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Nature genetics DOI:10.1038/ng.952

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

Publication TypeJournal Article
Year of Publication2011
AuthorsRivas, MA, Beaudoin, M, Gardet, A, Stevens, C, Sharma, Y, Zhang, CK, Boucher, G, Ripke, S, Ellinghaus, D, Burtt, N, Fennell, T, Kirby, A, Latiano, A, Goyette, P, Green, T, Halfvarson, J, Haritunians, T, Korn, JM, Kuruvilla, F, Lagacé, C, Neale, B, Lo, KS, Schumm, P, Törkvist, L, National Institute of Diabetes and Digestive Kidney Diseases Inflammatory Bowel Disease Genetics Consortium (NIDDK, IBDGC), United Kingdom Inflammatory Bowel Disease Genetics, C, International Inflammatory Bowel Disease Genetics, C, Dubinsky, MC, Brant, SR, Silverberg, MS, Duerr, RH, Altshuler, D, Gabriel, S, Lettre, G, Franke, A, D'Amato, M, McGovern, DP, Cho, JH, Rioux, JD, Xavier, RJ, Daly, MJ
JournalNature genetics
Date Published2011/10/09

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.