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      A genome-wide association study of anorexia nervosa

      research-article
      , PhD 1 , 2 , , PhD 1 , , PhD 1 , 3 , , PhD 4 , 1 , , BSc 1 , , PhD 1 , 5 , 6 , , PhD 1 , , PhD 7 , , PhD, FRCP, FRCPsych 8 , , PhD 8 , , MD, PhD, FRCPsych 8 , , MD 4 , , PhD, RNutr 10 , , MD 11 , , MD, PhD 12 , 13 , , PhD 14 , 15 , , PhD 14 , , MD, PhD 16 , , MD 16 , , PhD 17 , 18 , , MD, PhD 19 , 20 , 21 , 22 , , MD, PhD 23 , , PhD 24 , , MD, PhD 25 , 26 , 27 , , MD, PhD, MPH 25 , , MD, PhD 25 , 28 , , PhD 29 , 30 , , PhD 29 , 31 , , MD, ScD 32 , , MD, PhD 33 , 34 , , PhD 33 , , MD 35 , 36 , , MD, MSc, FRCP(C) 37 , 38 , , MD 39 , , MD, PhD 40 , 41 , , MD, PhD 42 , , PhD 40 , , PhD 40 , , PhD 43 , , MD, PhD 44 , 45 , , MD, PhD 44 , , PhD 46 , , PhD 47 , , PhD 47 , , PhD 48 , 49 , , MD, PhD 47 , 48 , , PhD 4 , , PhD 50 , , PhD 51 , , PhD, RN, PMHNP-BC 52 , , BS 4 , , MD, MPH 53 , , PhD 54 , , PhD 51 , , MSW, LCSW 4 , , PhD 4 , , PhD 4 , , PhD 9 , 55 , , PhD 9 , , MD 56 , , MD 57 , , MD 58 , 59 , , MD 60 , , MD 61 , 62 , , MD 56 , , MD 63 , , MD 64 , , PhD 65 , , PhD 11 , , MD 66 , , PhD 12 , , PhD 12 , , PhD 12 , , MSc 14 , 15 , , PhD 15 , , PhD 67 , 14 , , PhD 67 , , PhD 68 , 69 , , MSc 67 , , MD, PhD 15 , 70 , , PhD 71 , , MD 71 , , PhD 16 , , PhD 71 , , PhD 16 , , MD, PhD 19 , 20 , 21 , 22 , , PhD 19 , 20 , 21 , 22 , , PhD 17 , 18 , , PhD 72 , , MD, PhD 73 , , MD, PhD 73 , , MD, PhD 24 , , MD, PhD 24 , , PhD 74 , , PhD 31 , , PhD 31 , 75 , , MD 35 , , MD, PhD 35 , , PhD 76 , , MD 77 , , MD 78 , , MD, MSc 76 , , MD, PhD 79 , , MD, PhD 80 , , MSc 81 , , MSc 80 , , MD, MSc, FRCP(C) 37 , 38 , , MD, MSc, FRCP(C) 37 , 38 , , PhD 4 , 37 , , MD 39 , , MD 39 , , MD 39 , , MSc, Dr med sci 39 , , PhD 82 , , PhD 9 , , PhD 9 , , MD, FRCPsych 9 , , MD, PhD 9 , , PhD 83 , 84 , 85 , , PhD 86 , , PhD 83 , 85 , , MD, PhD 86 , , MD 87 , , MD 88 , 89 , , PhD 90 , , MD 91 , , MD, PhD 92 , , PhD 1 , , MD 93 , , MD, PhD 93 , , PhD 19 , 22 , , MS 94 , , PhD 95 , , MD, PhD 1 , 96 , 97 , , PhD 96 , 98 , , MD, PhD 96 , 98 , , MD, PhD 99 , , PhD 99 , 100 , , PhD 101 , 102 , 103 , , PhD 100 , , MD, PhD 104 , 105 , , PhD 104 , 105 , , MSc 99 , , PhD 76 , , MD 106 , , MD, PhD 107 , , MD 108 , , MD, PhD 107 , , MD, MSc, FRCS 109 , , PhD 110 , , PhD 111 , , MD 112 , , MD 112 , , MD, PhD 112 , , PhD 113 , , PhD 113 , , MD, PhD 114 , , MD, PhD 114 , , PhD 1 , , PhD 9 , , PhD 9 , , PhD 1 , , PhD 1 , , PhD 1 , 115 , , PhD 1 , The Wellcome Trust Case Control Consortium 3, , MD, PhD 19 , 20 , 21 , 22 , , PhD 11 , , MD, FRANZCP 4 , 51 , , PhD 9 , 116 , , PhD 1 , , PhD 4 , 117
      Molecular psychiatry
      anorexia nervosa, eating disorders, GWAS, genome-wide association study, body mass index, metabolic

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          Abstract

          Anorexia nervosa (AN) is a complex and heritable eating disorder characterized by dangerously low body weight. Neither candidate gene studies nor an initial genome wide association study (GWAS) have yielded significant and replicated results. We performed a GWAS in 2,907 cases with AN from 14 countries (15 sites) and 14,860 ancestrally matched controls as part of the Genetic Consortium for AN (GCAN) and the Wellcome Trust Case Control Consortium 3 (WTCCC3). Individual association analyses were conducted in each stratum and meta-analyzed across all 15 discovery datasets. Seventy-six (72 independent) SNPs were taken forward for in silico (two datasets) or de novo (13 datasets) replication genotyping in 2,677 independent AN cases and 8,629 European ancestry controls along with 458 AN cases and 421 controls from Japan. The final global meta-analysis across discovery and replication datasets comprised 5,551 AN cases and 21,080 controls. AN subtype analyses (1,606 AN restricting; 1,445 AN binge-purge) were performed. No findings reached genome-wide significance. Two intronic variants were suggestively associated: rs9839776 (P=3.01×10 −7) in SOX2OT and rs17030795 (P=5.84×10 −6) in PPP3CA. Two additional signals were specific to Europeans: rs1523921 (P=5.76×10 −6) between CUL3 and FAM124B and rs1886797 (P=8.05×10 −6) near SPATA13. Comparing discovery to replication results, 76% of the effects were in the same direction, an observation highly unlikely to be due to chance (P= 4×10 −6), strongly suggesting that true findings exist but that our sample, the largest yet reported, was underpowered for their detection. The accrual of large genotyped AN case-control samples should be an immediate priority for the field.

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          PLINK: a tool set for whole-genome association and population-based linkage analyses.

          Whole-genome association studies (WGAS) bring new computational, as well as analytic, challenges to researchers. Many existing genetic-analysis tools are not designed to handle such large data sets in a convenient manner and do not necessarily exploit the new opportunities that whole-genome data bring. To address these issues, we developed PLINK, an open-source C/C++ WGAS tool set. With PLINK, large data sets comprising hundreds of thousands of markers genotyped for thousands of individuals can be rapidly manipulated and analyzed in their entirety. As well as providing tools to make the basic analytic steps computationally efficient, PLINK also supports some novel approaches to whole-genome data that take advantage of whole-genome coverage. We introduce PLINK and describe the five main domains of function: data management, summary statistics, population stratification, association analysis, and identity-by-descent estimation. In particular, we focus on the estimation and use of identity-by-state and identity-by-descent information in the context of population-based whole-genome studies. This information can be used to detect and correct for population stratification and to identify extended chromosomal segments that are shared identical by descent between very distantly related individuals. Analysis of the patterns of segmental sharing has the potential to map disease loci that contain multiple rare variants in a population-based linkage analysis.
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              The past year has witnessed substantial advances in understanding the genetic basis of many common phenotypes of biomedical importance. These advances have been the result of systematic, well-powered, genome-wide surveys exploring the relationships between common sequence variation and disease predisposition. This approach has revealed over 50 disease-susceptibility loci and has provided insights into the allelic architecture of multifactorial traits. At the same time, much has been learned about the successful prosecution of association studies on such a scale. This Review highlights the knowledge gained, defines areas of emerging consensus, and describes the challenges that remain as researchers seek to obtain more complete descriptions of the susceptibility architecture of biomedical traits of interest and to translate the information gathered into improvements in clinical management.
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                Author and article information

                Journal
                9607835
                20545
                Mol Psychiatry
                Mol. Psychiatry
                Molecular psychiatry
                1359-4184
                1476-5578
                5 December 2013
                16 November 2010
                September 2011
                11 December 2013
                : 16
                : 9
                : 10.1038/mp.2010.107
                Affiliations
                [1 ]Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK
                [2 ]University of Split School of Medicine, Split, Croatia
                [3 ]William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, John Vane Science Centre, Charterhouse Square, London, UK
                [4 ]Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
                [5 ]Wellcome Trust Centre for Human Genetics (WTCHG), University of Oxford, Oxford, UK
                [6 ]Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), Oxford, UK
                [7 ]Department of Psychology, Michigan State University, East Lansing, MI, USA
                [8 ]Section of Eating Disorders, Institute of Psychiatry, King’s College London, London, UK
                [9 ]Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, King’s College London, London, UK
                [10 ]Health Services Research Unit, University of Aberdeen, Aberdeen, UK
                [11 ]Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, Universitätsklinikum Essen, University of Duisburg-Essen, Essen, Germany
                [12 ]INSERM U894, Centre of Psychiatry and Neuroscience, Paris, France
                [13 ]Sainte-Anne Hospital (CMME), University of Paris-Descartes, Paris, France
                [14 ]Brain Center Rudolf Magnus, Department of Neuroscience and Pharmacology, University Medical Center Utrecht, Utrecht, The Netherlands
                [15 ]Altrecht Eating Disorders Rintveld, Zeist, The Netherlands
                [16 ]Department of Neurosciences, University of Padova, Padova, Italy
                [17 ]Department of Psychiatry and CIBERON, University Hospital of Bellvitge-IDIBELL, Barcelona, Spain
                [18 ]Department of Clinical Sciences, School of Medicine, University of Barcelona, Barcelona, Spain
                [19 ]Genomics and Disease Group, Centre for Genomic Regulation (CRG), Barcelona, Spain
                [20 ]Universitat Pompeu Fabra (UPF), Barcelona, Spain
                [21 ]Centro de Investigación Biomédica en Red en Epidemiología y Salud Pública (CIBERESP), Barcelona, Spain
                [22 ]Hospital del Mar Medical Research Institute (IMIM), 08003, Barcelona, Catelonia, Spain
                [23 ]Department of Child and Adolescent Psychiatry, Institute of Psychiatry and Neurology, Warsaw, Poland
                [24 ]Department of Child and Adolescent Psychiatry, Department of Psychiatry, Poznan University of Medical Sciences, Poznan, Poland
                [25 ]Hjelt Institute, University of Helsinki, Helsinki, Finland
                [26 ]Institute of Molecular Medicine, University of Helsinki, Helsinki, Finland
                [27 ]Department of Mental Health and Substance Abuse Services, National Institute for Health and Welfare, Helsinki, Finland
                [28 ]Department of Adolescent Psychiatry, Helsinki University Central Hospital, Helsinki, Finland
                [29 ]Center for Eating Disorders Ursula, Leidschendam, The Netherlands
                [30 ]Leiden University Medical Centre, Department of Psychiatry, Leiden, The Netherlands
                [31 ]Leiden University Medical Centre, Molecular Epidemiology Section (Department of Medical Statistics), Leiden, The Netherlands
                [32 ]Department of Psychiatry, McLean Hospital/Harvard Medical School, Belmont, MA, USA
                [33 ]Department of Genetics, Environment and Mental Health, Norwegian Institute of Public Health, Oslo, Norway
                [34 ]Institute of Clinical Medicine, University of Oslo, Oslo, Norway
                [35 ]Department of Psychiatry, University of Naples SUN, Naples, Italy
                [36 ]Chair of Psychiatry, University of Salerno, Salerno, Italy
                [37 ]Centre for Addiction and Mental Health, University of Toronto, Toronto, Canada
                [38 ]Department of Psychiatry, University of Toronto, Toronto, Canada
                [39 ]Eating Disorders Unit, Department of Child and Adolescent Psychiatry, Medical University of Vienna, Vienna, Austria
                [40 ]The Center for Applied Genomics, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA
                [41 ]The Division of Human Genetics, Department of Pediatrics, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
                [42 ]Department of Psychiatry, University of Pennsylvania, Philadelphia, PA, USA
                [43 ]Department of Molecular and Experimental Medicine and The Scripps Translational Science Institute, The Scripps Research Institute, La Jolla, CA, USA
                [44 ]Department of Psychosomatic Research, National Institute of Mental Health, NCNP, Tokyo, Japan
                [45 ]School of Health Sciences at Fukuoka, International University of Health and Welfare, Fukuoka, Japan
                [46 ]Department of Molecular Life Sciences, Tokai University School of Medicine, Kanagawa, Japan
                [47 ]Estonian Genome Center, University of Tartu, Tartu, Estonia
                [48 ]Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia
                [49 ]Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland
                [50 ]Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN, USA
                [51 ]Department of Genetics, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
                [52 ]Seattle University College of Nursing, Seattle, WA, USA
                [53 ]Kartini Clinic, Portland, OR, USA
                [54 ]Centre de Psychiatrie et Neurosciences - Inserm U894, Paris, France
                [55 ]UCL Genetics Institute, Department of Genetics, Evolution and Environment, University College London, London, UK
                [56 ]Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University Clinics RWTH Aachen, Aachen, Germany
                [57 ]Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, Charité, Berlin, Germany
                [58 ]Department of Psychosomatic Medicine and Psychotherapy, Hannover Medical School, Hannover, Germany
                [59 ]Department of Psychosomatic Medicine and Psychotherapy, University of Erlangen-Nuremberg, Erlangen, Germany
                [60 ]Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University Würzburg, Würzburg, Germany
                [61 ]Department of Child and Adolescent Psychiatry, University Hospital Carl Gustav Carus, Dresden University of Technology, Dresden, Germany
                [62 ]Massachusetts General Hospital/Harvard Medical School, Athinoula A. Martinos Center for Biomedical Imaging, Psychiatric Neuroimaging Research Program, Charlestown, MA, USA
                [63 ]Departments of Psychosocial and Internal Medicine, Heidelberg University, Heidelberg, Germany
                [64 ]Parklandklinik, Bad Wildungen, Germany
                [65 ]Institute for Medical Informatics, Biometry and Epidemiology, Universitätsklinikum Essen, University of Duisburg-Essen, Essen, Germany
                [66 ]Department of Internal Medicine VI, Psychosomatic Medicine and Psychotherapy, University Medical Hospital Tübingen, Tübingen, Germany
                [67 ]Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands
                [68 ]Center for Neurobehavioral Genetics, University of California, Los Angeles, Los Angeles, CA, USA
                [69 ]Brain Center Rudolf Magnus, Department of Psychiatry, University Medical Center Utrecht, The Netherlands
                [70 ]Department of Child and Adolescent Psychiatry, University Medical Center Utrecht, Utrecht, The Netherlands
                [71 ]Clinical Genetics Unit, Department of Woman and Child Health, University of Padova, Padova, Italy
                [72 ]M. Sklodowska-Curie Cancer Center and Institute of Oncology, Warsaw, Poland
                [73 ]Department of Epidemiology, Institute of Occupational Medicine, Department of Epidemiology, Lodz, Poland
                [74 ]Department of Clinical Nutrition, Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland
                [75 ]Netherlands Consortium for Healthy Ageing, Leiden University Medical Center, The Netherlands
                [76 ]Department of Nutrition and Dietetics, Harokopio University, Athens, Greece
                [77 ]1st Department of Psychiatry, Athens University Medical School, Athens, Greece
                [78 ]Eating Disorders Unit, 1st Department of Psychiatry, Athens University Medical School, Athens, Greece
                [79 ]Adolescent Health Unit (A.H.U.), 2nd Department of Pediatrics – Medical School, University of Athens “P. & A. Kyriakou” Children’s Hospital, Athens, Greece
                [80 ]Department of Psychiatry, 1st Faculty of Medicine, Charles University, Prague, Czech Republic
                [81 ]Department of Pediatrics, 1 st Faculty of Medicine, Charles University, Prague, Czech Republic
                [82 ]Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
                [83 ]Institute of Human Genetics, Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany
                [84 ]Institute of Neuroscience and Medicine (INM-1), Research Center Jülich, Jülich, Germany
                [85 ]Division of Medical Genetics, Department of Biomedicine, University of Basel, Basel, Switzerland
                [86 ]Martin-Luther-Universität Halle-Wittenberg, Klinikum der Medizinischen Fakultät, Halle/Saale, Germany
                [87 ]Institute of Clinical Molecular Biology, University of Kiel, Germany
                [88 ]Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
                [89 ]Institute of Medical Informatics, Biometry and Epidemiology, Ludwig-Maximilians-University, Munich, Germany
                [90 ]CNRS 8090-Institute of Biology, Pasteur Institute, Lille, France
                [91 ]McGill University and Genome Quebec Innovation Centre, Montreal, Canada
                [92 ]Division of Nephrology, Department of Internal Medicine and Medical Specialties, Columbus-Gemelly Hospitals, Catholic University, Rome, Italy
                [93 ]Unitat de Recerca de Reumatologia (URR), Institut de Recerca Hospital Universitari Vall d’Hebron, Barcelona, Spain
                [94 ]Genetic Epidemiology Group, International Agency for Research on Cancer (IARC), Lyon, France
                [95 ]Virginia Institute for Psychiatric and Behavioral Genetics, Department of Psychiatry, Virginia Commonwealth University, VA, USA
                [96 ]The Finnish Institute of Molecular Medicine Finland (FIMM), University of Helsinki, Finland
                [97 ]The Program for Human and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA, USA
                [98 ]Finnish Institute of Occupational Health, Helsinki, Province of Southern Finland, Finland
                [99 ]NORMENT, K.G. Jebsen Centre for Psychosis Research, Division of Mental Health and Addiction, Oslo University Hospital & Institute of Clinical Medicine, University of Oslo, Oslo, Norway
                [100 ]Department of Psychology, University of Oslo, Norway
                [101 ]Department of Biological and Medical Psychology, University of Bergen, Norway
                [102 ]Kavli Research Centre for Aging and Dementia, Haraldsplass Deaconess Hospital, Bergen, Norway
                [103 ]K.G. Jebsen Centre for Research on Neuropsychiatric Disorders, University of Bergen, Norway
                [104 ]K.G. Jebsen Centre for Psychosis Research, Norwegian Centre For Mental Disorders Research (NORMENT), Department of Clinical Science, University of Bergen, Norway
                [105 ]Dr. Einar Martens Research Group for Biological Psychiatry, Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway
                [106 ]Institute of Hygiene and Epidemiology, 1st Faculty of Medicine, Charles University, Prague, Czech Republic
                [107 ]Department of Cancer Epidemiology and Genetics, Masaryk Memorial Cancer Institute, Brno, Czech Republic
                [108 ]Palacky University, Olomouc, Czech Republic
                [109 ]University Health Network and Mount Sinai Hospital, Toronto General Hospital, and Samuel Lunenfeld Research Institute, Toronto, Ontario, Canada
                [110 ]Departments of Psychiatry, and Genetics and Genomic Sciences, Seaver Autism Center, and the Mindich Child Health & Development Institute, Mount Sinai School of Medicine, New York, NY, USA
                [111 ]The Centre for Applied Genomics and Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada
                [112 ]Department of Psychiatry and Psychotherapy, Medical University Vienna, Austria
                [113 ]The Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
                [114 ]Rheumatology Unit, Department of Medicine at the Karolinska University Hospital, Solna, Sweden
                [115 ]European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD
                [116 ]Eli Lilly and Company Ltd, Erl Wood Manor, Windlesham, Surrey, UK
                [117 ]Department of Nutrition, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
                Author notes
                [*]

                These authors contributed equally to this manuscript

                [**]

                These authors contributed equally to this manuscript as investigators

                [+]

                These authors contributed equally to this manuscript

                Article
                EMS55785
                10.1038/mp.2010.107
                3859494
                21079607
                e7a0f0ec-64d9-48fe-91cd-bb7092123261

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                Categories
                Article

                Molecular medicine
                anorexia nervosa,eating disorders,gwas,genome-wide association study,body mass index,metabolic

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