Systematic permutation testing in GWAS pathway analyses: identification of genetic networks in dilated cardiomyopathy and ulcerative colitis.
Systematic permutation testing in GWAS pathway analyses: identification of genetic networks in dilated cardiomyopathy and ulcerative colitis.
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DOI：
10.1186/1471-2164-15-622
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发表时间：
2014-07-22
期刊：
影响因子：
4.4
通讯作者：
Keller A
中科院分区：
文献类型：
--
作者：
Backes C;Rühle F;Stoll M;Haas J;Frese K;Franke A;Lieb W;Wichmann HE;Weis T;Kloos W;Lenhof HP;Meese E;Katus H;Meder B;Keller A
全基因组关联研究（GWAS）被应用于识别与复杂性状和人类疾病相关的遗传位点。类似于基因表达分析的演变，通路分析已经成为揭示全基因组关联数据的功能网络的重要工具。通常，途径分析结合联合收割机统计方法与先验生物学知识。为了确定相关通路的显著性阈值，应用多重检验和过度代表性排列检验的校正。我们系统地研究了三种不同的置换检验方法对过度代表性分析的影响，以检测假阳性途径候选者，并评估它们对扩张型心肌病（DCM）和溃疡性结肠炎（UC）全基因组关联数据的影响。我们的研究结果提供的证据表明，金标准-置换病例对照状态-有效地提高了GWAS途径分析的特异性。虽然SNP的排列不能维持连锁不平衡（LD），但当病例对照排列不可能时，这些排列代表了GWAS数据的替代方案。然而，基因排列并没有显著增加特异性。最后，我们提供了所需的排列数的估计调查的方法。为了发现潜在的假阳性功能通路候选者，并支持标准统计检验（如超几何检验）的结果，应进行病例对照数据的排列检验。最合理的替代方案是病例对照排列，如果这是不可能的，可以进行SNP排列。我们的研究还表明，随着排列数量的增加，显著性值迅速收敛。通过应用所描述的统计框架，我们能够发现轴突引导、粘着斑和钙信号传导是重要的DCM相关途径，并且用于伊加产生的肠免疫网络是最重要的UC途径。
Genome wide association studies (GWAS) are applied to identify genetic loci, which are associated with complex traits and human diseases. Analogous to the evolution of gene expression analyses, pathway analyses have emerged as important tools to uncover functional networks of genome-wide association data. Usually, pathway analyses combine statistical methods with a priori available biological knowledge. To determine significance thresholds for associated pathways, correction for multiple testing and over-representation permutation testing is applied. We systematically investigated the impact of three different permutation test approaches for over-representation analysis to detect false positive pathway candidates and evaluate them on genome-wide association data of Dilated Cardiomyopathy (DCM) and Ulcerative Colitis (UC). Our results provide evidence that the gold standard - permuting the case–control status – effectively improves specificity of GWAS pathway analysis. Although permutation of SNPs does not maintain linkage disequilibrium (LD), these permutations represent an alternative for GWAS data when case–control permutations are not possible. Gene permutations, however, did not add significantly to the specificity. Finally, we provide estimates on the required number of permutations for the investigated approaches. To discover potential false positive functional pathway candidates and to support the results from standard statistical tests such as the Hypergeometric test, permutation tests of case control data should be carried out. The most reasonable alternative was case–control permutation, if this is not possible, SNP permutations may be carried out. Our study also demonstrates that significance values converge rapidly with an increasing number of permutations. By applying the described statistical framework we were able to discover axon guidance, focal adhesion and calcium signaling as important DCM-related pathways and Intestinal immune network for IgA production as most significant UC pathway.
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影响因子：
10.5
作者：
Bendig, Garnet;Grimmler, Matthias;Rottbauer, Wolfgang
通讯作者：
Rottbauer, Wolfgang
影响因子：
4.6
作者：
Fish, Jason E.;Wythe, Joshua D.;Woo, Stephanie
通讯作者：
Woo, Stephanie
DOI：
10.1111/j.2517-6161.1995.tb02031.x
发表时间：
1995-01-01
影响因子：
5.8
作者：
BENJAMINI, Y;HOCHBERG, Y
通讯作者：
HOCHBERG, Y
影响因子：
1.8
作者：
Gui H;Li M;Sham PC;Cherny SS
通讯作者：
Cherny SS
DOI：
10.1073/pnas.0903103106
发表时间：
2009-06-09
影响因子：
11.1
作者：
Hindorff, Lucia A.;Sethupathy, Praveen;Manolio, Teri A.
通讯作者：
Manolio, Teri A.