Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences, China.
J Neurochem. 2012 Jan;120(1):190-8. doi: 10.1111/j.1471-4159.2011.07547.x. Epub 2011 Nov 17.
Alzheimer's disease (AD) is a kind of complex neurological disorder. The complex genetic architecture of AD makes genetic analysis difficult. Fortunately, a pathway-based method to study the existing genome-wide association studies datasets has been applied into AD. However, no shared Kyoto Encyclopaedia of Genes and Genomes (KEGG) pathway was reported. In this study, we performed multiple pathway analyses of French AD genome-wide association studies dataset (discovery dataset, n = 7360, 2032 cases and 5328 controls) and Pfizer dataset (validation dataset, n = 2220, 1034 cases and 1186 controls). First, we performed multiple pathway analyses by Hypergeometric test, improved gene set enrichment analysis (IGSEA) and Z-statistic test in KEGG. Using Hypergeometric test, we identified 54 and 25 significant pathways (p < 0.05) in discovery dataset and validation dataset, respectively. Using IGSEA method, we identified three significant pathways in both discovery and validation datasets, respectively. Using Z-statistic test, we identified 19 significant pathways in validation dataset. Among the significant pathways, cell adhesion molecules (CAM) pathway was identified to be the only consistent signal emerging across multiple analyses in KEGG. After permutation and multiple testing corrections, CAM pathway was significant with p = 2.40E-05 (Hypergeometric test) and p = 3.00E-03 (IGSEA) in discovery dataset. In validation dataset, CAM pathway was significant with p = 1.84E-06 (Hypergeometric test), p = 1.00E-02 (IGSEA) and p = 2.81E-03 (Z-statistic test). We replicated the association by multiple pathway analyses in Gene Ontology using Hypergeometric test (WebGestalt), modified Fisher's exact test (DAVID) and Binomial test (PANTHER). Our findings provided further evidence on the association between CAM pathway and AD susceptibility, which would be helpful to study the genetic mechanisms of AD and may significantly assist in the development of therapeutic strategies.
阿尔茨海默病（AD）是一种复杂的神经退行性疾病。AD 的复杂遗传结构使得遗传分析变得困难。幸运的是，一种基于途径的方法已被应用于 AD 的现有全基因组关联研究数据集的研究。然而，尚未报道共同的京都基因与基因组百科全书（KEGG）途径。在这项研究中，我们对法国 AD 全基因组关联研究数据集（发现数据集，n = 7360，2032 例病例和 5328 例对照）和辉瑞数据集（验证数据集，n = 2220，1034 例病例和 1186 例对照）进行了多次途径分析。首先，我们使用超几何检验、改进的基因集富集分析（IGSEA）和 Z 统计检验在 KEGG 中进行了多次途径分析。使用超几何检验，我们在发现数据集和验证数据集中分别鉴定出 54 个和 25 个显著途径（p < 0.05）。使用 IGSEA 方法，我们在发现数据集和验证数据集中分别鉴定出三个显著途径。使用 Z 统计检验，我们在验证数据集中鉴定出 19 个显著途径。在显著途径中，细胞黏附分子（CAM）途径被鉴定为在 KEGG 中多个分析中出现的唯一一致信号。经过置换和多重检验校正后，CAM 途径在发现数据集中具有显著性，p = 2.40E-05（超几何检验）和 p = 3.00E-03（IGSEA）。在验证数据集中，CAM 途径具有显著性，p = 1.84E-06（超几何检验），p = 1.00E-02（IGSEA）和 p = 2.81E-03（Z 统计检验）。我们使用超几何检验（WebGestalt）、改良 Fisher 精确检验（DAVID）和二项式检验（PANTHER）在基因本体论中通过多种途径分析对关联进行了复制。我们的研究结果为 CAM 途径与 AD 易感性之间的关联提供了进一步的证据，这有助于研究 AD 的遗传机制，并可能显著有助于治疗策略的发展。
