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

Abstract

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.

Linking common and rare disease genetics through gene regulatory networks

“…These pathway enrichments recapitulated previous findings, for example the roles of T cell receptor (TCR) and cytokine signalling in CeD 78, 79 and the KEGG pathway representing T1D and asthma genes being significantly enriched for T1D and asthma, respectively (Data S1). However, we also observed new enrichments as a result of the increased statistical power of the predicted, as opposed to the directly annotated-pathway memberships (Fig.…”

Single-Cell RNA Sequencing of Peripheral Blood Mononuclear Cells From Pediatric Coeliac Disease Patients Suggests Potential Pre-Seroconversion Markers

“…To date, 43 genetic risk factors have been identified for CeD, excluding the HLA locus, which accounts for approximately 40% of disease risk ( 44 , 45 ). In order to detect the cell types that are most likely affected by CeD genetic factors, we intersected our DEGs with the CeD risk/causal genes prioritized in another study ( 24 ). Among 118 genes potentially causal in CeD, nine ( NCF2, RAC2, TAGAP, REL, GPR183, STAT1, IRF1, ICOS and RGS1 ) were significantly differentially expressed in at least one comparison in our data ( Figure 7A ).…”

“…(A) Heatmap with the log2FC of all intersected DEGs with the 118 risk genes prioritized from CeD loci from v. d. Graaf et al. ( 24 ). Vertical axis shows the name of the genes.…”

“…These genes are of great interest for diagnostic purposes because their levels are raised in individuals who later develop CeD and they are expressed in a high fraction of the NK cells ( Figure 5A ). Interestingly, one of these genes is TAGAP , whose locus has been genetically associated to several infectious and autoimmune diseases, including candidemia ( 54 ), multiple sclerosis ( 55 ) and CeD ( 24 ). We find TAGAP to be differentially expressed in both the CD4+ T cell and NK subsets.…”

“…We only characterized transcripts that were expressed in > 10% of the cells of each subset and filtered in DEGs with an absolute log2FC > 0.25 and an adjusted p-value < 0.05. We then checked the data for the presence of 118 genes previously genetically associated with CeD and prioritized to play a possible causal role in CeD ( 24 ).…”