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  • 1. Amundadottir, Laufey T.
    et al.
    Sulem, Patrick
    Gudmundsson, Julius
    Helgason, Agnar
    Baker, Adam
    Agnarsson, Bjarni A.
    Sigurdsson, Asgeir
    Benediktsdottir, Kristrun R.
    Cazier, Jean-Baptiste
    Sainz, Jesus
    Jakobsdottir, Margret
    Kostic, Jelena
    Magnusdottir, Droplaug N.
    Ghosh, Shyamali
    Agnarsson, Kari
    Birgisdottir, Birgitta
    Le Roux, Louise
    Olafsdottir, Adalheidur
    Blondal, Thorarinn
    Andresdottir, Margret
    Gretarsdottir, Olafia Svandis
    Bergthorsson, Jon T.
    Gudbjartsson, Daniel
    Gylfason, Arnaldur
    Thorleifsson, Gudmar
    Manolescu, Andrei
    Kristjansson, Kristleifur
    Geirsson, Gudmundur
    Isaksson, Helgi
    Douglas, Julie
    Johansson, Jan-Erik
    Örebro University, Department of Clinical Medicine.
    Bälter, Katarina
    Wiklund, Fredrik
    Montie, James E.
    Yu, Xiaoying
    Suarez, Brian K.
    Ober, Carole
    Cooney, Kathleen A.
    Gronberg, Henrik
    Catalona, William J.
    Einarsson, Gudmundur V.
    Barkardottir, Rosa B.
    Gulcher, Jeffrey R.
    Kong, Augustine
    Thorsteinsdottir, Unnur
    Stefansson, Kari
    A common variant associated with prostate cancer in European and African populations2006In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 38, no 6, p. 652-658Article in journal (Refereed)
    Abstract [en]

    With the increasing incidence of prostate cancer, identifying common genetic variants that confer risk of the disease is important. Here we report such a variant on chromosome 8q24, a region initially identified through a study of Icelandic families. Allele -8 of the microsatellite DG8S737 was associated with prostate cancer in three case-control series of European ancestry from Iceland, Sweden and the US. The estimated odds ratio (OR) of the allele is 1.62 (P = 2.7 x 10(-11)). About 19% of affected men and 13% of the general population carry at least one copy, yielding a population attributable risk (PAR) of approximately 8%. The association was also replicated in an African American case-control group with a similar OR, in which 41% of affected individuals and 30% of the population are carriers. This leads to a greater estimated PAR (16%) that may contribute to higher incidence of prostate cancer in African American men than in men of European ancestry.

  • 2.
    Anderson, Carl A.
    et al.
    Wellcome Trust Genome Campus Hinxton, Wellcome Trust Sanger Institute, Cambridge, United Kingdom.
    Halfvarson, Jonas
    Örebro University, School of Health and Medical Sciences.
    Rioux, John D.
    Inflammatory Bowel Diseases, Queensland Institute of Medical Research, Brisbane, Australia.
    Meta-analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 472011In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 43, no 3, p. 246-252Article in journal (Refereed)
    Abstract [en]

    Genome-wide association studies and candidate gene studies in ulcerative colitis have identified 18 susceptibility loci. We conducted a meta-analysis of six ulcerative colitis genome-wide association study datasets, comprising 6,687 cases and 19,718 controls, and followed up the top association signals in 9,628 cases and 12,917 controls. We identified 29 additional risk loci (P < 5 × 10(-8)), increasing the number of ulcerative colitis-associated loci to 47. After annotating associated regions using GRAIL, expression quantitative trait loci data and correlations with non-synonymous SNPs, we identified many candidate genes that provide potentially important insights into disease pathogenesis, including IL1R2, IL8RA-IL8RB, IL7R, IL12B, DAP, PRDM1, JAK2, IRF5, GNA12 and LSP1. The total number of confirmed inflammatory bowel disease risk loci is now 99, including a minimum of 28 shared association signals between Crohn's disease and ulcerative colitis.

  • 3.
    Ellinghaus, David
    et al.
    Institute of Clinical Molecular Biology, Christian Albrechts University of Kiel, Kiel, Germany.
    Jostins, Luke
    Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.
    Spain, Sarah L.
    Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.
    Cortes, Adrian
    Nuffield Department of Clinical Neurosciences, Division of Clinical Neurology, John Radcliffe Hospital, University of Oxford, Oxford, UK; Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
    Bethune, Jörn
    Institute of Clinical Molecular Biology, Christian Albrechts University of Kiel, Kiel, Germany.
    Han, Buhm
    Department of Convergence Medicine, University of Ulsan College of Medicine, Seoul, Republic of Korea; Asan Institute for Life Sciences, Asan Medical Center, Seoul, Republic of Korea.
    Park, Yu Rang
    Asan Institute for Life Sciences, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea.
    Raychaudhuri, Soumya
    Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge MA, United States; Division of Genetics, Brigham and Women's Hospital, Boston MA, United States; Division of Rheumatology, Brigham and Women's Hospital, Boston MA, United States.
    Pouget, Jennie G.
    Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada; Department of Psychiatry, University of Toronto, Toronto, Canada.
    Hübenthal, Matthias
    Institute of Clinical Molecular Biology, Christian Albrechts University of Kiel, Kiel, Germany.
    Folseraas, Trine
    Norwegian PSC Research Center, Department of Transplantation Medicine, Oslo University Hospital, Oslo, Norway; K.G. Jebsen Inflammation Research Centre, Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Research Institute of Internal Medicine, Division of Cancer Medicine,Surgery and Transplantation, Oslo University Hospital, Oslo, Norway; Section of Gastroenterology, Department of Transplantation Medicine, Oslo University Hospital, Oslo, Norway.
    Wang, Yunpeng
    Department of Neurosciences, University of California, San Diego, USA.
    Esko, Tonu
    Estonian Genome Center, University of Tartu, Tartu, Estonia; Division of Endocrinology, Boston Children's Hospital, Cambridge MA, USA; Center for Basic and Translational Obesity Research, Boston Children's Hospital, Cambridge MA, USA.
    Metspalu, Andres
    Estonian Genome Center, University of Tartu, Tartu, Estonia.
    Westra, Harm-Jan
    Program in Medical and Population Genetics, Broad Institute of mit and Harvard, Cambridge MA, United States; Division of Genetics, Brigham and Women's Hospital, Boston MA, United States; Division of Rheumatology, Brigham and Women's Hospital, Boston MA, United States; Department of Medicine, Harvard Medical School, Boston MA, United States.
    Franke, Lude
    University Medical Center Groningen, Department of Genetics, University of Groningen, Groningen, the Netherlands.
    Pers, Tune H.
    Program in Medical and Population Genetics, Broad Institute of mit and Harvard, Cambridge MA, United States; Center for Basic and Translational Obesity Research, Boston Children's Hospital, Cambridge MA, United States; Novo Nordisk Foundation, Centre for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark; Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark.
    Weersma, Rinse K.
    Department of Gastroenterology and Hepatology, University Medical Center, University of Groningen, Groningen, the Netherlands.
    Collij, Valerie
    Department of Gastroenterology and Hepatology, University Medical Center, University of Groningen, Groningen, the Netherlands.
    D'Amato, Mauro
    Department of Bioscience and Nutrition, Karolinska Institutet, Stockholm, Sweden; BioCruces Health Research Institute, Basque Foundation for Science (Ikerbasque), Bilbao, Spain.
    Halfvarson, Jonas
    Örebro University, School of Medical Sciences. Department of Gastroenterology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Jensen, Anders Boeck
    Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
    Lieb, Wolfgang
    Institute of Epidemiology, University Hospital Schleswig-Holstein, Kiel, Germany; PopGen Biobank, University Hospital Schleswig-Holstein, Kiel, Germany.
    Degenhardt, Franziska
    Institute of Human Genetics, University of Bonn, Bonn, Germany; Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany.
    Forstner, Andreas J.
    Institute of Human Genetics, University of Bonn, Bonn, Germany; Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany.
    Hofmann, Andrea
    Institute of Human Genetics, University of Bonn, Bonn, Germany; Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany.
    The International IBD Genetics Consortium, (IIBDGC)
    International Genetics of Ankylosing Spondylitis Consortium, (IGAS)
    International PSC Study Group, (IPSCSG)
    Genetic Analysis of Psoriasis Consortium, (GAPC)
    Psoriasis Association Genetics Extension, (PAGE)
    Schreiber, Stefan
    Institute of Clinical Molecular Biology, Christian Albrechts University of Kiel, Kiel, Germany; Institute of Human Genetics, University of Bonn, Bonn, Germany; Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany.
    Mrowietz, Ulrich
    Department of Dermatology, University Hospital Schleswig-Holstein, Christian Albrechts University of Kiel, Kiel, Germany.
    Juran, Brian D.
    Center for Basic Research in Digestive Diseases, Division of Gastroenterology and Hepatology, Mayo Clinic, College of Medicine, Rochester MN, USA.
    Lazaridis, Konstantinos N.
    Center for Basic Research in Digestive Diseases, Division of Gastroenterology and Hepatology, Mayo Clinic, College of Medicine, Rochester MN, USA.
    Brunak, Søren
    Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
    Dale, Anders M.
    Department of Neurosciences, University of California, San Diego, USA; Department of Radiology, University of California, San Diego, USA.
    Trembath, Richard C.
    Division of Genetics and Molecular Medicine, King's College London, London, UK.
    Weidinger, Stephan
    Department of Dermatology, University Hospital Schleswig-Holstein, Christian Albrechts University of Kiel, Kiel, Germany.
    Weichenthal, Michael
    Department of Dermatology, University Hospital Schleswig-Holstein, Christian Albrechts University of Kiel, Kiel, Germany.
    Ellinghaus, Eva
    Institute of Clinical Molecular Biology, Christian Albrechts University of Kiel, Kiel, Germany.
    Elder, James T.
    Department of Dermatology, University of Michigan, Ann Arbor, USA; Ann Arbor Veterans Affairs Hospital, Ann Arbor, USA.
    Barker, Jonathan N. W. N.
    St. John's Institute of Dermatology, Division of Genetics and Molecular Medicine, King's College London, London, UK.
    Andreassen, Ole A.
    NORMENT, K.G. Jebsen Centre for Psychosis Research, Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Division of Mental Health and Addiction, Oslo University Hospital Ullevål, Oslo, Norway.
    McGovern, Dermot P.
    F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Los Angeles, USA; Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, USA.
    Karlsen, Tom H.
    Norwegian PSC Research Center, Department of Transplantation Medicine, Oslo University Hospital, Oslo, Norway; K.G. Jebsen Inflammation Research Centre, Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Research Institute of Internal Medicine, Division of Cancer Medicine,Surgery and Transplantation, Oslo University Hospital, Oslo, Norway; Section of Gastroenterology, Department of Transplantation Medicine, Oslo University Hospital, Oslo, Norway.
    Barrett, Jeffrey C.
    Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.
    Parkes, Miles
    Inflammatory Bowel Disease Research Group, Addenbrooke's Hospital, University of Cambridge, Cambridge, UK.
    Brown, Matthew A.
    University of Queensland Diamantina Institute, Translational Research Institute, Brisbane QLD, Australia; Institute of Health and Biomedical Innovation (IHBI), Translational Research Institute, Queensland University of Technology (QUT), Brisbane QLD, Australia .
    Franke, Andre
    Institute of Clinical Molecular Biology, Christian Albrechts University of Kiel, Kiel, Germany.
    Analysis of five chronic inflammatory diseases identifies 27 new associations and highlights disease-specific patterns at shared loci2016In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 48, no 5, p. 510-518Article in journal (Refereed)
    Abstract [en]

    We simultaneously investigated the genetic landscape of ankylosing spondylitis, Crohn's disease, psoriasis, primary sclerosing cholangitis and ulcerative colitis to investigate pleiotropy and the relationship between these clinically related diseases. Using high-density genotype data from more than 86,000 individuals of European ancestry, we identified 244 independent multidisease signals, including 27 new genome-wide significant susceptibility loci and 3 unreported shared risk loci. Complex pleiotropy was supported when contrasting multidisease signals with expression data sets from human, rat and mouse together with epigenetic and expressed enhancer profiles. The comorbidities among the five immune diseases were best explained by biological pleiotropy rather than heterogeneity (a subgroup of cases genetically identical to those with another disease, possibly owing to diagnostic misclassification, molecular subtypes or excessive comorbidity). In particular, the strong comorbidity between primary sclerosing cholangitis and inflammatory bowel disease is likely the result of a unique disease, which is genetically distinct from classical inflammatory bowel disease phenotypes.

  • 4. Franke, Andre
    et al.
    McGovern, Dermot P B
    Barrett, Jeffrey C
    Wang, Kai
    Radford-Smith, Graham L
    Ahmad, Tariq
    Lees, Charlie W
    Balschun, Tobias
    Lee, James
    Roberts, Rebecca
    Anderson, Carl A
    Bis, Joshua C
    Bumpstead, Suzanne
    Ellinghaus, David
    Festen, Eleonora M
    Georges, Michel
    Green, Todd
    Haritunians, Talin
    Jostins, Luke
    Latiano, Anna
    Mathew, Christopher G
    Montgomery, Grant W
    Prescott, Natalie J
    Raychaudhuri, Soumya
    Rotter, Jerome I
    Schumm, Philip
    Sharma, Yashoda
    Simms, Lisa A
    Taylor, Kent D
    Whiteman, David
    Wijmenga, Cisca
    Baldassano, Robert N
    Barclay, Murray
    Bayless, Theodore M
    Brand, Stephan
    Büning, Carsten
    Cohen, Albert
    Colombel, Jean-Frederick
    Cottone, Mario
    Stronati, Laura
    Denson, Ted
    De Vos, Martine
    D'Inca, Renata
    Dubinsky, Marla
    Edwards, Cathryn
    Florin, Tim
    Franchimont, Denis
    Gearry, Richard
    Glas, Jürgen
    Van Gossum, Andre
    Guthery, Stephen L
    Halfvarson, Jonas
    Örebro University, School of Health and Medical Sciences.
    Verspaget, Hein W
    Hugot, Jean-Pierre
    Karban, Amir
    Laukens, Debby
    Lawrance, Ian
    Lemann, Marc
    Levine, Arie
    Libioulle, Cecile
    Louis, Edouard
    Mowat, Craig
    Newman, William
    Panés, Julián
    Phillips, Anne
    Proctor, Deborah D
    Regueiro, Miguel
    Russell, Richard
    Rutgeerts, Paul
    Sanderson, Jeremy
    Sans, Miquel
    Seibold, Frank
    Steinhart, A Hillary
    Stokkers, Pieter C F
    Torkvist, Leif
    Kullak-Ublick, Gerd
    Wilson, David
    Walters, Thomas
    Targan, Stephan R
    Brant, Steven R
    Rioux, John D
    D'Amato, Mauro
    Weersma, Rinse K
    Kugathasan, Subra
    Griffiths, Anne M
    Mansfield, John C
    Vermeire, Severine
    Duerr, Richard H
    Silverberg, Mark S
    Satsangi, Jack
    Schreiber, Stefan
    Cho, Judy H
    Annese, Vito
    Hakonarson, Hakon
    Daly, Mark J
    Parkes, Miles
    Genome-wide meta-analysis increases to 71 the number of confirmed Crohn's disease susceptibility loci2010In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 42, no 12, p. 1118-1125Article in journal (Refereed)
    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 × 10⁻⁸). 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.

  • 5.
    Goyette, Philippe
    et al.
    Research Center, Montreal Heart Institute, Montreal QC, Canada.
    Boucher, Gabrielle
    Research Center, Montreal Heart Institute, Montreal QC, Canada.
    Mallon, Dermot
    Department of Surgery, University of Cambridge, Cambridge, UK; National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre, Cambridge, UK.
    Ellinghaus, Eva
    Institute of Clinical Molecular Biology, Christian Albrechts University, Kiel, Germany.
    Jostins, Luke
    Wellcome Trust Centre for Human Genetics, University of Oxford, Headington, UK; Christ Church, University of Oxford, Oxford, UK.
    Huang, Hailiang
    Analytic and Translational Genetics Unit, Massachusetts General Hospital, Harvard Medical School, Boston MA, USA; Broad Institute of MIT and Harvard, Cambridge MA, USA.
    Ripke, Stephan
    Analytic and Translational Genetics Unit, Massachusetts General Hospital, Harvard Medical School, Boston MA, USA; Broad Institute of MIT and Harvard, Cambridge MA, USA.
    Gusareva, Elena S.
    Systems and Modeling Unit, Montefiore Institute, University of Liege, Liege, Belgium; Bioinformatics and Modeling, GIGA-R (Groupe Interdisciplinaire de Génoprotéomique Appliquée) Research Center, University of Liege, Liege, Belgium.
    Annese, Vito
    Unit of Gastroenterology, IRCCS-CSS (Istituto di Ricovero e Cura a Carattere Scientifico–Casa Sollievo della Sofferenza) Hospital, San Giovanni Rotondo, Italy; Unit of Gastroenterology SOD2 (Strutture Organizzative Dipartimentali), Azienda Ospedaliero Universitaria (AOU) Careggi, Florence, Italy.
    Hauser, Stephen L.
    Department of Neurology, University of California, San Francisco, USA.
    Oksenberg, Jorge R.
    Department of Neurology, University of California,San Francisco, USA.
    Thomsen, Ingo
    Institute of Clinical Molecular Biology, Christian Albrechts University, Kiel, Germany.
    Leslie, Stephen
    Murdoch Children's Research Institute, Parkville Vic, Australia; Department of Mathematics and Statistics, University of Melbourne, Melbourne Vic, Australia.
    Daly, Mark J.
    Analytic and Translational Genetics Unit, Massachusetts General Hospital, Harvard Medical School, Boston MA, USA; Broad Institute of MIT and Harvard, Cambridge MA, USA.
    Van Steen, Kristel
    Systems and Modeling Unit, Montefiore Institute, University of Liege, Liege, Belgium; Bioinformatics and Modeling, GIGA-R (Groupe Interdisciplinaire de Génoprotéomique Appliquée) Research Center, University of Liege, Liege, Belgium.
    Duerr, Richard H.
    Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh PA, USA; Department of Human Genetics, University of Pittsburgh Graduate School of Public Health, Pittsburgh PA, USA.
    Barrett, Jeffrey C.
    Wellcome Trust Sanger Institute, Hinxton, UK.
    McGovern, Dermot P. B.
    Schumm, L. Philip
    Department of Public Health Sciences, University of Chicago, Chicago ILL, USA.
    Traherne, James A.
    Cambridge Institute for Medical Research, Cambridge, UK; Department of Pathology, University of Cambridge, Cambridge, UK.
    Carrington, Mary N.
    Cancer and Inflammation Program, Laboratory of Experimental Immunology, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick MD, USA; Ragon Institute of Massachusetts General Hospital, MIT and Harvard, Cambridge MA, USA.
    Kosmoliaptsis, Vasilis
    Department of Surgery, University of Cambridge, Cambridge, UK; National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre, Cambridge, UK.
    Karlsen, Tom H.
    Research Institute of Internal Medicine, Department of Transplantation Medicine, Division of Cancer, Surgery and Transplantation, Oslo University Hospital (Rikshospitalet), Oslo, Norway; Norwegian Primary Sclerosing Cholangitis Research Center, Department of Transplantation Medicine, Division of Cancer, Surgery and Transplantation, Oslo University Hospital (Rikshospitalet), Oslo, Norway.
    Franke, Andre
    Institute of Clinical Molecular Biology, Christian Albrechts University, Kiel, Germany.
    Rioux, John D.
    Research Center, Montreal Heart Institute, Montreal QC, Canada; Faculté de Médecine, Université de Montréal, Montreal QC, Canada.
    High-density mapping of the MHC identifies a shared role for HLA-DRB1*01: 03 in inflammatory bowel diseases and heterozygous advantage in ulcerative colitis2015In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 47, no 2, p. 172-179Article in journal (Refereed)
    Abstract [en]

    Genome-wide association studies of the related chronic inflammatory bowel diseases (IBD) known as Crohn's disease and ulcerative colitis have shown strong evidence of association to the major histocompatibility complex (MHC). This region encodes a large number of immunological candidates, including the antigen-presenting classical human leukocyte antigen (HLA) molecules. Studies in IBD have indicated that multiple independent associations exist at HLA and non-HLA genes, but they have lacked the statistical power to define the architecture of association and causal alleles. To address this, we performed high-density SNP typing of the MHC in >32,000 individuals with IBD, implicating multiple HLA alleles, with a primary role for HLA-DRB1*01:03 in both Crohn's disease and ulcerative colitis. Noteworthy differences were observed between these diseases, including a predominant role for class II HLA variants and heterozygous advantage observed in ulcerative colitis, suggesting an important role of the adaptive immune response in the colonic environment in the pathogenesis of IBD.

  • 6.
    Harris, Simon R.
    et al.
    Pathogen Genomics, Wellcome Trust Sanger Institute, Hinxton, United Kingdom.
    Clarke, Ian N.
    Molecular Microbiology Group, Southampton General Hospital, University Medical School, Southampton, United Kingdom.
    Seth-Smith, Helena M. B.
    Pathogen Genomics, Wellcome Trust Sanger Institute, Hinxton, United Kingdom.
    Solomon, Anthony W.
    Department of Clinical Research, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, United Kingdom.
    Cutcliffe, Lesley T.
    Molecular Microbiology Group, Southampton General Hospital, University Medical School, Southampton, United Kingdom.
    Marsh, Peter
    Health Protection Agency, Public Health Laboratory Southampton, Southampton General Hospital, Southampton, United Kingdom.
    Skilton, Rachel J.
    Molecular Microbiology Group, Southampton General Hospital, University Medical School, Southampton, United Kingdom.
    Holland, Martin J.
    Department of Clinical Research, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, United Kingdom.
    Mabey, David
    Department of Clinical Research, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, United Kingdom.
    Peeling, Rosanna W.
    Department of Clinical Research, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, United Kingdom.
    Lewis, David A.
    Department of Clinical Research, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, United Kingdom; Sexually Transmitted Infections Reference Centre, National Health Laboratory Service, National Institute for Communicable Diseases, Johannesburg, South Africa; Department of Internal Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.
    Spratt, Brian G.
    Department of Infectious Disease Epidemiology, St. Mary's Hospital Campus, Imperial College, London, United Kingdom.
    Unemo, Magnus
    Örebro University Hospital. Department of Laboratory Medicine and Clinical Microbiology, National Reference Laboratory for Pathogenic Neisseria, Örebro University Hospital, Örebro, Sweden.
    Persson, Kenneth
    Department of Laboratory Medicine, Clinical Microbiology, Malmö University Hospital, Malmö, Sweden.
    Bjartling, Carina
    Department of Obstetrics and Gynecology, Institute of Clinical Sciences, Malmö University Hospital, Malmö, Sweden.
    Brunham, Robert
    British Columbia Centre for Disease Control, Vancouver BC, Canada.
    de Vries, Henry J. C.
    Department of Dermatology, Academic Medical Centre, University of Amsterdam, Amsterdam, Netherlands; Sexually Transmitted Infections Outpatient Clinic, Infectious Diseases Cluster, Public Health Service Amsterdam, Amsterdam, Netherlands; Centre for Infection and Immunity Amsterdam, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands.
    Morré, Servaas A.
    Department of Medical Microbiology of Infection Prevention, Laboratory of Immunogenetics, Vrije University Medical Center, Amsterdam, Netherlands; Department of Genetics and Cell Biology, Institute of Public Health Genomics, University of Maastricht, Maastricht, Netherlands.
    Speksnijder, Arjen
    Geneeskundige en Gezondheidsdienst (GGD), Amsterdam, The Netherlands.
    Bébéar, Cecile M.
    Unité Sous Contrat (USC) Mycoplasmal and Chlamydial Infections in Humans, French National Reference Center for Chlamydial Infections, Université de Bordeaux, Bordeaux, France; USC Mycoplasmal and Chlamydial Infections in Humans, French National Reference Center for Chlamydial Infections, Institut National de la Recherche Agronomique, Bordeaux, France.
    Clerc, Maite
    Unité Sous Contrat (USC) Mycoplasmal and Chlamydial Infections in Humans, French National Reference Center for Chlamydial Infections, Université de Bordeaux, Bordeaux, France; USC Mycoplasmal and Chlamydial Infections in Humans, French National Reference Center for Chlamydial Infections, Institut National de la Recherche Agronomique, Bordeaux, France.
    de Barbeyrac, Bertille
    Unité Sous Contrat (USC) Mycoplasmal and Chlamydial Infections in Humans, French National Reference Center for Chlamydial Infections, Université de Bordeaux, Bordeaux, France; USC Mycoplasmal and Chlamydial Infections in Humans, French National Reference Center for Chlamydial Infections, Institut National de la Recherche Agronomique, Bordeaux, France.
    Parkhill, Julian
    Pathogen Genomics, Wellcome Trust Sanger Institute, Hinxton, United Kingdom.
    Thomson, Nicholas R.
    Pathogen Genomics, Wellcome Trust Sanger Institute, Hinxton, United Kingdom.
    Whole-genome analysis of diverse Chlamydia trachomatis strains identifies phylogenetic relationships masked by current clinical typing2012In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 44, no 4, p. 413-419Article in journal (Refereed)
    Abstract [en]

    Chlamydia trachomatis is responsible for both trachoma and sexually transmitted infections, causing substantial morbidity and economic cost globally. Despite this, our knowledge of its population and evolutionary genetics is limited. Here we present a detailed phylogeny based on whole-genome sequencing of representative strains of C. trachomatis from both trachoma and lymphogranuloma venereum (LGV) biovars from temporally and geographically diverse sources. Our analysis shows that predicting phylogenetic structure using ompA, which is traditionally used to classify Chlamydia, is misleading because extensive recombination in this region masks any true relationships present. We show that in many instances, ompA is a chimera that can be exchanged in part or as a whole both within and between biovars. We also provide evidence for exchange of, and recombination within, the cryptic plasmid, which is another key diagnostic target. We used our phylogenetic framework to show how genetic exchange has manifested itself in ocular, urogenital and LGV C. trachomatis strains, including the epidemic LGV serotype L2b.

  • 7.
    Heap, Graham A.
    et al.
    IBD Pharmacogenet, Royal Devon & Exeter Hosp, Exeter, England; Precis Med, Univ Exeter, Exeter, England.
    Weedon, Michael N.
    Precision medicine, Exeter Medical School, University of Exeter, Exeter, England.
    Bewshea, Claire M.
    IBD Pharmacogenet, Royal Devon & Exeter Hosp, Exeter, England; Precision Med Exeter, Univ Exeter, Exeter, England.
    Singh, Abhey
    IBD Pharmacogenet, Royal Devon & Exeter Hosp, Exeter, England.
    Chen, Mian
    Oxford Transplant Ctr, Royal Devon & Exeter Hosp, Oxford, England.
    Satchwel, Jack B.
    Oxford Transplant Ctr, Oxford Univ Hosp Natl Hlth Serv NHS Trust, Oxford, England.
    Vivian, Julian P.
    Sch Biomed Sci, Dept Biochem & Mol Biol, Monash Univ, Clayton Vic, Australia.
    So, Kenji
    IBD Pharmacogenet, Royal Devon & Exeter Hosp, Exeter, England.
    Dubois, Patrick C.
    Dept Gastroenterol, Kings Coll Hosp, London, England.
    Andrews, Jane M.
    Dept Gastroenterol, IBD Serv, Adelaide SA, Australia; Royal Adelaide Hosp, Univ Adelaide, Adelaide SA, Australia.
    Annese, Vito
    Div Gastroenterol, Azienda Osped, Univ Careggi, Florence, Italy.
    Bampton, Peter
    Flinders Med Ctr, Flinders Univ South Australia, Adelaide SA, Australia.
    Barnardo, Martin
    Oxford Transplant Ctr, Oxford Univ Hosp Natl Hlth Serv NHS Trust, Oxford, England.
    Bell, Sally
    Dept Gastroenterol, St Vincent Hosp, Fitzroy Vic, Australia.
    Cole, Andy
    Royal Derby Hosp, Derby, England.
    Connor, Susan J.
    Dept Gastroenterol & Hepatol, Liverpool Hosp, Sydney NSW, Australia.
    Creed, Tom
    Joint Clin Res Unit, Univ Hosp Bristol NHS Fdn Trust, Bristol, England.
    Cummings, Fraser R.
    Dept Gastroenterol, Univ Hosp Southampton NHS Fdn Trust, Southampton, England.
    D'Amato, Mauro
    Dept Biosci & Nutr, Karolinska Inst, Stockholm, Sweden.
    Daneshmend, Tawfique K.
    IBD Pharmacogenet, Royal Devon & Exeter Hosp, Exeter, England.
    Fedorak, Richard N.
    Div Gastroenterol, Univ Alberta, Edmonton AB, Canada.
    Florin, Timothy H.
    Sch Med, Univ Queensland, South Brisbane Qld, Australia.
    Gaya, Daniel R.
    Gastroenterol Unit, Glasgow Royal Infirm, Glasgow, UK.
    Greig, Emma
    Dept Gastroenterol, Taunton & Somerset NHS Fdn Trust, Taunton, England.
    Halfvarson, Jonas
    Örebro University, School of Medicine, Örebro University, Sweden. Örebro University Hospital. Division of Gastroenterology, Örebro University Hospital, Örebro, Sweden.
    Hart, Alisa
    Dept Med, St Marks Hosp, London, England; Acad Inst, North West London Hosp NHS Trust, London, England.
    Irving, Peter M.
    Dept Gastroenterol, Guys & St Thomas NHS Fdn Trust, London, England.
    Jones, Gareth
    Dept Gastroenterol, Western Gen Hosp, Edinburgh, UK.
    Karban, Amir
    Dept Gastroenterol, Rambam Med Ctr, Haifa, Israel.
    Lawrance, Ian C.
    Ctr Inflammatory Bowel Dis, Fremantle Hosp, Univ Western Australia, Fremantle WA, Australia.
    Lee, James C.
    Dept Gastroenterol, Cambridge Univ Hosp NHS Trust, Cambridge, England.
    Lees, Charlie
    Dept Gastroenterol, Western Gen Hosp, Edinburgh, UK.
    Lev-Tzion, Raffi
    Paediatr Gastroenterol & Nutr Unit, Shaare Zedek Med Ctr, Jerusalem, Israel.
    Lindsay, James
    Dept Gastroenterol, Barts & London NHS Trust, London, England.
    Mansfield, John
    Dept Gastroenterol, Newcastle Univ Hosp NHS Trust, Newcastle NSW, Australia.
    Mawdsley, Joel
    Dept Gastroenterol, West Middlesex Univ Hosp NHS Trust, Isleworth, England.
    Mazhar, Zia
    Dept Gastroenterol, Basildon & Thurrock Hosp NHS Trust, Basildon, England.
    Parkes, Miles
    Dept Gastroenterol, Cambridge Univ Hosp NHS Trust, Cambridge, England.
    Parnell, Kirstie
    Precision Med Exeter, Univ Exeter, Exeter, England.
    Orchard, Timothy R.
    Dept Med, Imperial Coll Healthcare NHS, London, England.
    Radford-Smith, Graham
    Dept Gastroenterol, Royal Brisbane & Womens Hosp, Brisbane Qld, Australia; IBD Grp, Queensland Inst Med Res, Brisbane Qld, Australia; Sch Med, Univ Queensland, Brisbane Qld, Australia.
    Russell, Richard K.
    Dept Paediat Gastroenterol, Yorkhill Hosp, Glasgow, UK.
    Reffitt, David
    Dept Gastroenterol, Lewisham & Greenwich NHS Trust, London, England.
    Satsangi, Jack
    Dept Gastroenterol, Western Gen Hosp, Edinburgh, UK.
    Silverberg, Mark S.
    Zane Cohen Ctr Digest Dis, Inflammatory Bowel Dis Grp, Mt Sinai Hosp, Toronto ON, Canada.
    Sturniolo, Giacomo C.
    Univ Padua, Padua, Italy.
    Tremelling, Mark
    Dept Gastroenterol, Norfolk & Norwich Hosp NHS Trust, Norwich, England.
    Tsianos, Epameinondas V.
    Fac Med, Div Internal Med 1, Univ Ioannina, Ioannina, Greece; Fac Med, Div Gastroenterol, Univ Ioannina, Ioannina, Greece.
    van Heel, David A.
    Barts & London Sch Med & Dent, Blizard Inst, Queen Mary Univ, London, England.
    Walsh, Alissa
    Dept Gastroenterol, St Vincents Hosp, Sydney NSW, Australia.
    Watermeyer, Gill
    Gastrointestinal Clin, Groote Schuur Hosp, Cape Town, South Africa.
    Weersma, Rinse K.
    Dept Gastroenterol & Hepatol, Univ Med Ctr, Groningen, Netherlands; Univ Groningen, Groningen, Netherlands.
    Zeissig, Sebastian
    Dept Internal Med, Univ Med Ctr Schleswig Holstein, Kiel, Germany.
    Rossjohn, Jamie
    Sch Biomed Sci, Dept Biochem & Mol Biol, Monash Univ, Clayton Vic, Australia.
    Holden, Arthur L.
    Int Serious Adverse Events Consortium, Chicago IL, USA.
    Ahmad, Tariq
    IBD Pharmacogenet, Royal Devon & Exeter Hosp, Exeter, England; Precision Med, Univ Exeter, Exeter, England.
    HLA-DQA1-HLA-DRB1 variants confer susceptibility to pancreatitis induced by thiopurine immunosuppressants2014In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 46, no 10, p. 1131-1134Article in journal (Refereed)
    Abstract [en]

    Pancreatitis occurs in approximately 4% of patients treated with the thiopurines azathioprine or mercaptopurine. Its development is unpredictable and almost always leads to drug withdrawal. We identified patients with inflammatory bowel disease (IBD) who had developed pancreatitis within 3 months of starting these drugs from 168 sites around the world. After detailed case adjudication, we performed a genome-wide association study on 172 cases and 2,035 controls with IBD. We identified strong evidence of association within the class II HLA region, with the most significant association identified at rs2647087 (odds ratio 2.59, 95% confidence interval 2.07-3.26, P = 2 x 10(-16)). We replicated these findings in an independent set of 78 cases and 472 controls with IBD matched for drug exposure. Fine mapping of the H LA region identified association with the HLA-DQA1*02:01-HLA-DRB1*07:01 haplotype. Patients heterozygous at rs2647087 have a 9% risk of developing pancreatitis after administration of a thiopurine, whereas homozygotes have a 17% risk.

  • 8. Kaminsky, Zachary A.
    et al.
    Tang, Thomas
    Wang, Sun-Chong
    Ptak, Carolyn
    Oh, Gabriel H. T.
    Wong, Albert H. C.
    Feldcamp, Laura A.
    Virtanen, Carl
    Halfvarson, Jonas
    Tysk, Curt
    Örebro University, School of Health and Medical Sciences.
    McRae, Allan F.
    Visscher, Peter M.
    Montgomery, Grant W.
    Gottesman, Irving I.
    Martin, Nicholas G.
    Petronis, Art
    DNA methylation profiles in monozygotic and dizygotic twins2009In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 41, no 2, p. 240-245Article in journal (Refereed)
    Abstract [en]

    Twin studies have provided the basis for genetic and epidemiological studies in human complex traits. As epigenetic factors can contribute to phenotypic outcomes, we conducted a DNA methylation analysis in white blood cells (WBC), buccal epithelial cells and gut biopsies of 114 monozygotic (MZ) twins as well as WBC and buccal epithelial cells of 80 dizygotic (DZ) twins using 12K CpG island microarrays. Here we provide the first annotation of epigenetic metastability of approximately 6,000 unique genomic regions in MZ twins. An intraclass correlation (ICC)-based comparison of matched MZ and DZ twins showed significantly higher epigenetic difference in buccal cells of DZ co-twins (P = 1.2 x 10(-294)). Although such higher epigenetic discordance in DZ twins can result from DNA sequence differences, our in silico SNP analyses and animal studies favor the hypothesis that it is due to epigenomic differences in the zygotes, suggesting that molecular mechanisms of heritability may not be limited to DNA sequence differences.

  • 9. McGovern, Dermot P. B.
    et al.
    Gardet, Agnes
    Törkvist, Leif
    Goyette, Philippe
    Essers, Jonah
    Taylor, Kent D.
    Neale, Benjamin M.
    Ong, Rick T. H.
    Lagace, Caroline
    Li, Chun
    Green, Todd
    Stevens, Christine R.
    Beauchamp, Claudine
    Fleshner, Phillip R.
    Carlson, Marie
    D'Amato, Mauro
    Halfvarson, Jonas
    Örebro University, School of Medicine, Örebro University, Sweden.
    Hibberd, Martin L.
    Loerdal, Mikael
    Padyukov, Leonid
    Andriulli, Angelo
    Colombo, Elisabetta
    Latiano, Anna
    Palmieri, Orazio
    Bernard, Edmond-Jean
    Deslandres, Colette
    Hommes, Daan W.
    de Jong, Dirk J.
    Stokkers, Pieter C.
    Weersma, Rinse K.
    Sharma, Yashoda
    Silverberg, Mark S.
    Cho, Judy H.
    Wu, Jing
    Roeder, Kathryn
    Brant, Steven R.
    Schumm, L. Phillip
    Duerr, Richard H.
    Dubinsky, Marla C.
    Glazer, Nicole L.
    Haritunians, Talin
    Ippoliti, Andy
    Melmed, Gil Y.
    Siscovick, David S.
    Vasiliauskas, Eric A.
    Targan, Stephan R.
    Annese, Vito
    Wijmenga, Cisca
    Pettersson, Sven
    Rotter, Jerome I.
    Xavier, Ramnik J.
    Daly, Mark J.
    Rioux, John D.
    Seielstad, Mark
    Genome-wide association identifies multiple ulcerative colitis susceptibility loci (vol 42, pg 332, 2010)2011In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 43, no 4, p. 388-388Article in journal (Refereed)
  • 10. McGovern, Dermot P B
    et al.
    Gardet, Agnès
    Törkvist, Leif
    Goyette, Philippe
    Essers, Jonah
    Taylor, Kent D
    Neale, Benjamin M
    Ong, Rick T H
    Lagacé, Caroline
    Li, Chun
    Green, Todd
    Stevens, Christine R
    Beauchamp, Claudine
    Fleshner, Phillip R
    Carlson, Marie
    D'Amato, Mauro
    Halfvarson, Jonas
    Örebro University, School of Health and Medical Sciences.
    Hibberd, Martin L
    Lördal, Mikael
    Padyukov, Leonid
    Andriulli, Angelo
    Colombo, Elisabetta
    Latiano, Anna
    Palmieri, Orazio
    Bernard, Edmond-Jean
    Deslandres, Colette
    Hommes, Daan W
    de Jong, Dirk J
    Stokkers, Pieter C
    Weersma, Rinse K
    Sharma, Yashoda
    Silverberg, Mark S
    Cho, Judy H
    Wu, Jing
    Roeder, Kathryn
    Brant, Steven R
    Schumm, L Phillip
    Duerr, Richard H
    Dubinsky, Marla C
    Glazer, Nicole L
    Haritunians, Talin
    Ippoliti, Andy
    Melmed, Gil Y
    Siscovick, David S
    Vasiliauskas, Eric A
    Targan, Stephan R
    Annese, Vito
    Wijmenga, Cisca
    Pettersson, Sven
    Rotter, Jerome I
    Xavier, Ramnik J
    Daly, Mark J
    Rioux, John D
    Seielstad, Mark
    Genome-wide association identifies multiple ulcerative colitis susceptibility loci2010In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 42, no 4, p. 332-337Article in journal (Refereed)
    Abstract [en]

    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.

  • 11.
    Momozawa, Yukihide
    et al.
    Fac Vet Med, Univ Liege B34, Liege, Belgium.
    Mni, Myriam
    Fac Vet Med, Univ Liege B34, Liege, Belgium.
    Nakamura, Kayo
    Fac Vet Med, Univ Liege B34, Liege, Belgium.
    Coppieters, Wouter
    Fac Vet Med, Univ Liege B34, Liege, Belgium.
    Almer, Sven
    Inst Mol & Klin Med IMK, Div Gastroenterol & Hepatol, Linköpings Univ, Linköping, Sweden .
    Amininejad, Leila
    Dept Gastroenterol, Erasme Hosp, Univ Libre Brussels, Brussels, Belgium .
    Cleynen, Isabelle
    Dept Pathophysiol, Gastroenterol Sect, Catholic Univ Louvain, Louvain, Belgium.
    Colombel, Jean-Frédéric
    Registre MICI Nord Quest France EPIMAD, Hop Calmette, Lille, France.
    de Rijk, Peter
    Dept Mol Genet, Univ Antwerp VIB, Antwerp, Belgium.
    Dewit, Olivier
    Dept Gastroenterol, Clin Univ St Luc, Catholic Univ Louvain, Brussels, Belgium.
    Finkel, Yigael
    Dept Gastroenterol, Karolinska Childrens Hosp, Stockholm, Sweden.
    Gassull, Miquel A.
    Dept Gastroenterol, Hosp Badalona Germans Trias & Pujol, Badalona, Spain.
    Goossens, Dirk
    Dept Mol Genet, Univ Antwerp VIB, Antwerp, Belgium.
    Laukens, Debby
    Dept Gastroenterol, Univ Hosp, Univ Ghent, Ghent, Belgium.
    Lémann, Marc
    AP HP, Dept Gastroenterol, Hop St Louis, Univ Paris 07, Paris, France.
    Libioulle, Cécile
    Fac Vet Med, Univ Liege B34, Liege, Belgium.
    O'Morain, Colm
    Adelaide & Meath Hosp, Dublin, Ireland.
    Reenaers, Catherine
    Fac Med, Univ Liege B34, Liege, Belgium.
    Rutgeerts, Paul
    Dept Pathophysiol, Gastroenterol Sect, Catholic Univ Louvain, Louvain, Belgium.
    Tysk, Curt
    Örebro University, School of Health and Medical Sciences.
    Zelenika, Diana
    Ctr Natl Genotypage, Evry, France.
    Lathrop, Mark
    Ctr Natl Genotypage, Evry, France.
    Del-Favero, Jurgen
    Dept Mol Genet, Univ Antwerp VIB, Antwerp, Belgium .
    Hugot, Jean-Pierre
    INSERM, U843, Hop Robert Debre, IParis, France.
    de Vos, Martine
    Dept Gastroenterol,Univ Hosp, Univ Ghent, Ghent, Belgium.
    Franchimont, Denis
    Dept Gastroenterol, Erasme Hosp, Univ Libre Brussels, Brussels, Belgium.
    Vermeire, Severine
    Dept Pathophysiol, Gastroenterol Sect, Catholic Univ Louvain, Louvain, Belgium.
    Louis, Edouard
    Fac Med, Univ Liege B34, Liege, Belgium.
    Georges, Michel
    Fac Med, Univ Liege B34, Liege, Belgium.
    Resequencing of positional candidates identifies low frequency IL23R coding variants protecting against inflammatory bowel disease2011In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 43, no 1, p. 43-47Article in journal (Refereed)
    Abstract [en]

    Genome-wide association studies (GWAS) have identified dozens of risk loci for many complex disorders, including Crohn's disease. However, common disease-associated SNPs explain at most ∼20% of the genetic variance for Crohn's disease. Several factors may account for this unexplained heritability, including rare risk variants not adequately tagged thus far in GWAS. That rare susceptibility variants indeed contribute to variation in multifactorial phenotypes has been demonstrated for colorectal cancer, plasma high-density lipoprotein cholesterol levels, blood pressure, type 1 diabetes, hypertriglyceridemia and, in the case of Crohn's disease, for NOD2 (refs. 14,15). Here we describe the use of high-throughput resequencing of DNA pools to search for rare coding variants influencing susceptibility to Crohn's disease in 63 GWAS-identified positional candidate genes. We identify low frequency coding variants conferring protection against inflammatory bowel disease in IL23R, but we conclude that rare coding variants in positional candidates do not make a large contribution to inherited predisposition to Crohn's disease.

  • 12. Ong, Ken K.
    et al.
    Elks, Cathy E.
    Li, Shengxu
    Zhao, Jing Hua
    Luan, Jian'an
    Andersen, Lars B.
    Bingham, Sheila A.
    Brage, Sören
    Smith, George Davey
    Ekelund, Ulf
    Örebro University, School of Health and Medical Sciences.
    Gillson, Christopher J.
    Glaser, Beate
    Golding, Jean
    Hardy, Rebecca
    Khaw, Kay-Tee
    Kuh, Diana
    Luben, Robert
    Marcus, Michele
    McGeehin, Michael A.
    Ness, Andrew R.
    Northstone, Kate
    Ring, Susan M.
    Rubin, Carol
    Sims, Matthew A.
    Song, Kijoung
    Strachan, David P.
    Vollenweider, Peter
    Waeber, Gerard
    Waterworth, Dawn M.
    Wong, Andrew
    Deloukas, Panagiotis
    Barroso, Ines
    Mooser, Vincent
    Loos, Ruth J.
    Wareham, Nicholas J.
    Genetic variation in LIN28B is associated with the timing of puberty2009In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 41, no 6, p. 729-733Article in journal (Refereed)
    Abstract [en]

    The timing of puberty is highly variable(1). We carried out a genome-wide association study for age at menarche in 4,714 women and report an association in LIN28B on chromosome 6 (rs314276, minor allele frequency (MAF) = 0.33, P = 1.5 x 10(-8)). In independent replication studies in 16,373 women, each major allele was associated with 0.12 years earlier menarche (95% CI = 0.08-0.16; P = 2.8 x 10(-10); combined P = 3.6 x 10(-16)). This allele was also associated with earlier breast development in girls (P = 0.001; N = 4,271); earlier voice breaking (P = 0.006, N = 1,026) and more advanced pubic hair development in boys (P = 0.01; N = 4,588); a faster tempo of height growth in girls (P = 0.00008; N = 4,271) and boys (P = 0.03; N = 4,588); and shorter adult height in women (P = 3.6 x 10(-7); N = 17,274) and men (P = 0.006; N = 9,840) in keeping with earlier growth cessation. These studies identify variation in LIN28B, a potent and specific regulator of microRNA processing(2), as the first genetic determinant regulating the timing of human pubertal growth and development.

  • 13. Rivas, Manuel A.
    et al.
    Beaudoin, Melissa
    Gardet, Agnes
    Stevens, Christine
    Sharma, Yashoda
    Zhang, Clarence K.
    Boucher, Gabrielle
    Ripke, Stephan
    Ellinghaus, David
    Burtt, Noel
    Fennell, Tim
    Kirby, Andrew
    Latiano, Anna
    Goyette, Philippe
    Green, Todd
    Halfvarson, Jonas
    Örebro University, School of Health and Medical Sciences.
    Haritunians, Talin
    Korn, Joshua M.
    Kuruvilla, Finny
    Lagace, Caroline
    Neale, Benjamin
    Lo, Ken Sin
    Schumm, Phil
    Torkvist, Leif
    Dubinsky, Marla C.
    Brant, Steven R.
    Silverberg, Mark S.
    Duerr, Richard H.
    Altshuler, David
    Gabriel, Stacey
    Lettre, Guillaume
    Franke, Andre
    D'Amato, Mauro
    McGovern, Dermot P. B.
    Cho, Judy H.
    Rioux, John D.
    Xavier, Ramnik J.
    Daly, Mark J.
    Deep resequencing of GWAS loci identifies independent rare variants associated with inflammatory bowel disease2011In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 43, no 11, p. 1066-U50Article in journal (Refereed)
    Abstract [en]

    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.

  • 14. Sun, Jielin
    et al.
    Zheng, Siqun Lilly
    Wiklund, Fredrik
    Isaacs, Sarah D.
    Purcell, Lina D.
    Gao, Zhengrong
    Hsu, Fang-Chi
    Kim, Seong-Tae
    Liu, Wennuan
    Zhu, Yi
    Stattin, Pär
    Adami, Hans-Olov
    Wiley, Kathleen E.
    Dimitrov, Latchezar
    Sun, Jishan
    Li, Tao
    Turner, Aubrey R.
    Adams, Tamara S.
    Adolfsson, Jan
    Johansson, Jan-Erik
    Örebro University, School of Health and Medical Sciences.
    Lowey, James
    Trock, Bruce J.
    Partin, Alan W.
    Walsh, Patrick C.
    Trent, Jeffrey M.
    Duggan, David
    Carpten, John
    Chang, Bao-Li
    Grönberg, Henrik
    Isaacs, William B.
    Xu, Jianfeng
    Evidence for two independent prostate cancer risk-associated loci in the HNF1B gene at 17q122008In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 40, no 10, p. 1153-1155Article in journal (Other academic)
    Abstract [en]

    We carried out a fine-mapping study in the HNF1B gene at 17q12 in two study populations and identified a second locus associated with prostate cancer risk, 26 kb centromeric to the first known locus (rs4430796); these loci are separated by a recombination hot spot. We confirmed the association with a SNP in the second locus (rs11649743) in five additional populations, with P = 1.7 10-9 for an allelic test of the seven studies combined. The association at each SNP remained significant after adjustment for the other SNP.

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