Systematic Prioritization of Candidate Genes in Disease Loci Identifies TRAFD1 as a Master Regulator of IFN gamma Signaling in Celiac Disease

BIOS Consortium, Adriaan van der Graaf, Maria M. Zorro, Annique Claringbould, Urmo Vosa, Raul Aguirre-Gamboa, Chan Li, Joram Mooiweer, Isis Ricano-Ponce, Zuzanna Borek, Frits Koning, Yvonne Kooy-Winkelaar, Ludvig M. Sollid, Shuo-Wang Qiao, Vinod Kumar, Yang Li, Lude Franke, Sebo Withoff, Cisca Wijmenga, Serena Sanna*Iris Jonkers

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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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)gamma 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 IFN gamma signaling as well as with MHC I antigen processing, both major players of immune activation and CeD pathogenesis.

Original languageEnglish
Article number562434
Number of pages16
JournalFrontiers in Genetics
Volume11
DOIs
Publication statusPublished - 25-Jan-2021

Keywords

  • celiac disease
  • gene prioritization
  • expression quantitative trait locus (eQTL)
  • TRAFD1
  • trans regulation
  • NF-KAPPA-B
  • INTRAEPITHELIAL LYMPHOCYTES
  • MULTIPLE COMMON
  • TRANS-EQTLS
  • VARIANTS
  • ASSOCIATION
  • CELLS
  • CYTOKINES
  • RESPONSES
  • SUGGESTS

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