Pathway-based analysis of primary biliary cirrhosis genome-wide association studies.
Pathway-based analysis of primary biliary cirrhosis genome-wide association studies.
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DOI：
10.1038/gene.2013.1
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发表时间：
2013-04
影响因子：
5
通讯作者：
Amos, C. I.
中科院分区：
文献类型：
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作者：
Kar, S. P.;Seldin, M. F.;Chen, W.;Lu, E.;Hirschfield, G. M.;Invernizzi, P.;Heathcote, J.;Cusi, D.;Gershwin, M. E.;Siminovitch, K. A.;Amos, C. I.
全基因组关联研究（GWAS）已经成功地确定了与原发性胆汁性肝硬化（PBC）风险相关的几个位点。途径分析补充了传统的GWAS分析。我们应用最近开发的线性组合测试的途径，数据集来自独立的PBC GWAS在意大利和加拿大的主题。在所测试的京都基因和基因组百科全书以及BioCarta途径中，意大利数据集（449例，940例对照）中的25条途径和加拿大数据集（530例，398例对照）中的26条途径与PBC易感性相关（P < 0.05）。在对多重比较进行校正后，意大利数据集中只有8个最重要的通路FDR < 0.25，肿瘤坏死因子/应激相关信号通路成为最重要的通路（P = 7.38 × 10−4，FDR = 0.18）。两种途径，磷脂酰肌醇信号传导和hedgehog信号传导，在两个数据集中重复（P < 0.05），并进行两个额外的互补途径测试。在意大利数据集中，两种途径信号在改良基因集富集分析中均保持显著性（P < 0.05）。在两个GWAS中，名义上与PBC相关的变体在磷脂酰肌醇途径中显著过度表达（Fisher精确P < 0.05）。这些结果表明，建立和新的途径水平的关联与PBC的遗传易感性，进一步独立复制和功能验证，可能会提供新的见解PBC病因。
Genome-wide association studies (GWAS) have successfully identified several loci associated with primary biliary cirrhosis (PBC) risk. Pathway analysis complements conventional GWAS analysis. We applied the recently developed linear combination test for pathways to datasets drawn from independent PBC GWAS in Italian and Canadian subjects. Of the Kyoto Encyclopedia of Genes and Genomes and BioCarta pathways tested, 25 pathways in the Italian dataset (449 cases, 940 controls) and 26 pathways in the Canadian dataset (530 cases, 398 controls) were associated with PBC susceptibility (P < 0.05). After correcting for multiple comparisons, only the eight most significant pathways in the Italian dataset had FDR < 0.25 with tumor necrosis factor/stress-related signaling emerging as the top pathway (P = 7.38 × 10−4, FDR = 0.18). Two pathways, phosphatidylinositol signaling and hedgehog signaling, were replicated in both datasets (P < 0.05), and subjected to two additional complementary pathway tests. Both pathway signals remained significant in the Italian dataset on modified gene set enrichment analysis (P < 0.05). In both GWAS, variants nominally associated with PBC were significantly overrepresented in the phosphatidylinositol pathway (Fisher exact P < 0.05). These results point to established and novel pathway-level associations with inherited predisposition to PBC that on further independent replication and functional validation, may provide fresh insights into PBC etiology.
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影响因子：
13.5
作者：
Lleo, Ana;Selmi, Carlo;Invernizzi, Pietro;Podda, Mauro;Coppel, Ross L.;Maclay, Ian R.;Gores, Gregory J.;Ansari, Aftab A.;de Water, Judy Van;Gershwin, M. Eric
通讯作者：
Gershwin, M. Eric
影响因子：
25.7
作者：
Jones, DEJ;Watt, FE;James, OFW
通讯作者：
James, OFW
影响因子：
13.5
作者：
Jung, Youngmi;McCall, Shannon J.;Diehl, Anna Mae
通讯作者：
Diehl, Anna Mae
影响因子：
30.8
作者：
通讯作者：
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全基因组的荟萃分析鉴定了与原发性胆道肝硬化相关的三个基因座。
影响因子：
30.8
作者：
通讯作者：
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