Systematic prioritization of candidate genes in disease loci identifies TRAFD1 as a master regulator of IFNγ signalling in celiac disease

Abstract

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.

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

“…TRAFD1 Is Trans-Regulator in CeD IE-CTL cell lines, Prof. Morris Swertz for data storage and cluster facilities, and Kate McIntyre for editing the manuscript. A preliminary version of this manuscript has been released as a preprint at BioRxiv (Graaf et al, 2020).…”

“…We prioritized CeD-associated genes using three eQTL-based methods-MR-IVW (Burgess and Thompson, 2017), COLOC (Giambartolomei et al, 2014), and LD overlap-and one coregulation-based method, DEPICT (Pers et al, 2015). For the MR-IVW method, we used the independent variants identified by GCTA-COJO as instrumental variables (Yang et al, 2012;Burgess et al, 2013) to test causal relationships between changes in gene expression and CeD, as we have demonstrated that this procedure is preferred over p-value clumping (van der Graaf et al, 2020). MR-IVW was only performed when there were three or more independent eQTLs available (164 genes).…”

Molecular Biomarkers for Celiac Disease: Past, Present and Future

“…Together, these loci and the HLA loci explain more than 40% of the heritability of CeD [ 30 ]. Many of the genes in these loci are immune genes [ 31 ]. Since most of the non-HLA CeD single-nucleotide polymorphisms (SNPs) are located in the non-coding genome, they are likely to contribute to CeD pathology by affecting the expression of genes involved in the biological pathways that are perturbed in CeD.…”

“…Since most of the non-HLA CeD single-nucleotide polymorphisms (SNPs) are located in the non-coding genome, they are likely to contribute to CeD pathology by affecting the expression of genes involved in the biological pathways that are perturbed in CeD. Although a single SNP might affect only the risk of developing CeD to a small extent, a combination of multiple SNPs and loci may affect downstream central hub genes that could implicate novel biomarkers and therapeutic targets [ 31 , 32 ]. Accompanying the recent publication of data from large case–control genome-wide association studies and population controls, such as the UK biobank, is the now possible ability to calculate genetic risk scores that combine the additive risk of multiple CeD risk-SNPs into one score to indicate the risk of developing CeD [ 10 , 33 , 34 ].…”

Potential impact of celiac disease genetic risk factors on T cell receptor signaling in gluten-specific CD4+ T cells

“…More than 95% of the single nucleotide polymorphisms (SNPs) associated with CeD are located in the non-coding genome and presumably deregulate genes important for CeD etiology 27 . Enrichment analysis of the CeD SNPs in regulatory regions suggests that CD4+ T cells are the major cell type affected by genetic risk factors 28 – 30 . Moreover, pathway and cis -eQTL analyses of genes in CeD loci suggest that they affect T cell receptor (TCR) signaling via alteration of expression of genes such as UBASH3A , CD28 and CSK 30 – 32 .…”