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

      research-article
      1 , 2 , 3 , , 4 , 5 , 2 , 6 , 6 , 4 , 1 , 2 , 7 , 2 , 2 , 1 , 2 , 8 , 4 , 2 , 9 , 10 , 2 , 2 , 11 , 4 , 1 , 2 , 4 , 12 , 14 , NIDDK IBD Genetics Consortium, International Inflammatory Bowel Disease Genetics Consortium, 15 , 17 , 13 , 17 , 1 , 2 , 2 , 4 , 7 , 18 , 10 , 19 , 6 , 4 , 1 , 2 , 5 , 1 , 2 ,
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          Abstract

          More than a thousand disease susceptibility loci have been identified via genome-wide association studies (GWAS) of common variants; however, the specific genes and full allelic spectrum of causal variants underlying these findings generally remain to be defined. We utilize pooled next-generation sequencing to study 56 genes in regions associated to Crohn’s Disease in 350 cases and 350 controls. Follow up genotyping of 70 rare and low-frequency protein-altering variants (MAF ~ .001-.05) in nine independent case-control series (16054 CD patients, 12153 UC patients, 17575 healthy controls) identifies four additional independent risk factors in NOD2, two additional protective variants in IL23R, a highly significant association to a novel, protective splice variant in CARD9 ( p < 1e-16, OR ~ 0.29), as well as additional associations to coding variants in IL18RAP, CUL2, C1orf106, PTPN22 and MUC19. We extend the results of successful GWAS by providing novel, rare, and likely functional variants that will empower functional experiments and predictive models.

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          Most cited references26

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          Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn's disease.

          Crohn's disease and ulcerative colitis, the two main types of chronic inflammatory bowel disease, are multifactorial conditions of unknown aetiology. A susceptibility locus for Crohn's disease has been mapped to chromosome 16. Here we have used a positional-cloning strategy, based on linkage analysis followed by linkage disequilibrium mapping, to identify three independent associations for Crohn's disease: a frameshift variant and two missense variants of NOD2, encoding a member of the Apaf-1/Ced-4 superfamily of apoptosis regulators that is expressed in monocytes. These NOD2 variants alter the structure of either the leucine-rich repeat domain of the protein or the adjacent region. NOD2 activates nuclear factor NF-kB; this activating function is regulated by the carboxy-terminal leucine-rich repeat domain, which has an inhibitory role and also acts as an intracellular receptor for components of microbial pathogens. These observations suggest that the NOD2 gene product confers susceptibility to Crohn's disease by altering the recognition of these components and/or by over-activating NF-kB in monocytes, thus documenting a molecular model for the pathogenic mechanism of Crohn's disease that can now be further investigated.
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            Generation of Pathogenic Th17 Cells in the Absence of TGF-β Signaling

            CD4+ T cells that selectively produce interleukin (IL)-17, are critical for host defense and autoimmunity 1–4 . Crucial for T helper17 (Th17) cells in vivo 5,6 , IL-23 has been thought to be incapable of driving initial differentiation. Rather, IL-6 and transforming growth factor (TGF)-β1 have been argued to be the factors responsible for initiating specification 7–10 . Herein, we show that Th17 differentiation can occur in the absence of TGF-β signaling. Neither IL-6 nor IL-23 alone efficiently generated Th17 cells; however, these cytokines in combination with IL-1β effectively induced IL-17 production in naïve precursors, independently of TGF-β. Epigenetic modification of the Il17a/Il17f and Rorc promoters proceeded without TGF-β1, allowing the generation of cells that co-expressed Rorγt and T-bet. T-bet+ Rorγt+ Th17 cells are generated in vivo during experimental allergic encephalomyelitis (EAE), and adoptively transferred Th17 cells generated with IL-23 without TGF-β1 were pathogenic in this disease model. These data suggest an alternative mode for Th17 differentiation. Consistent with genetic data linking IL23R with autoimmunity, our findings re-emphasize the importance of IL-23 and therefore have may have therapeutic implications.
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              Genome-wide association identifies multiple ulcerative colitis susceptibility loci.

              Ulcerative colitis is a chronic, relapsing inflammatory condition of the gastrointestinal tract with a complex genetic and environmental etiology. In an effort to identify genetic variation underlying ulcerative colitis risk, we present two distinct genome-wide association studies of ulcerative colitis and their joint analysis with a previously published scan, comprising, in aggregate, 2,693 individuals with ulcerative colitis and 6,791 control subjects. Fifty-nine SNPs from 14 independent loci attained an association significance of P < 10(-5). Seven of these loci exceeded genome-wide significance (P < 5 x 10(-8)). After testing an independent cohort of 2,009 cases of ulcerative colitis and 1,580 controls, we identified 13 loci that were significantly associated with ulcerative colitis (P < 5 x 10(-8)), including the immunoglobulin receptor gene FCGR2A, 5p15, 2p16 and ORMDL3 (orosomucoid1-like 3). We confirmed association with 14 previously identified ulcerative colitis susceptibility loci, and an analysis of acknowledged Crohn's disease loci showed that roughly half of the known Crohn's disease associations are shared with ulcerative colitis. These data implicate approximately 30 loci in ulcerative colitis, thereby providing insight into disease pathogenesis.
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                Author and article information

                Journal
                9216904
                2419
                Nat Genet
                Nat. Genet.
                Nature Genetics
                1061-4036
                1546-1718
                24 May 2012
                09 October 2011
                19 June 2012
                : 43
                : 11
                : 1066-1073
                Affiliations
                [1 ]Analytic and Translational Genetics Unit (ATGU), Massachusetts General Hospital, Boston, MA, USA
                [2 ]Broad Institute of Harvard and MIT, Cambridge, MA, USA
                [3 ]Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK
                [4 ]Université de Montréal and Research Centre, Montreal Heart Institute, Montreal, Quebec, Canada
                [5 ]Gastrointenstinal Unit, Center for the Study of the Inflammatory Bowel Disease and Center for Computational and Integrative Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
                [6 ]Keck Biotechnology Resource Laboratory and Yale School of Medicine, New Haven, Connecticut, USA
                [7 ]Institute of Clinical Molecular Biology, Schittenhelmstr. 12, D-24105 Kiel, Germany
                [8 ]Unit of Gastroenterology, IRCCS - Casa Sollievo della Sofferenza Hospital, San Giovanni Rotondo, Italy
                [9 ]Örebro University Hospital, Department of Medicine and School of Health and Medical Sciences, Örebro University, Örebro, Sweden
                [10 ]The Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA
                [11 ]Clarus Ventures, Cambridge, MA, USA
                [12 ]Department of Health Studies, University of Chicago, Chicago, Illinois, USA
                [13 ]Mount Sinai Hospital Inflammatory Bowel Disease Centre, University of Toronto, Toronto, Ontario, Canada
                [14 ]Karolinska Institutet, Department of Clinical Science Intervention and Technology, Stockholm, Sweden
                [15 ]The Pedriatic IBD Center, Cedars-Sinai Medical Center, Los Angeles, California, USA
                [16 ]Meyerhoff Inflammatory Bowel Disease Center, Department of Medicine, School of Medicine, and Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, USA
                [17 ]Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, School of Medicine, and Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
                [18 ]Karolinska Institutet, Department of Biosciences and Nutrition, Stockholm, Sweden
                [19 ]Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA
                Author notes
                []Correspondence should be addressed to MJD ( mjdaly@ 123456atgu.mgh.harvard.edu ) and MAR ( rivas@ 123456broadinstitute.org )
                [*]

                These authors contributed equally to the study

                [¶]

                Full listing of authors from the NIDDK IBD Genetics Consortium and the International Inflammatory Bowel Disease Genetics Consortium is available in the Supplementary Note.

                Article
                nihpa335188
                10.1038/ng.952
                3378381
                21983784
                a718808b-9341-4ff3-8edb-8701d0b76b9c

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                History
                Funding
                Funded by: National Human Genome Research Institute : NHGRI
                Award ID: U54 HG003067-01 || HG
                Funded by: National Human Genome Research Institute : NHGRI
                Award ID: U01 HG005923-01 || HG
                Funded by: National Institute of Diabetes and Digestive and Kidney Diseases : NIDDK
                Award ID: U01 DK062432-07 || DK
                Funded by: National Institute of Diabetes and Digestive and Kidney Diseases : NIDDK
                Award ID: U01 DK062432-01 || DK
                Funded by: National Institute of Diabetes and Digestive and Kidney Diseases : NIDDK
                Award ID: U01 DK062431-01 || DK
                Funded by: National Institute of Diabetes and Digestive and Kidney Diseases : NIDDK
                Award ID: U01 DK062429-01 || DK
                Funded by: National Institute of Diabetes and Digestive and Kidney Diseases : NIDDK
                Award ID: U01 DK062423-01 || DK
                Funded by: National Institute of Diabetes and Digestive and Kidney Diseases : NIDDK
                Award ID: U01 DK062422-01 || DK
                Funded by: National Institute of Diabetes and Digestive and Kidney Diseases : NIDDK
                Award ID: U01 DK062420-06 || DK
                Funded by: National Institute of Diabetes and Digestive and Kidney Diseases : NIDDK
                Award ID: U01 DK062413-08 || DK
                Funded by: National Institute of Diabetes and Digestive and Kidney Diseases : NIDDK
                Award ID: RC1 DK086502-01 || DK
                Funded by: National Institute of Diabetes and Digestive and Kidney Diseases : NIDDK
                Award ID: R21 DK084554-01 || DK
                Funded by: National Institute of Diabetes and Digestive and Kidney Diseases : NIDDK
                Award ID: R01 DK083756-01 || DK
                Funded by: National Institute of Diabetes and Digestive and Kidney Diseases : NIDDK
                Award ID: R01 DK060049-08 || DK
                Funded by: National Institute of Allergy and Infectious Diseases Extramural Activities : NIAID
                Award ID: R01 AI062773-01A1 || AI
                Funded by: National Institute of Diabetes and Digestive and Kidney Diseases : NIDDK
                Award ID: P30 DK063491-06 || DK
                Funded by: National Institute of Diabetes and Digestive and Kidney Diseases : NIDDK
                Award ID: P30 DK043351-21 || DK
                Funded by: National Institute of Diabetes and Digestive and Kidney Diseases : NIDDK
                Award ID: P30 DK043351-18 || DK
                Funded by: National Center for Research Resources : NCRR
                Award ID: M01 RR000425-30S1 || RR
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