Common polygenic variation in coeliac disease and confirmation of ZNF335 and NIFA as disease susceptibility loci

Abstract

Coeliac disease (CD) is a chronic immune-mediated disease triggered by the ingestion of gluten. It has an estimated prevalence of approximately 1% in European populations. Specific HLA-DQA1 and HLA-DQB1 alleles are established coeliac susceptibility genes and are required for the presentation of gliadin to the immune system resulting in damage to the intestinal mucosa. In the largest association analysis of CD to date, 39 non-HLA risk loci were identified, 13 of which were new, in a sample of 12,014 individuals with CD and 12 228 controls using the Immunochip genotyping platform. Including the HLA, this brings the total number of known CD loci to 40. We have replicated this study in an independent Irish CD case-control population of 425 CD and 453 controls using the Immunochip platform. Using a binomial sign test, we show that the direction of the effects of previously described risk alleles were highly correlated with those reported in the Irish population, (P=2.2 × 10(-16)). Using the Polygene Risk Score (PRS) approach, we estimated that up to 35% of the genetic variance could be explained by loci present on the Immunochip (P=9 × 10(-75)). When this is limited to non-HLA loci, we explain a maximum of 4.5% of the genetic variance (P=3.6 × 10(-18)). Finally, we performed a meta-analysis of our data with the previous reports, identifying two further loci harbouring the ZNF335 and NIFA genes which now exceed genome-wide significance, taking the total number of CD susceptibility loci to 42.

Figure 1

QQ (left) and Manhattan plot (right) of −log10 (P values) for association for all SNPs on the Immunochip to CD in the Irish sample excluding the HLA/MHC locus (chr6:20–40 Mb).

Figure 2

Variance explained in an Irish Coeliac cohort by PRS derived from LD-independent SNPs from Trynka et al. Red represents the percentage variance explained (R²) when all markers are analysed (red) and for the non-HLA markers (teal). Shading indicates the proportion of total SNPs included in the model.

Figure 3

Receiver operator characteristic (ROC) curves and AUCs for the risk scores at (a) including all markers under the 0.05 threshold and (b) for the non-HLA markers at the 0.01 threshold.