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. 2011 Nov 6;43(12):1193-201.
doi: 10.1038/ng.998.

Dense Genotyping Identifies and Localizes Multiple Common and Rare Variant Association Signals in Celiac Disease

Free PMC article

Dense Genotyping Identifies and Localizes Multiple Common and Rare Variant Association Signals in Celiac Disease

Gosia Trynka et al. Nat Genet. .
Free PMC article


Using variants from the 1000 Genomes Project pilot European CEU dataset and data from additional resequencing studies, we densely genotyped 183 non-HLA risk loci previously associated with immune-mediated diseases in 12,041 individuals with celiac disease (cases) and 12,228 controls. We identified 13 new celiac disease risk loci reaching genome-wide significance, bringing the number of known loci (including the HLA locus) to 40. We found multiple independent association signals at over one-third of these loci, a finding that is attributable to a combination of common, low-frequency and rare genetic variants. Compared to previously available data such as those from HapMap3, our dense genotyping in a large sample collection provided a higher resolution of the pattern of linkage disequilibrium and suggested localization of many signals to finer scale regions. In particular, 29 of the 54 fine-mapped signals seemed to be localized to single genes and, in some instances, to gene regulatory elements. Altogether, we define the complex genetic architecture of the risk regions of and refine the risk signals for celiac disease, providing the next step toward uncovering the causal mechanisms of the disease.


Figure 1
Figure 1. Manhattan plot of association statistics for known and novel celiac disease risk loci
Novel loci indicated in blue, loci with multiple signals indicated with grey highlight. Significance threshold drawn at P=5×10−8.
Figure 2
Figure 2. Loci with multiple independent signals
Non-conditioned P values shown for loci with multiple independent signals (from Table 2). The most associated variant for a signal shown in bold colour, further variants in r2>0.90 (calculated from the 24,249 sample Immunochip dataset) shown in normal colour. First signal coloured blue, second coloured red, third coloured green. Squares indicate markers present in our previous celiac disease GWAS post quality control dataset (Illumina Hap550).

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