Dai Yulin, Pei Guangsheng, Zhao Zhongming, Jia Peilin
Center for Precision Health, School of Biomedical Informatics, The University of Texas Health Science Center at Houston, Houston, TX, United States.
Human Genetics Center, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, United States.
Front Genet. 2019 Apr 9;10:318. doi: 10.3389/fgene.2019.00318. eCollection 2019.
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.
克罗恩病（CD）是炎症性肠病（IBD）的主要形式之一。据报道，遗传和非遗传风险因素的组合会导致CD的发生。已经进行了许多高通量组学研究，以确定可能导致CD的疾病相关风险变异，如全基因组关联研究（GWAS）和下一代测序研究。仍然迫切需要对构成CD病因的候选基因进行优先级排序和特征描述。在本研究中，我们从GWAS、基因表达和甲基化研究中收集了全面的多维度数据，并生成了转录组范围关联研究（TWAS）数据，以进一步解释GWAS关联结果。我们应用我们之前开发的称为优势比元分析（MegaOR）的方法对CD候选基因（CDgenes）进行优先级排序。结果，我们基于证据矩阵确定了CDgenes的共识集（62 - 235个基因）。我们证明，这些CDgenes相互之间的相互作用明显比随机预期的更频繁。这些基因的功能注释突出了关键的免疫相关过程，如免疫反应、MHC II类受体活性和免疫紊乱。特别是，发现组成型光形态建成9（COP9）信号体相关基因在CDgenes中显著富集，这意味着COP9信号体在CD发病机制中可能发挥作用。最后，我们发现一些CDgenes与已知的CD药物靶点具有共同的生物学功能，如炎症反应调节和白细胞与血管内皮细胞的粘附。总之，我们从多维度证据中确定了高度可信的CDgenes，为理解CD病因提供了见解。
