽管具有潜在的重要性，但发现 LME 遗传变异并评估它们在高维数据上的联合关联（例如全基因组关联研究）仍然是一个巨大的挑战。为了促进 LME 遗传变异大型集合之间的联合关联分析，我们提出了一种计算高效且功能强大的方法，我们将其称为树组装 Mann-Whitney (TAMW)。通过模拟研究和实证数据应用，我们发现当潜在的复杂疾病涉及多个 LME 位点及其相互作用时，TAMW 优于多因素降维 (MDR) 和基于似然比的曼-惠特尼方法 (LRMW)。例如，在具有 20 个相互作用的 LME 位点的模拟中，TAMW 获得了比 MDR（功效 = 0.599）和 LRMW（功效 = 0.704）更高的功效（功效 = 0.931）。在对 29 个已知克罗恩病 (CD) 位点的实证研究中，TAMW 还发现与 CD 的联合关联性比 MDR 和 LRMW 检测到的关联性更强。最后，我们将 TAMW 应用于 Wellcome Trust CD GWAS 进行全基因组分析。使用并行计算在 40 小时内完成了 459K 单核苷酸多态性的分析，并揭示了易患 CD 的联合关联（p 值=2.763e-19）。对新发现的关联的进一步分析表明，ATG16L1和LACC1等13个基因可能在CD病理生理和病因过程中发挥重要作用。
Common complex diseases are likely influenced by the interplay of hundreds, or even thousands, of genetic variants. Converging evidence shows that genetic variants with low-marginal-effects (LME) play an important role in disease development. Despite their potential significance, discovering LME genetic variants and assessing their joint association on high-dimensional data (e.g., genome-wide association studies) remain a great challenge. To facilitate joint association analysis among a large ensemble of LME genetic variants, we proposed a computationally efficient and powerful approach, which we call Trees Assembling Mann-Whitney (TAMW). Through simulation studies and an empirical data application, we found that TAMW outperformed multifactor dimensionality reduction (MDR) and the likelihood-ratio-based Mann-Whitney approach (LRMW) when the underlying complex disease involves multiple LME loci and their interactions. For instance, in a simulation with 20 interacting LME loci, TAMW attained a higher power (power=0.931) than both MDR (power=0.599) and LRMW (power=0.704). In an empirical study of 29 known Crohn’s disease (CD) loci, TAMW also identified a stronger joint association with CD than those detected by MDR and LRMW. Finally, we applied TAMW to Wellcome Trust CD GWAS to conduct a genome-wide analysis. The analysis of 459K single nucleotide polymorphisms was completed in 40 hours using parallel computing, and revealed a joint association predisposing to CD (p-value=2.763e-19). Further analysis of the newly discovered association suggested that 13 genes, such as ATG16L1 and LACC1, may play an important role in CD pathophysiological and etiological processes.
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DOI：
10.1038/nrg2579
发表时间：
2009-06
期刊：
Nature reviews. Genetics
影响因子：
--
作者：
Cordell HJ
通讯作者：
Cordell HJ
影响因子：
30.8
作者：
通讯作者：
--
影响因子：
2.1
作者：
Pattin, Kristine A.;White, Bill C.;Barney, Nate;Gui, Jiang;Nelson, Heather H.;Kelsey, Karl T.;Andrew, Angeline S.;Karagas, Margaret R.;Moore, Jason H.
通讯作者：
Moore, Jason H.
影响因子：
9.8
作者：
Ritchie, MD;Hahn, LW;Moore, JH
通讯作者：
Moore, JH
影响因子：
4.9
作者：
Hanauer, SB
通讯作者：
Hanauer, SB