Abstract
Coeliac disease (CeD) is a highly heritable common autoimmune disease involving chronic small intestinal inflammation in response to dietary wheat. The human leukocyte antigen (HLA) region, and 40 newer regions identified by genome wide association studies (GWAS) and dense fine mapping, account for ∼40% of the disease heritability. We hypothesized that in pedigrees with multiple individuals with CeD rare [minor allele frequency (MAF) <0.5%] mutations of larger effect size (odds ratios of ∼ 2–5) might exist. We sequenced the exomes of 75 coeliac individuals of European ancestry from 55 multiply affected families. We selected interesting variants and genes for further follow up using a combination of: an assessment of shared variants between related subjects, a model-free linkage test, and gene burden tests for multiple, potentially causal, variants. We next performed highly multiplexed amplicon resequencing of all RefSeq exons from 24 candidate genes selected on the basis of the exome sequencing data in 2,248 unrelated coeliac cases and 2,230 controls. 1,335 variants with a 99.9% genotyping call rate were observed in 4,478 samples, of which 939 were present in coding regions of 24 genes (Ti/Tv 2.99). 91.7% of coding variants were rare (MAF <0.5%) and 60% were novel. Gene burden tests performed on rare functional variants identified no significant associations (p<1×10−3) in the resequenced candidate genes. Our strategy of sequencing multiply affected families with deep follow up of candidate genes has not identified any new CeD risk mutations.
Highlights
Coeliac disease (CeD) is a common complex disease of the small intestine that occurs in approximately 1% of individuals of white European ancestry [1]
We focused on the twelve families for which the pedigree is well described and examined 57 risk variants (S2 Table), including the human leukocyte antigen (HLA) subtype inferred from ImmunoChip genotype, owing to its major impact on CeD risk
These results provide some support for the hypothesis that rare highly penetrant variants may be present in these families
Summary
Coeliac disease (CeD) is a common complex disease of the small intestine that occurs in approximately 1% of individuals of white European ancestry [1]. The current number of non-HLA genetic loci found through GWAS, and more recently dense fine mapping and resequencing studies, is 40 (58 independent signals) [6,7,8]. These studies have identified common and low frequency variation in CeD, with modest effect sizes that account for *13.7% of heritability (*40% including HLA). In the last ten years, a vast number of discoveries identifying genetic variants strongly associated with susceptibility to complex traits have been made, with similar heritability estimates e.g. only 13.6% of total disease variance to Crohn’s disease risk is explained by 163 inflammatory bowel disease regions [9]
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