Systematic prioritization of candidate genes in disease loci identifies TRAFD1 as a master regulator of IFN gamma signaling in Celiac disease
| Autor: | Adriaan van der Graaf, Maria M. Zorro, Annique Claringbould, Urmo Võsa, Raúl Aguirre-Gamboa, Chan Li, Joram Mooiweer, Isis Ricaño-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, BIOS Consortium |
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| Přispěvatelé: | Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Stem Cell Aging Leukemia and Lymphoma (SALL), Molecular Neuroscience and Ageing Research (MOLAR) |
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Candidate gene
gene prioritization lcsh:QH426-470 In silico T cell NF-KAPPA-B lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4] Regulator TRAFD1 Computational biology VARIANTS 03 medical and health sciences All institutes and research themes of the Radboud University Medical Center 0302 clinical medicine Immune system INTRAEPITHELIAL LYMPHOCYTES MHC class I Genetics medicine trans regulation MULTIPLE COMMON expression quantitative trait locus (eQTL) Genetics (clinical) Original Research 030304 developmental biology 0303 health sciences biology Antigen processing TRANS-EQTLS fungi CYTOKINES ASSOCIATION Acquired immune system SUGGESTS lcsh:Genetics medicine.anatomical_structure CELLS biology.protein Molecular Medicine 030217 neurology & neurosurgery celiac disease RESPONSES |
| Zdroj: | Frontiers in Genetics, 11:562434. Frontiers Media S.A. Frontiers in Genetics, Vol 11 (2021) Frontiers in Genetics, 11 Frontiers in Genetics Frontiers in Genetics, 11. FRONTIERS MEDIA SA |
| ISSN: | 1664-8021 |
| Popis: | BackgroundCeliac 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.ResultsWe 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.ConclusionsOur 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. |
| Databáze: | OpenAIRE |
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