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Systematic Prioritization of Candidate Genes in Disease Loci Identifies TRAFD1 as a Master Regulator of IFNγ Signaling in Celiac Disease
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 differen...
Autores principales: | , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7868554/ https://www.ncbi.nlm.nih.gov/pubmed/33569077 http://dx.doi.org/10.3389/fgene.2020.562434 |
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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 |
author_facet | 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 |
author_sort | van der Graaf, Adriaan |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-7868554 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-78685542021-02-09 Systematic Prioritization of Candidate Genes in Disease Loci Identifies TRAFD1 as a Master Regulator of IFNγ Signaling in Celiac Disease 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 Front Genet Genetics 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. Frontiers Media S.A. 2021-01-25 /pmc/articles/PMC7868554/ /pubmed/33569077 http://dx.doi.org/10.3389/fgene.2020.562434 Text en Copyright © 2021 van der Graaf, Zorro, Claringbould, Võsa, Aguirre-Gamboa, Li, Mooiweer, Ricaño-Ponce, Borek, Koning, Kooy-Winkelaar, Sollid, Qiao, Kumar, Li, Franke, Withoff, Wijmenga, Sanna, Jonkers and BIOS Consortium. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Genetics 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 Systematic Prioritization of Candidate Genes in Disease Loci Identifies TRAFD1 as a Master Regulator of IFNγ Signaling in Celiac Disease |
title | Systematic Prioritization of Candidate Genes in Disease Loci Identifies TRAFD1 as a Master Regulator of IFNγ Signaling in Celiac Disease |
title_full | Systematic Prioritization of Candidate Genes in Disease Loci Identifies TRAFD1 as a Master Regulator of IFNγ Signaling in Celiac Disease |
title_fullStr | Systematic Prioritization of Candidate Genes in Disease Loci Identifies TRAFD1 as a Master Regulator of IFNγ Signaling in Celiac Disease |
title_full_unstemmed | Systematic Prioritization of Candidate Genes in Disease Loci Identifies TRAFD1 as a Master Regulator of IFNγ Signaling in Celiac Disease |
title_short | Systematic Prioritization of Candidate Genes in Disease Loci Identifies TRAFD1 as a Master Regulator of IFNγ Signaling in Celiac Disease |
title_sort | systematic prioritization of candidate genes in disease loci identifies trafd1 as a master regulator of ifnγ signaling in celiac disease |
topic | Genetics |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7868554/ https://www.ncbi.nlm.nih.gov/pubmed/33569077 http://dx.doi.org/10.3389/fgene.2020.562434 |
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