Immunochip meta-analysis in European and Argentinian populations identifies two novel genetic loci associated with celiac disease

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

“…Interestingly, gsCD4 + T cells exhibit a Th1 profile, that predominantly produce IFNγ, a cytokine that affects the integrity of the intestinal epithelial cells contributing to villous atrophy 52–54 . REL , that is also contained in cluster 4, is a key regulator of NFκB signalling pathway, a major mediator of inflammation 71 , which is in line with the novel genetic association reported between NFκB and CeD by Ricano-Ponce et al 5 Moreover, CeD patients show a persistent activation of the NFκB pathway in the intestinal mucosa 72 as well as a significant increase in the methylation level of 8 genes that belong to this pathway 73 . Thus, these results indicate that CeD patients present with a major defect in the NFκB signalling complex.…”

“…To identify genes that most likely play a role in CeD (prioritized genes), we combined a recent genome-wide association meta analysis 5 with (1) eQTLs derived from whole-blood transcriptomes of 3,503 Dutch individuals 16 and (2) a co-regulation matrix derived from expression data in multiple different tissues and 77,000 gene expression samples 15 . We selected 1,258 genes that were within 1Mb of the 58 CeD-associated non-HLA variant regions ( p < 5×10 −6 ) (see Methods), and prioritized the genes that are the most likely causally related to CeD using four different gene prioritization methods: MR-IVW 13 , COLOC 12 , LD overlap and DEPICT 15 ( Fig.…”

“…In the present study we aimed to identify CeD candidate genes using four in silico methods (MR-IVW, COLOC, LD overlap and DEPICT) and whole blood transcriptomics data from a population-based cohort. While previous studies have used at least one of these methods 3,5,6,11 , to our knowledge this is the first effort that integrates the four different statistical approaches. This systematic prioritization approach resulted in 118 prioritized causal genes, including 26 that are direct targets of an approved drug or of drugs under development for other complex diseases, including autoimmune diseases.…”

“…We used summary statistics from a CeD GWAS meta-analysis of 12,948 cases and 14,826 controls that analysed 127,855 variants identified using the Immunochip array 5 . SNP positions were lifted over to human genome build 37 using the UCSC liftover tool.…”

“…Here, we systematically applied all four methods to the latest meta-analysis results for CeD 5 and coupled them with eQTL results from the Biobank Integrative Omics Study (BIOS) cohort 16 , one of the largest cohorts for which there is genotype and RNA-seq expression data of peripheral blood mononuclear cells (schematic overview Fig. 1A-B ).…”