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

Abstract

Celiac disease (CeD) is a common immune-mediated disease of the small intestine that is triggered by exposure to dietary gluten. While the HLA locus plays a major role in disease susceptibility, 39 non-HLA loci were also identified in a study of 24,269 individuals. We now build on this earlier study by adding 4125 additional Caucasian samples including an Argentinian cohort. In doing so, we not only confirm the previous associations, we also identify two novel independent genome-wide significant associations at loci: 12p13.31 and 22q13.1. By applying a genomics approach and differential expression analysis in CeD intestinal biopsies, we prioritize potential causal genes at these novel loci, including LTBR, CYTH4, and RAC2. Nineteen prioritized causal genes are overlapping known drug targets. Pathway enrichment analysis and expression of these genes in CeD biopsies suggest that they have roles in regulating multiple pathways such as the tumor necrosis factor (TNF) mediated signaling pathway and positive regulation of I-κB kinase/NF-κB signaling.

Fig. 1

Regional plots of genome-wide significant loci. SNP with the strongest association in the region is shown in purple. SNPs in LD with the strongest associated SNP are shown in red (r² < 1 and >0.8), orange (r² < 0.8 and >0.6), green (r² < 0.6 and >0.4), light blue (r² < 0.4 and >0.2), and dark blue (r² < 0.2). Lower panel shows the genes located within the region. a Association signals at the 1q25.3 locus. b Association signals at the 3p14.1 locus. c Association signals at the 12p13.31 locus. d Association signals at the 22q13.1 locus

Fig. 2

FRMD4B (3p14.1) locus. a The risk allele (underlined in red) of the Top-SNP rs6806528:C>T increases the expression of the FRMD4B gene (p = 3.36 × 10⁻⁶). The number of individuals analyzed is shown under each genotype. b FRMD4B gene function predictions based on GeneNetwork, a co-expression-based network

Fig. 3

12p13.31 locus. a Functional predictions based on GeneNetwork for genes affected by the most-associated SNP in the locus (rs9610686:C>T). b Expression of the CYTH4 and RAC2 genes is significantly higher in CeD cases with a Marsh III diagnosis, as compared to healthy controls

Fig. 4

Functional annotation of the 12p13.31 locus containing LTBR. a The risk allele (underlined in red) of Top-SNP rs2364484:C>R, the strongest association in the 12p13.31 locus, increases the expression of the LTBR gene (p = 1.51 × 10⁻⁹). Number of individuals analyzed is shown under each genotype. b The expression of the LTBR gene is significantly higher in CeD cases with a Marsh III diagnosis, compared with healthy controls. c The risk allele of Top-SNP rs2364484:C>R (underlined in red) significantly increases the concentration of LTBR in plasma of healthy individuals