Systematic Prioritization of Candidate Genes in Disease Loci Identifies as a Master Regulator of IFNγ Signaling in Celiac Disease.
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Authors
van der Graaf, AdriaanZorro, 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
Issue Date
2021-01-25
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Show full item recordAbstract
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.Citation
Front Genet. 2021 Jan 25;11:562434. doi: 10.3389/fgene.2020.562434.Affiliation
CiiM, Zentrum für individualisierte Infektionsmedizin, Feodor-Lynen-Str.7, 30625 Hannover.Publisher
FrontiersJournal
Frontiers in geneticsPubMed ID
33569077Type
ArticleLanguage
enISSN
1664-8021ae974a485f413a2113503eed53cd6c53
10.3389/fgene.2020.562434
Scopus Count
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