Journal
NATURE GENETICS
Volume 43, Issue 11, Pages 1066-U50Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ng.952
Keywords
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Categories
Funding
- US National Human Genome Research Institute [DK83756, AI062773, DK060049, DK086502, HG005923, DK043351]
- Helmsley Trust
- La Fondation pour la Recherche Medicale
- CCFA
- Canada Research Chair
- US National Institutes of Allergy and Infectious Diseases [AI065687, AI067152]
- NIDDK [DK064869, DK062432]
- CCFA [SRA512]
- La Fondation de l'Institut de Cardiologie de Montreal
- Crohn's and Colitis Foundation of Canada (CCFC)
- Fonds de Recherche en Sante du Quebec [17199]
- Canadian Institutes of Health Research [01038]
- Italian Ministry for Health [GR-2008-1144485]
- Giuliani
- NCRR [M01-RR00425, U01-DK062413, P01-DK046763]
- Southern California Diabetes Endocrinology Research Center [DK063491, R21-DK84554-01, U01 DK062413]
- German Ministry of Education and Research through the National Genome Research Network
- Swedish Research Council
- Bengt Ihre Foundation
- rebro University Hospital Research Foundation
- [DK062431]
- [DK062422]
- [DK062420]
- [DK062423]
- [DK062413]
- [DK062429]
- MRC [G0600329, G0800675] Funding Source: UKRI
- Chief Scientist Office [ETM/75, CZB/4/540] Funding Source: researchfish
- Crohn's and Colitis UK [M11-1] Funding Source: researchfish
- Medical Research Council [G0600329, G0800675] Funding Source: researchfish
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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 x 10(-16), odds ratio approximate to 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.
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