@article{1c154e7231e14272a48406cf7a4fee1b,
title = "Deep resequencing of GWAS loci identifies independent rare variants associated with inflammatory bowel disease",
abstract = "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.",
author = "Rivas, {Manuel A.} and M{\'e}lissa Beaudoin and Agnes Gardet and Christine Stevens and Yashoda Sharma and Zhang, {Clarence K.} and Gabrielle Boucher and Stephan Ripke and David Ellinghaus and Noel Burtt and Tim Fennell and Andrew Kirby and Anna Latiano and Philippe Goyette and Todd Green and Jonas Halfvarson and Talin Haritunians and Korn, {Joshua M.} and Finny Kuruvilla and Caroline Lagac{\'e} and Benjamin Neale and Lo, {Ken Sin} and Phil Schumm and Leif T{\"o}rkvist and Dubinsky, {Marla C.} and Brant, {Steven R.} and Silverberg, {Mark S.} and Duerr, {Richard H.} and David Altshuler and Stacey Gabriel and Guillaume Lettre and Andre Franke and Mauro D'Amato and McGovern, {Dermot P.B.} and Cho, {Judy H.} and Rioux, {John D.} and Xavier, {Ramnik J.} and Daly, {Mark J.}",
note = "Funding Information: We thank L. Solomon for designing figures, R. Onofrio for designing PCR primers, K. Ardlie and S. Mahan for assistance in DNA sample preparation, J. Wilkinson and L. Ambrogio for Illumina sequence project management, B. Thomson, G. Crenshaw and A. Taylor for genotyping assistance, E.S. Lander for helpful comments, the Broad Institute Sequencing Platform for sequence data production, J. Flannick and J. Maguire for assistance with pooled sequence analysis, and M. dePristo and the Broad Institute Genome Sequence Analysis Group for sequencing analysis help and useful discussions. The work was supported by US National Human Genome Research Institute sequencing grant DK83756; Funds from the Helmsley Trust to M.J.D. and R.J.X.; and US National Institutes of Health grants AI062773, DK060049, DK086502, HG005923 and DK043351 (to R.J.X.). A.G. was supported by fellowships from La Fondation pour la Recherche Medicale and the CCFA. J.D.R. holds a Canada Research Chair and is funded by grants from the US National Institutes of Allergy and Infectious Diseases (AI065687; AI067152) from the NIDDK (DK064869; DK062432), the CCFA (SRA512), La Fondation de l{\textquoteright}Institut de Cardiologie de Montr{\'e}al, the Crohn{\textquoteright}s and Colitis Foundation of Canada (CCFC), the Fonds de Recherche en Sant{\'e} du Qu{\'e}bec (17199) and the Canadian Institutes of Health Research (01038). Genotyping of the Italian samples was supported by the Italian Ministry for Health GR-2008-1144485 and unrestricted research grant of Giuliani, with case collections provided by the Italian Group for IBD. The NIDDK IBDGC is funded by the following grants: DK062431 (S.R.B.), DK062422 (J.H.C.), DK062420 (R.H.D.), DK062432 (J.D.R.), DK062423 (M.S.), DK062413 (D.P.B.M.) and DK062429 (J.H.C.). D.P.B.M. is supported by NCRR grant M01-RR00425 to the Cedars-Sinai General Research Center Genotyping Core, U01-DK062413 (IBD Genetics Research Center), P01-DK046763 (IBD Program Project Grant) and Southern California Diabetes Endocrinology Research Center grants DK063491, R21-DK84554-01 and U01 DK062413. Genotyping of the German samples was supported by the German Ministry of Education and Research through the National Genome Research Network with infrastructure support through the Deutsche Forschungsgemeinschaft cluster of excellence Inflammation at Interfaces. Genotyping of the Swedish samples was supported by the Swedish Research Council, the Bengt Ihre Foundation and the {\"O}rebro University Hospital Research Foundation.",
year = "2011",
month = nov,
doi = "10.1038/ng.952",
language = "English (US)",
volume = "43",
pages = "1066--1073",
journal = "Nature genetics",
issn = "1061-4036",
publisher = "Nature Publishing Group",
number = "11",
}