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      Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease

      research-article
      1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 1 , 13 , 14 , 15 , 12 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 12 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 5 , 32 , 33 , 34 , 23 , 35 , 36 , 37 , 38 , 39 , 4 , 29 , 40 , 41 , 32 , 42 , 28 , 5 , 43 , 44 , 45 , 17 , 46 , 34 , 8 , 47 , 48 , 12 , 20 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 18 , 56 , 57 , 42 , 58 , 59 , 52 , 60 , 14 , 61 , 62 , 5 , 8 , 63 , 64 , 65 , 66 , 55 , 67 , 68 , 69 , 50 , 7 , 7 , 8 , 70 , 71 , 53 , 43 , 63 , 72 , 73 , 29 , 74 , 75 , 37 , 76 , 76 , The International IBD Genetics Consortium, 78 , 52 , 79 , 80 , 81 , 82 , 69 , 83 , 19 , 23 , 37 , 2 , 3 , 32 , 10 ,   85 , 1 , 9 , 12
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          Abstract

          Crohn’s disease (CD) and ulcerative colitis (UC), the two common forms of inflammatory bowel disease (IBD), affect over 2.5 million people of European ancestry with rising prevalence in other populations 1 . Genome-wide association studies (GWAS) and subsequent meta-analyses of CD and UC 2, 3 as separate phenotypes implicated previously unsuspected mechanisms, such as autophagy 4 , in pathogenesis and showed that some IBD loci are shared with other inflammatory diseases 5 . Here we expand knowledge of relevant pathways by undertaking a meta-analysis of CD and UC genome-wide association scans, with validation of significant findings in more than 75,000 cases and controls. We identify 71 new associations, for a total of 163 IBD loci that meet genome-wide significance thresholds. Most loci contribute to both phenotypes, and both directional and balancing selection effects are evident. Many IBD loci are also implicated in other immune-mediated disorders, most notably with ankylosing spondylitis and psoriasis. We also observe striking overlap between susceptibility loci for IBD and mycobacterial infection. Gene co-expression network analysis emphasizes this relationship, with pathways shared between host responses to mycobacteria and those predisposing to IBD.

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          Most cited references30

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          A general framework for weighted gene co-expression network analysis.

          Gene co-expression networks are increasingly used to explore the system-level functionality of genes. The network construction is conceptually straightforward: nodes represent genes and nodes are connected if the corresponding genes are significantly co-expressed across appropriately chosen tissue samples. In reality, it is tricky to define the connections between the nodes in such networks. An important question is whether it is biologically meaningful to encode gene co-expression using binary information (connected=1, unconnected=0). We describe a general framework for ;soft' thresholding that assigns a connection weight to each gene pair. This leads us to define the notion of a weighted gene co-expression network. For soft thresholding we propose several adjacency functions that convert the co-expression measure to a connection weight. For determining the parameters of the adjacency function, we propose a biologically motivated criterion (referred to as the scale-free topology criterion). We generalize the following important network concepts to the case of weighted networks. First, we introduce several node connectivity measures and provide empirical evidence that they can be important for predicting the biological significance of a gene. Second, we provide theoretical and empirical evidence that the ;weighted' topological overlap measure (used to define gene modules) leads to more cohesive modules than its ;unweighted' counterpart. Third, we generalize the clustering coefficient to weighted networks. Unlike the unweighted clustering coefficient, the weighted clustering coefficient is not inversely related to the connectivity. We provide a model that shows how an inverse relationship between clustering coefficient and connectivity arises from hard thresholding. We apply our methods to simulated data, a cancer microarray data set, and a yeast microarray data set.
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            Increasing incidence and prevalence of the inflammatory bowel diseases with time, based on systematic review.

            We conducted a systematic review to determine changes in the worldwide incidence and prevalence of ulcerative colitis (UC) and Crohn's disease (CD) in different regions and with time. We performed a systematic literature search of MEDLINE (1950-2010; 8103 citations) and EMBASE (1980-2010; 4975 citations) to identify studies that were population based, included data that could be used to calculate incidence and prevalence, and reported separate data on UC and/or CD in full manuscripts (n = 260). We evaluated data from 167 studies from Europe (1930-2008), 52 studies from Asia and the Middle East (1950-2008), and 27 studies from North America (1920-2004). Maps were used to present worldwide differences in the incidence and prevalence of inflammatory bowel diseases (IBDs); time trends were determined using joinpoint regression. The highest annual incidence of UC was 24.3 per 100,000 person-years in Europe, 6.3 per 100,000 person-years in Asia and the Middle East, and 19.2 per 100,000 person-years in North America. The highest annual incidence of CD was 12.7 per 100,000 person-years in Europe, 5.0 person-years in Asia and the Middle East, and 20.2 per 100,000 person-years in North America. The highest reported prevalence values for IBD were in Europe (UC, 505 per 100,000 persons; CD, 322 per 100,000 persons) and North America (UC, 249 per 100,000 persons; CD, 319 per 100,000 persons). In time-trend analyses, 75% of CD studies and 60% of UC studies had an increasing incidence of statistical significance (P < .05). Although there are few epidemiologic data from developing countries, the incidence and prevalence of IBD are increasing with time and in different regions around the world, indicating its emergence as a global disease. Copyright © 2012 AGA Institute. Published by Elsevier Inc. All rights reserved.
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              The mystery of missing heritability: Genetic interactions create phantom heritability.

              Human genetics has been haunted by the mystery of "missing heritability" of common traits. Although studies have discovered >1,200 variants associated with common diseases and traits, these variants typically appear to explain only a minority of the heritability. The proportion of heritability explained by a set of variants is the ratio of (i) the heritability due to these variants (numerator), estimated directly from their observed effects, to (ii) the total heritability (denominator), inferred indirectly from population data. The prevailing view has been that the explanation for missing heritability lies in the numerator--that is, in as-yet undiscovered variants. While many variants surely remain to be found, we show here that a substantial portion of missing heritability could arise from overestimation of the denominator, creating "phantom heritability." Specifically, (i) estimates of total heritability implicitly assume the trait involves no genetic interactions (epistasis) among loci; (ii) this assumption is not justified, because models with interactions are also consistent with observable data; and (iii) under such models, the total heritability may be much smaller and thus the proportion of heritability explained much larger. For example, 80% of the currently missing heritability for Crohn's disease could be due to genetic interactions, if the disease involves interaction among three pathways. In short, missing heritability need not directly correspond to missing variants, because current estimates of total heritability may be significantly inflated by genetic interactions. Finally, we describe a method for estimating heritability from isolated populations that is not inflated by genetic interactions.
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                Author and article information

                Journal
                0410462
                6011
                Nature
                Nature
                Nature
                0028-0836
                1476-4687
                9 October 2012
                1 November 2012
                01 May 2013
                : 491
                : 7422
                : 119-124
                Affiliations
                [1 ]Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK
                [2 ]Analytic and Translational Genetics Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
                [3 ]Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
                [4 ]Department of Gastroenterology and Hepatology, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands
                [5 ]Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
                [6 ]Department of Human Genetics, University of Pittsburgh Graduate School of Public Health, Pittsburgh, Pennsylvania, USA
                [7 ]Cedars-Sinai F. Widjaja Inflammatory Bowel and Immunobiology Research Institute, Los Angeles, California, USA
                [8 ]Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA
                [9 ]Department of Genetics, Yale School of Medicine, New Haven, Connecticut, USA
                [10 ]Inflammatory Bowel Disease Research Group, Addenbrooke’s Hospital, University of Cambridge, Cambridge, UK
                [11 ]Department of Health Studies, University of Chicago, Chicago, Illinois, USA
                [12 ]Department of Internal Medicine, Section of Digestive Diseases, Yale School of Medicine, New Haven, Connecticut, USA
                [13 ]Center for Human Genetic Research, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
                [14 ]University of Maribor, Faculty of Medicine, Center for Human Molecular Genetics and Pharmacogenomics, Maribor, Slovenia
                [15 ]University Medical Center Groningen, Department of Genetics, Groningen, The Netherlands
                [16 ]Department of Pathophysiology, Gastroenterology section, KU Leuven, Leuven, Belgium
                [17 ]Unit of Animal Genomics, Groupe Interdisciplinaire de Genoproteomique Appliquee (GIGA-R) and Faculty of Veterinary Medicine, University of Liege, Liege, Belgium
                [18 ]Division of Gastroenterology, Centre Hospitalier Universitaire, Universite de Liege, Liege, Belgium
                [19 ]Department of Medical and Molecular Genetics, King’s College London School of Medicine, Guy’s Hospital, London, UK
                [20 ]Division of Rheumatology Immunology and Allergy, Brigham and Women’s Hospital, Boston, Massachusetts, USA
                [21 ]Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, USA
                [22 ]Division of Genetics, Brigham and Women’s Hospital, Boston, Massachusetts, USA
                [23 ]Université de Montréal and the Montreal Heart Institute, Research Center, Montréal, Québec, Canada
                [24 ]Department of Computer Science, New Jersey Institute of Technology, Newark, NJ 07102, USA
                [25 ]Department of Gastroenterology & Hepatology, Digestive Disease Institute, Cleveland Clinic, Cleveland, Ohio
                [26 ]Department of Pathobiology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA
                [27 ]Peninsula College of Medicine and Dentistry, Exeter, UK
                [28 ]Erasmus Hospital, Free University of Brussels, Department of Gastroenterology, Brussels, Belgium
                [29 ]Massachusetts General Hospital, Harvard Medical School, Gastroenterology Unit, Boston, Massachusetts, USA
                [30 ]Viborg Regional Hospital, Medical Department, Viborg, Denmark
                [31 ]Inflammatory Bowel Disease Service, Department of Gastroenterology and Hepatology, Royal Adelaide Hospital, and School of Medicine, University of Adelaide, Adelaide, Australia
                [32 ]Institute of Clinical Molecular Biology, Christian-Albrechts-University, Kiel, Germany
                [33 ]Department of Gastroenterology and Hepatology, Flinders Medical Centre and School of Medicine, Flinders University, Adelaide, Australia
                [34 ]Division of Gastroenterology, McGill University Health Centre, Royal Victoria Hospital, Montréal, Québec, Canada
                [35 ]Department of Medicine II, University Hospital Munich-Grosshadern, Ludwig-Maximilians-University, Munich, Germany
                [36 ]Department of Gastroenterology, Charit, Campus Mitte, UniversitŠtsmedizin Berlin, Berlin, Germany
                [37 ]Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York City, New York, USA
                [38 ]Department of Genomics, Life & Brain Center, University Hospital Bonn, Bonn, Germany
                [39 ]Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden
                [40 ]Department of Pediatrics, Cedars Sinai Medical Center, Los Angeles, California, USA
                [41 ]Torbay Hospital, Department of Gastroenterology, Torbay, Devon, UK
                [42 ]School of Medical Sciences, Faculty of Medical & Health Sciences, The University of Auckland, Auckland, New Zealand
                [43 ]University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, The Netherlands
                [44 ]Department of Medicine, University of Otago, Christchurch, New Zealand
                [45 ]Department of Gastroenterology, Christchurch Hospital, Christchurch, New Zealand
                [46 ]Institute of Genetic Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany
                [47 ]St Mark’s Hospital, Watford Road, Harrow, Middlesex, HA1 3UJ
                [48 ]Nottingham Digestive Diseases Centre, Queens Medical Centre, Nottingham NG7 1AW, UK
                [49 ]Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway
                [50 ]Kaunas University of Medicine, Department of Gastroenterology, Kaunas, Lithuania
                [51 ]Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia, USA
                [52 ]Unit of Gastroenterology, Istituto di Ricovero e Cura a Carattere Scientifico-Casa Sollievo della Sofferenza (IRCCS-CSS) Hospital, San Giovanni Rotondo, Italy
                [53 ]Ghent University Hospital, Department of Gastroenterology and Hepatology, Ghent, Belgium
                [54 ]School of Medicine and Pharmacology, The University of Western Australia, Fremantle, Australia
                [55 ]Gastrointestinal Unit, Molecular Medicine Centre, University of Edinburgh, Western General Hospital, Edinburgh, UK
                [56 ]Department of Gastroenterology, The Townsville Hospital, Townsville, Australia
                [57 ]Institute of Human Genetics, Newcastle University, Newcastle upon Tyne, UK
                [58 ]Department of Medicine, Ninewells Hospital and Medical School, Dundee, UK
                [59 ]Genetic Medicine, MAHSC, University of Manchester, Manchester, UK
                [60 ]Academic Medical Center, Department of Gastroenterology, Amsterdam, The Netherlands
                [61 ]University of Maribor, Faculty for Chemistry and Chemical Engineering, Maribor, Slovenia
                [62 ]King’s College London School of Medicine, Guy’s Hospital, Department of Medical and Molecular Genetics, London, UK
                [63 ]Royal Hospital for Sick Children, Paediatric Gastroenterology and Nutrition, Glasgow, UK
                [64 ]Guy’s & St. Thomas’ NHS Foundation Trust, St. Thomas’ Hospital, Department of Gastroenterology, London, UK
                [65 ]Department of Gastroenterology, Hospital Cl’nic/Institut d’Investigaci— Biomdica August Pi i Sunyer (IDIBAPS), Barcelona, Spain
                [66 ]Centro de Investigaci—n Biomdica en Red de Enfermedades Hep‡ticas y Digestivas (CIBER EHD), Barcelona, Spain
                [67 ]Christian-Albrechts-University, Institute of Clinical Molecular Biology, Kiel, Germany
                [68 ]Department for General Internal Medicine, Christian-Albrechts-University, Kiel, Germany
                [69 ]Inflammatory Bowel Diseases, Genetics and Computational Biology, Queensland Institute of Medical Research, Brisbane, Australia
                [70 ]Norfolk and Norwich University Hospital
                [71 ]Department of Gastroenterology, Leiden University Medical Center, Leiden, The Netherlands
                [72 ]Child Life and Health, University of Edinburgh, Edinburgh, Scotland, UK
                [73 ]Institute of Human Genetics and Department of Neurology, Technische Universität München, Munich, Germany
                [74 ]Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, Massachusetts, USA
                [75 ]Department for General Internal Medicine, Christian-Albrechts-University, Kiel, Germany
                [76 ]Department of Biostatistics, School of Public Health, Yale University, New Haven, Connecticut, USA
                [78 ]Mount Sinai Hospital Inflammatory Bowel Disease Centre, University of Toronto, Toronto, Ontario, Canada
                [79 ]Azienda Ospedaliero Universitaria (AOU) Careggi, Unit of Gastroenterology SOD2, Florence, Italy
                [80 ]Center for Applied Genomics, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
                [81 ]Department of Pediatrics, Center for Pediatric Inflammatory Bowel Disease, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
                [82 ]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
                [83 ]Department of Gastroenterology, Royal Brisbane and Womens Hospital, and School of Medicine, University of Queensland, Brisbane, Australia
                [84 ]Inflammatory Bowel Disease Research Group, Addenbrooke’s Hospital, University of Cambridge, Cambridge, UK
                [85 ]Division of Gastroenterology, University Hospital Gasthuisberg, Leuven, Belgium
                Author notes
                Correspondence and requests for materials should be addressed to JHC ( judy.cho@ 123456yale.edu )
                [*]

                denotes equal contributions

                [‡]

                denotes equal contributions

                [†]

                denotes equal contributions

                [77]

                A full list of consortium members is provided in the Supplementary Note

                Article
                NIHMS407586
                10.1038/nature11582
                3491803
                23128233
                f1857201-423d-4b6d-82b2-509e3f03f9fa

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