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Resequencing of positional candidates identifies low frequency IL23R coding variants protecting against inflammatory bowel disease

Abstract

Genome-wide association studies (GWAS) have identified dozens of risk loci for many complex disorders, including Crohn's disease1,2. However, common disease-associated SNPs explain at most 20% of the genetic variance for Crohn's disease. Several factors may account for this unexplained heritability3,4,5, including rare risk variants not adequately tagged thus far in GWAS6,7,8. That rare susceptibility variants indeed contribute to variation in multifactorial phenotypes has been demonstrated for colorectal cancer9, plasma high-density lipoprotein cholesterol levels10, blood pressure11, type 1 diabetes12, hypertriglyceridemia13 and, in the case of Crohn's disease, for NOD2 (refs. 14,15). Here we describe the use of high-throughput resequencing of DNA pools to search for rare coding variants influencing susceptibility to Crohn's disease in 63 GWAS-identified positional candidate genes. We identify low frequency coding variants conferring protection against inflammatory bowel disease in IL23R, but we conclude that rare coding variants in positional candidates do not make a large contribution to inherited predisposition to Crohn's disease.

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Figure 1: Frequency distribution of minor allele frequencies for different categories of variants.

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Acknowledgements

This work was funded by the Walloon Region (IPSEQ, Crohn & CIBLES projects), by the Politique Scientifique Fédérale (IAP GENFUNC), by the Fonds National de la Recherche Scientifique (FNRS) and by the Communauté Française de Belgique (ARC BIOMOD). E.L. is a senior research associate from the FNRS. K.N. benefitted from a post-doctoral fellowship from the University of Liège. We are grateful to A. Kvasz, F. Farnir and D. Baurain for their help with bioinformatic analyses. We thank the personnel of the Flanders Institute for Biotechnology (VIB) Genetic Service Facility (http://www.vibgeneticservicefacility.be) and the GIGA-R genotranscriptomic platform for their contribution to sequencing. We are grateful to N. Wray and P. Visscher for fruitful discussions.

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Y.M., M.M., K.N., L.A., D.G. and D.Z. performed experiments. Y.M., W.C., P.d.R. and M.G. analyzed data. M. Lathrop and J.D.-F. supervised experiments. S.A., L.A., J.-F.C., O.D., Y.F., M.A.G., M. Lémann, C.O., C.R., P.R., C.T., J.-P.H., M.d.V., D.F., S.V. and E.L. examined cases and collected samples. I.C., D.L. and C.L. prepared and organized samples. Y.M. and M.G. wrote the manuscript.

Corresponding author

Correspondence to Michel Georges.

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The authors declare no competing financial interests.

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Supplementary Note, Supplementary Tables 1–10 and Supplementary Figures 1–3 (PDF 1015 kb)

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Momozawa, Y., Mni, M., Nakamura, K. et al. Resequencing of positional candidates identifies low frequency IL23R coding variants protecting against inflammatory bowel disease. Nat Genet 43, 43–47 (2011). https://doi.org/10.1038/ng.733

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