Deep resequencing of GWAS loci identifies independent rare variants associated with inflammatory bowel disease

By M. Rivas, M. Beaudoin, A. Gardet, C. Stevens, Y. Sharma, Clarence K. Zhang, G. Boucher, S. Ripke, David Ellinghaus, N. Burtt and 28 more. Nature Genetics, 2011

813 citations recorded by the source corpus.

More than 1,000 susceptibility loci have been identified through genome-wide association studies (GWAS) of common variants; however, the specific genes and full allelic spectrum of causal variants underlying these findings have not yet been defined. Here we used pooled next-generation sequencing to study 56 genes from regions associated with Crohn's disease in 350 cases and 350 controls. Through follow-up genotyping of 70 rare and low-frequency protein-altering variants in nine independent case-control series (16,054 Crohn's disease cases, 12,153 ulcerative colitis cases and 17,575 healthy controls), we identified four additional independent risk factors in NOD2, two additional protective variants in IL23R, a highly significant association with a protective splice variant in CARD9 (P < 1 × 10−16, odds ratio ≈ 0.29) and additional associations with coding variants in IL18RAP, CUL2, C1orf106, PTPN22 and MUC19. We extend the results of successful GWAS by identifying new, rare and probably functional variants that could aid functional experiments and predictive models.

Subfields: Genetics, Immunology, Surgery

View Paper: https://www.semanticscholar.org/paper/caed768735bed84d2e78fe385d8d824fc3282456

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Citations in the corpus

Cellular and inter-cellular rewiring of the human colon during ulcerative colitis (2019, background): “Known disease risk alleles highlight key pathways in the pathogenesis of IBD, including innate and adaptive immunity, gut barrier function, and pathogen sensing and response (Liu et al., 2015; Rivas et al., 2011).”
Structural activation of pro-inflammatory human cytokine IL-23 by cognate IL-23 receptor enables recruitment of the shared receptor IL-12Rβ1 (2017, background): “For instance, a G149R substitution in IL-23R D2 is thought to exert its protective behavior in IBD and Crohn’s disease via reduced expression at the cell surface (Momozawa et al., 2011; Onodera et al., 2015; Rivas et al., 2011; Sivanesan et al., 2016).”
Medical relevance of protein-truncating variants across 337,205 individuals in the UK Biobank study (2017, methodology): “html) in two cases: (1) one of the cells in the 2 × 2 allele count by case/control status contingency table is empty (2) logistic regression was attempted as all the contingency table cells were nonzero, but it failed to converge within the usual number of steps.”
Innate Immune Activity Conditions the Effect of Regulatory Variants upon Monocyte Gene Expression (2014, background): “We hypothesized that if differential expression of CARD9 is the functional mechanism underlying observed GWAS signals, the independent IFNg-specific eQTL may additionally show evidence of disease association.”
Fine-mapping inflammatory bowel disease loci to single variant resolution (2017, background): “The single variant credible sets included five previously reported coding variants: three in NOD2 (fs1007insC, R702W, G908R), a rare protective allele in IL23R (V362I) and a splice variant in CARD9 (c.IVS11+1G>C) 16,19.”