Table_1_Systematic Prioritization of Candidate Genes in Disease Loci Identifies TRAFD1 as a Master Regulator of IFNγ Signaling in Celiac Disease.XLSX

Celiac disease (CeD) is a complex T cell-mediated enteropathy induced by gluten. Although genome-wide association studies have identified numerous genomic regions associated with CeD, it is difficult to accurately pinpoint which genes in these loci are most likely to cause CeD. We used four different in silico approaches—Mendelian randomization inverse variance weighting, COLOC, LD overlap, and DEPICT—to integrate information gathered from a large transcriptomics dataset. This identified 118 prioritized genes across 50 CeD-associated regions. Co-expression and pathway analysis of these genes indicated an association with adaptive and innate cytokine signaling and T cell activation pathways. Fifty-one of these genes are targets of known drug compounds or likely druggable genes, suggesting that our methods can be used to pinpoint potential therapeutic targets. In addition, we detected 172 gene combinations that were affected by our CeD-prioritized genes in trans. Notably, 41 of these trans-mediated genes appear to be under control of one master regulator, TRAF-type zinc finger domain containing 1 (TRAFD1), and were found to be involved in interferon (IFN)γ signaling and MHC I antigen processing/presentation. Finally, we performed in vitro experiments in a human monocytic cell line that validated the role of TRAFD1 as an immune regulator acting in trans. Our strategy confirmed the role of adaptive immunity in CeD and revealed a genetic link between CeD and IFNγ signaling as well as with MHC I antigen processing, both major players of immune activation and CeD pathogenesis.

乳糜泻（Celiac disease, CeD）是一种由麸质诱导的复杂T细胞介导的肠病。尽管全基因组关联研究已鉴定出众多与CeD相关的基因组区域，但精准定位这些位点中最可能介导乳糜泻发病的基因仍极具挑战。我们采用四种不同的计算机模拟（in silico）方法——孟德尔随机化逆方差加权法、COLOC、连锁不平衡（Linkage Disequilibrium, LD）重叠分析及DEPICT——整合了大型转录组数据集的相关信息，最终在50个乳糜泻相关基因组区域中鉴定出118个优先候选基因。对这些基因的共表达分析与通路分析显示，其与适应性及先天细胞因子信号通路、T细胞活化通路显著相关。其中51个基因是已知药物化合物的作用靶点或潜在可药用基因，这表明本研究方法可用于精准挖掘潜在治疗靶点。此外，我们还检测到172个受乳糜泻优先候选基因反式（trans）调控的基因组合。值得注意的是，其中41个反式调控基因似乎受单一主调控因子——含TRAF型锌指结构域1（TRAFD1）——的调控，并参与干扰素γ（IFNγ）信号通路及主要组织相容性复合体I类（MHC I）抗原加工与提呈过程。最后，我们在人单核细胞系中开展体外实验，验证了TRAFD1作为反式作用免疫调控因子的功能。本研究策略证实了适应性免疫在乳糜泻发病中的作用，并揭示了乳糜泻与IFNγ信号通路及MHC I抗原加工通路之间的遗传关联，而这两者均是免疫活化及乳糜泻发病机制的核心环节。