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

Manuel A. Rivas, Mélissa Beaudoin, Agnes Gardet, Christine Stevens, Yashoda Sharma, Clarence K. Zhang, Gabrielle Boucher, Stephan Ripke, David Ellinghaus, Noel Burtt, Tim Fennell, Andrew Kirby, Anna Latiano, Philippe Goyette, Todd Green, Jonas Halfvarson, Talin Haritunians, Joshua M. Korn, Finny Kuruvilla, Caroline LagacéBenjamin Neale, Ken Sin Lo, Phil Schumm, Leif Törkvist, Marla C. Dubinsky, Steven R. Brant, Mark S. Silverberg, Richard H. Duerr, David Altshuler, Stacey Gabriel, Guillaume Lettre, Andre Franke, Mauro D'Amato, Dermot P B McGovern, Judy H. Cho, John D. Rioux, Ramnik J. Xavier, Mark J. Daly

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)1066-1073
Number of pages8
JournalNature Genetics
Issue number11
Publication statusPublished - Nov 2011

ASJC Scopus subject areas

  • Genetics


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