A Convergent Study of Genetic Variants Associated With Crohn's Disease: Evidence From GWAS, Gene Expression, Methylation, eQTL and TWAS
A Convergent Study of Genetic Variants Associated With Crohn's Disease: Evidence From GWAS, Gene Expression, Methylation, eQTL and TWAS
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DOI：
10.3389/fgene.2019.00318
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发表时间：
2019-04-09
影响因子：
3.7
通讯作者：
Jia, Peilin
中科院分区：
文献类型：
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作者：
Dai, Yulin;Pei, Guangsheng;Jia, Peilin
克罗恩病（CD）是炎症性肠道疾病（IBD）的主要形式之一。据报道，遗传和非遗传风险因素的组合有助于CD的发展。已经进行了许多高通量组学研究来鉴定可能导致CD的疾病相关风险变体，例如全基因组关联研究（GWAS）和下一代测序研究。一个迫切的需要仍然优先考虑和表征候选基因的病因CD。在这项研究中，我们从GWAS、基因表达和甲基化研究中收集了全面的多维数据，并生成了全转录组关联研究（TWAS）数据，以进一步解释GWAS关联结果。我们应用我们以前开发的称为巨型比值比分析（MegaOR）的方法来优先考虑CD候选基因（CDgenes）。因此，我们根据证据矩阵确定了CD基因的共识集（62-235个基因）。我们证明了这些CD基因比随机预期的更频繁地相互作用。这些基因的功能注释突出了关键的免疫相关过程，如免疫应答，MHC II类受体活性和免疫疾病。特别是，组成型光形态发生9（COP 9）信号体相关基因被发现显着丰富的CD基因，这意味着COP 9信号体参与CD的发病机制的潜在作用。最后，我们发现一些CD基因与已知的CD药物靶点具有共同的生物学功能，如调节炎症反应和白细胞与血管内皮细胞的粘附。总之，我们从多方面的证据中确定了高度可信的CD基因，为CD病因学的理解提供了见解。
Crohn's Disease (CD) is one of the predominant forms of inflammatory bowel disease (IBD). A combination of genetic and non-genetic risk factors have been reported to contribute to the development of CD. Many high-throughput omics studies have been conducted to identify disease associated risk variants that might contribute to CD, such as genome-wide association studies (GWAS) and next generation sequencing studies. A pressing need remains to prioritize and characterize candidate genes that underlie the etiology of CD. In this study, we collected a comprehensive multi-dimensional data from GWAS, gene expression, and methylation studies and generated transcriptome-wide association study (TWAS) data to further interpret the GWAS association results. We applied our previously developed method called mega-analysis of Odds Ratio (MegaOR) to prioritize CD candidate genes (CDgenes). As a result, we identified consensus sets of CDgenes (62-235 genes) based on the evidence matrix. We demonstrated that these CDgenes were significantly more frequently interact with each other than randomly expected. Functional annotation of these genes highlighted critical immune-related processes such as immune response, MHC class II receptor activity, and immunological disorders. In particular, the constitutive photomorphogenesis 9 (COP9) signalosome related genes were found to be significantly enriched in CDgenes, implying a potential role of COP9 signalosome involved in the pathogenesis of CD. Finally, we found some of the CDgenes shared biological functions with known drug targets of CD, such as the regulation of inflammatory response and the leukocyte adhesion to vascular endothelial cell. In summary, we identified highly confident CDgenes from multi-dimensional evidence, providing insights for the understanding of CD etiology.