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, 42 (4), 295-302

Multiple Common Variants for Celiac Disease Influencing Immune Gene Expression

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Multiple Common Variants for Celiac Disease Influencing Immune Gene Expression

Patrick C A Dubois et al. Nat Genet.

Erratum in

  • Nat Genet.2010 May;42(5):465

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.

Figures

Figure 1
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

Comment in

  • Unlocking the Pathogenesis of Celiac Disease
    RM Plenge. Nat Genet 42 (4), 281-2. PMID 20348961.
    A genome-wide association study reports more than a dozen new susceptibility loci for celiac disease. Analysis of eQTL data from these and previously established risk loc …

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