Systematic Prioritization of Candidate Genes in Disease Loci Identifies as a Master Regulator of IFNγ Signaling in Celiac Disease.
Cast your vote
You can rate an item by clicking the amount of stars they wish to award to this item.
When enough users have cast their vote on this item, the average rating will also be shown.
Your vote was cast
Thank you for your feedback
Thank you for your feedback
Authorsvan der Graaf, Adriaan
Zorro, Maria M
Sollid, Ludvig M
MetadataShow full item record
AbstractCeliac 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.
CitationFront Genet. 2021 Jan 25;11:562434. doi: 10.3389/fgene.2020.562434.
AffiliationCiiM, Zentrum für individualisierte Infektionsmedizin, Feodor-Lynen-Str.7, 30625 Hannover.
JournalFrontiers in genetics
The following license files are associated with this item:
- Creative Commons
- Genome-Wide Association Study-Guided Exome Rare Variant Burden Analysis Identifies IL1R1 and CD3E as Potential Autoimmunity Risk Genes for Celiac Disease.
- Authors: Mansour H, Banaganapalli B, Nasser KK, Al-Aama JY, Shaik NA, Saadah OI, Elango R
- Issue date: 2022
- Mendelian randomization analysis of celiac GWAS reveals a blood expression signature with diagnostic potential in absence of gluten consumption.
- Authors: Fernandez-Jimenez N, Bilbao JR
- Issue date: 2019 Sep 15
- Systematic annotation of celiac disease loci refines pathological pathways and suggests a genetic explanation for increased interferon-gamma levels.
- Authors: Kumar V, Gutierrez-Achury J, Kanduri K, Almeida R, Hrdlickova B, Zhernakova DV, Westra HJ, Karjalainen J, Ricaño-Ponce I, Li Y, Stachurska A, Tigchelaar EF, Abdulahad WH, Lähdesmäki H, Hofker MH, Zhernakova A, Franke L, Lahesmaa R, Wijmenga C, Withoff S
- Issue date: 2015 Jan 15
- Summary-data-based Mendelian randomization prioritizes potential druggable targets for multiple sclerosis.
- Authors: Jacobs BM, Taylor T, Awad A, Baker D, Giovanonni G, Noyce AJ, Dobson R
- Issue date: 2020
- A Two-Sample Mendelian Randomization Analysis Investigates Associations Between Gut Microbiota and Celiac Disease.
- Authors: García-Santisteban I, Cilleros-Portet A, Moyua-Ormazabal E, Kurilshikov A, Zhernakova A, Garcia-Etxebarria K, Fernandez-Jimenez N, Bilbao JR
- Issue date: 2020 May 14