TY - JOUR T1 - Systematic prioritization of candidate genes in disease loci identifies <em>TRAFD1</em> as a master regulator of IFNγ signalling in celiac disease JF - bioRxiv DO - 10.1101/2020.03.04.973487 SP - 2020.03.04.973487 AU - Adriaan van der Graaf AU - Maria Zorro AU - Annique Claringbould AU - Urmo Vosa AU - Raul Aguirre-Gamboa AU - Chan Li AU - Joram Mooiweer AU - Isis Ricano-Ponce AU - Zuzanna Borek AU - Frits Koning AU - Yvonne Kooy-Winkelaar AU - Ludvig Sollid AU - Shuo-Wang Qiao AU - BIOS consortium AU - Vinod Kumar AU - Yang Li AU - Lude Franke AU - Sebo Withoff AU - Cisca Wijmenga AU - Serena Sanna AU - Iris Jonkers Y1 - 2020/01/01 UR - http://biorxiv.org/content/early/2020/03/05/2020.03.04.973487.abstract N2 - Background 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.Results 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 signalling and T cell activation pathways. 51 of these genes are targets of known drug compounds and 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, TRAFD1, and were found to be involved in IFNγ signalling and MHC I antigen processing/presentation. Finally, we performed in vitro experiments that validated the role of TRAFD1 as an immune regulator acting in trans.Conclusions Our strategy has confirmed the role of adaptive immunity in CeD and revealed a genetic link between CeD and the IFNγ signalling and MHC I antigen processing pathways, both major players of immune activation and CeD pathogenesis.eQTLexpression quantitative trait locus, a location on the genome that is statistically associated to changes in gene expression.cis-eQTLan eQTL located in the same locus of the gene that is being interrogated (within 1.5Mb from gene transcript start or end).trans-eQTLan eQTL that is not physically close to the gene that is being interrogated (&gt;1.5Mb from transcript start/end or on a different chromosome).cis-eQTL genea gene that is associated with a change in expression as a consequence of a cis-eQTL.trans-eQTL genea gene that is associated with a change in expression as a consequence of a trans-eQTL.CeDceliac diseaseCeD-associated regiona genomic region that is associated to CeD based on results from genome-wide association studies on CeD.Prioritized genea gene prioritized as being potentially causal for CeD according to the four statistical methods depicted in Figure 1A-B. In this study, prioritized genes are always within the CeD-associated regions.Mediating cis genea prioritized gene that is statistically responsible for the change in expression of a trans-eQTL gene. Of note, while the trans-eQTL is located in the same CeD-associated region of the mediating cis-gene, the mediated trans-gene is not.Mediated trans genea gene located outside CeD-associated regions that is statistically mediated by a mediating cis gene located in the same region of the corresponding trans-eQTL. ER -