AUTHOR=van der Graaf Adriaan , Zorro Maria M. , Claringbould Annique , Võsa Urmo , Aguirre-Gamboa Raúl , Li Chan , Mooiweer Joram , Ricaño-Ponce Isis , Borek Zuzanna , Koning Frits , Kooy-Winkelaar Yvonne , Sollid Ludvig M. , Qiao Shuo-Wang , Kumar Vinod , Li Yang , Franke Lude , Withoff Sebo , Wijmenga Cisca , Sanna Serena , Jonkers Iris , BIOS Consortium TITLE=Systematic Prioritization of Candidate Genes in Disease Loci Identifies TRAFD1 as a Master Regulator of IFNγ Signaling in Celiac Disease JOURNAL=Frontiers in Genetics VOLUME=11 YEAR=2021 URL=https://www.frontiersin.org/journals/genetics/articles/10.3389/fgene.2020.562434 DOI=10.3389/fgene.2020.562434 ISSN=1664-8021 ABSTRACT=

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.