Computational Biology; Crohn Disease/etiology/genetics; Genetic Linkage; Genetic Loci/genetics; Genetic Predisposition to Disease; Genetic Variation; Genome, Human/genetics; Genome-Wide Association Study; Humans; Reproducibility of Results
Abstract :
[en] We undertook a meta-analysis of six Crohn's disease genome-wide association studies (GWAS) comprising 6,333 affected individuals (cases) and 15,056 controls and followed up the top association signals in 15,694 cases, 14,026 controls and 414 parent-offspring trios. We identified 30 new susceptibility loci meeting genome-wide significance (P < 5 x 10). A series of in silico analyses highlighted particular genes within these loci and, together with manual curation, implicated functionally interesting candidate genes including SMAD3, ERAP2, IL10, IL2RA, TYK2, FUT2, DNMT3A, DENND1B, BACH2 and TAGAP. Combined with previously confirmed loci, these results identify 71 distinct loci with genome-wide significant evidence for association with Crohn's disease.
Barrett, J.C. et al. Genome-wide association defnes more than 30 distinct susceptibility loci for Crohn's disease. Nat. Genet. 40, 955-962 (2008).
Duerr, R.H. et al. A genome-wide association study identifes IL23R as an infammatory bowel disease gene. Science 314, 1461-1463 (2006).
Wellcome Trust Case Control Consortium. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 447, 661-678 (2007).
Libioulle, C. et al. Novel Crohn disease locus identifed by genome-wide association maps to a gene desert on 5p13.1 and modulates expression of PTGER4. PLoS Genet. 3, e58 (2007).
Imielinski, M. et al. Common variants at fve new loci associated with early-onset infammatory bowel disease. Nat. Genet. 41, 1335-1340 (2009).
McGovern, D.P. et al. Fucosyltransferase 2 (FUT2) non-secretor status is associated with Crohn's disease. Hum. Mol. Genet. 19, 3468-3476 (2010).
Zhernakova, A. et al. Genetic analysis of innate immunity in Crohn's disease and ulcerative colitis identifes two susceptibility loci harboring CARD9 and IL18RAP. Am. J. Hum. Genet. 82, 1202-1210 (2008).
Dixon, A.L. et al. A genome-wide association study of global gene expression. Nat. Genet. 39, 1202-1207 (2007).
Raychaudhuri, S. et al. Identifying relationships among genomic disease regions: predicting genes at pathogenic SNP associations and rare deletions. PLoS Genet. 5, e1000534 (2009).
Rueda, B. et al. The IL23R Arg381Gln non-synonymous polymorphism confers susceptibility to ankylosing spondylitis. Ann. Rheum. Dis. 67, 1451-1454 (2008).
Yamazaki, K. et al. Single nucleotide polymorphisms in TNFSF15 confer susceptibility to Crohn′s disease. Hum. Mol. Genet. 14, 3499-3506 (2005).
Zinovieva, E. et al. Comprehensive linkage and association analyses identify haplotype, near to the TNFSF15 gene, signifcantly associated with spondyloarthritis. PLoS Genet. 5, e1000528 (2009).
Franke, A. et al. Sequence variants in IL10, ARPC2 and multiple other loci contribute to ulcerative colitis susceptibility. Nat. Genet. 40, 1319-1323 (2008).
Carlsson, B. et al. The G428A nonsense mutation in FUT2 provides strong but not absolute protection against symptomatic GII.4 Norovirus infection. PLoS ONE 4, e5593 (2009).
Gamper, C.J., Agoston, A.T., Nelson, W.G. & Powell, J.D. Identifcation of DNA methyltransferase 3a as a T cell receptor-induced regulator of Th1 and Th2 differentiation. J. Immunol. 183, 2267-2276 (2009).
El Gazzar, M. et al. G9a and HP1 couple histone and DNA methylation to TNFα transcription silencing during endotoxin tolerance. J. Biol. Chem. 283, 32198-32208 (2008).
Park, J.H. et al. Estimation of effect size distribution from genome-wide association studies and implications for future discoveries. Nat. Genet. 42, 570-575 (2010).
Yang, J. et al. Common SNPs explain a large proportion of the heritability for human height. Nat. Genet. 42, 565-569 (2010).
Murray, R.Z., Kay, J.G., Sangermani, D.G. & Stow, J.L. A role for the phagosome in cytokine secretion. Science 310, 1492-1495 (2005).
Luftman, K., Hasan, N., Day, P., Hardee, D. & Hu, C. Silencing of VAMP3 inhibits cell migration and integrin-mediated adhesion. Biochem. Biophys. Res. Commun. 380, 65-70 (2009).
Campbell, B.J., Yu, L.G. & Rhodes, J.M. Altered glycosylation in infammatory bowel disease: a possible role in cancer development. Glycoconj. J. 18, 851-858 (2001).
McAuley, J.L. et al. MUC1 cell surface mucin is a critical element of the mucosal barrier to infection. J. Clin. Invest. 117, 2313-2324 (2007).
Mota, L.J., Ramsden, A.E., Liu, M., Castle, J.D. & Holden, D.W. SCAMP3 is a component of the Salmonella-induced tubular network and reveals an interaction between bacterial effectors and post-Golgi traffcking. Cell. Microbiol. 11, 1236-1253 (2009).
Sleiman, P.M. et al. Variants of DENND1B associated with asthma in children. N. Engl. J. Med. 362, 36-44 (2010).
Glocker, E.O. et al. Infammatory bowel disease and mutations affecting the interleukin-10 receptor. N. Engl. J. Med. 361, 2033-2045 (2009).
Danik, J.S. et al. Novel loci, including those related to Crohn disease, psoriasis, and infammation, identifed in a genome-wide association study of fbrinogen in 17,686 women: the Women's Genome Health Study. Circ. Cardiovasc. Genet. 2, 134-141 (2009).
Rippe, V. et al. Identifcation of a gene rearranged by 2p21 aberrations in thyroid adenomas. Oncogene 22, 6111-6114 (2003).
Saveanu, L. et al. Concerted peptide trimming by human ERAP1 and ERAP2 aminopeptidase complexes in the endoplasmic reticulum. Nat. Immunol. 6, 689-697 (2005).
Burton, P.R. et al. Association scan of 14,500 nonsynonymous SNPs in four diseases identifes autoimmunity variants. Nat. Genet. 39, 1329-1337 (2007).
Harvey, K.F., Shearwin-Whyatt, L.M., Fotia, A., Parton, R.G. & Kumar, S. N4WBP5, a potential target for ubiquitination by the Nedd4 family of proteins, is a novel Golgi-associated protein. J. Biol. Chem. 277, 9307-9317 (2002).
Putz, U. et al. Nedd4 family-interacting protein 1 (Ndfp1) is required for the exosomal secretion of Nedd4 family proteins. J. Biol. Chem. 283, 32621-32627 (2008).
Xi, H., Schwartz, R., Engel, I., Murre, C. & Kersh, G.J. Interplay between RORγt, Egr3, and E proteins controls proliferation in response to pre-TCR signals. Immunity 24, 813-826 (2006).
Mao, M. et al. T lymphocyte activation gene identifcation by coregulated expression on DNA microarrays. Genomics 83, 989-999 (2004).
Dendrou, C.A. et al. Cell-specifc protein phenotypes for the autoimmune locus IL2RA using a genotype-selectable human bioresource. Nat. Genet. 41, 1011-1015 (2009).
Burchill, M.A., Yang, J., Vang, K.B. & Farrar, M.A. Interleukin-2 receptor signaling in regulatory T cell development and homeostasis. Immunol. Lett. 114, 1-8 (2007).
Stroud, C.K. et al. Disruption of FADS2 gene in mice impairs male reproduction and causes dermal and intestinal ulceration. J. Lipid Res. 50, 1870-1880 (2009).
Loser, K. et al. Epidermal RANKL controls regulatory T-cell numbers via activation of dendritic cells. Nat. Med. 12, 1372-1379 (2006).
Moschen, A.R. et al. The RANKL/OPG system is activated in infammatory bowel disease and relates to the state of bone loss. Gut 54, 479-487 (2005).
Lu, L. et al. Role of SMAD and non-SMAD signals in the development of Th17 and regulatory T cells. J. Immunol. 184, 4295-4306 (2010).
Ghoreschi, K., Laurence, A. & O'Shea, J.J. Janus kinases in immune cell signaling. Immunol. Rev. 228, 273-287 (2009).
Hazra, A. et al. Common variants of FUT2 are associated with plasma vitamin B12 levels. Nat. Genet. 40, 1160-1162 (2008).
Hindorff, L.A. et al. Potential etiologic and functional implications of genome-wide association loci for human diseases and traits. Proc. Natl. Acad. Sci. USA 106, 9362-9367 (2009).
Yu, W., Clyne, M., Khoury, M.J. & Gwinn, M. Phenopedia and Genopedia: disease-centered and gene-centered views of the evolving knowledge of human genetic associations. Bioinformatics 26, 145-146 (2010).
Rioux, J.D. et al. Genome-wide association study identifes new susceptibility loci for Crohn disease and implicates autophagy in disease pathogenesis. Nat. Genet. 39, 596-604 (2007).
Parkes, M. et al. Sequence variants in the autophagy gene IRGM and multiple other replicating loci contribute to Crohn's disease susceptibility. Nat. Genet. 39, 830-832 (2007).
Fried, L.P. et al. The Cardiovascular Health Study: design and rationale. Ann. Epidemiol. 1, 263-276 (1991).
Browning, B.L. & Browning, S.R. A unifed approach to genotype imputation and haplotype-phase inference for large data sets of trios and unrelated individuals. Am. J. Hum. Genet. 84, 210-223 (2009).
Browning, S.R. & Browning, B.L. Rapid and accurate haplotype phasing and missing-data inference for whole-genome association studies by use of localized haplotype clustering. Am. J. Hum. Genet. 81, 1084-1097 (2007).