Multiple common variants for celiac disease influencing immune gene expression

Abstract

We performed a second-generation genome-wide association study of 4,533 individuals with celiac disease (cases) and 10,750 control subjects. We genotyped 113 selected SNPs with P(GWAS) < 10(-4) and 18 SNPs from 14 known loci in a further 4,918 cases and 5,684 controls. Variants from 13 new regions reached genome-wide significance (P(combined) < 5 x 10(-8)); most contain genes with immune functions (BACH2, CCR4, CD80, CIITA-SOCS1-CLEC16A, ICOSLG and ZMIZ1), with ETS1, RUNX3, THEMIS and TNFRSF14 having key roles in thymic T-cell selection. There was evidence to suggest associations for a further 13 regions. In an expression quantitative trait meta-analysis of 1,469 whole blood samples, 20 of 38 (52.6%) tested loci had celiac risk variants correlated (P < 0.0028, FDR 5%) with cis gene expression.

Figure 1. Co-expression analysis of genes mapping to 40 genome-wide significant and suggestive celiac disease regions in 33,109 heterogenous human samples from the Gene Expression Omnibus

Genes mapping within a 1Mb window of associated SNPs (Table 2) were tested for interaction with genes from other loci. Interactions with Pearson correlation >0.5 shown (P<10⁻¹⁰⁰). Only the genes known to contain causal mutations (HLA-DQA1, HLA-DQB1) were analysed from the HLA region, “HLA-DQB2 / HLA-DQB1” is a single expression probeset mapping to both genes. No probe for THEMIS was present on the earlier version of the U133 array, however in a subset analysis of U133 Plus2.0 data, THEMIS is co-expressed in the major immune gene cluster