title: A genome-wide association study of anorexia nervosa.
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 2907 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 data sets. Seventy-six (72 independent) single nucleotide polymorphisms were taken forward for in silico (two data sets) or de novo (13 data sets) replication genotyping in 2677 independent AN cases and 8629 European ancestry controls along with 458 AN cases and 421 controls from Japan. The final global meta-analysis across discovery and replication data sets comprised 5551 AN cases and 21 080 controls. AN subtype analyses (1606 AN restricting; 1445 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 with 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 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.
authors: 1] Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK [2] University of Split School of Medicine, Split, Croatia.
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authors: Boraska
authors: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK.
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authors: Franklin
authors: 1] Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK [2] 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.
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authors: Floyd
authors: Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
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authors: Thornton
authors: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK.
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authors: Huckins
authors: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK.
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authors: Southam
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authors: Rayner
authors: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK.
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authors: Tachmazidou
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authors: Section of Eating Disorders, Institute of Psychiatry, King's College London, London, UK.
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authors: Schmidt
authors: Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
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authors: Tozzi
authors: Health Services Research Unit, University of Aberdeen, Aberdeen, UK.
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authors: 1] INSERM U894, Centre of Psychiatry and Neuroscience, Paris, France [2] Sainte-Anne Hospital (CMME), University of Paris-Descartes, Paris, France.
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authors: Gorwood
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authors: Favaro
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authors: Fernández-Aranda
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authors: Dmitrzak-Weglarz
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authors: Hjelt Institute, University of Helsinki, Helsinki, Finland.
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authors: Reichborn-Kjennerud
authors: Department of Genetics, Environment and Mental Health, Norwegian Institute of Public Health, Oslo, Norway.
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authors: 1] Department of Psychiatry, University of Naples SUN, Naples, Italy [2] Chair of Psychiatry, University of Salerno, Salerno, Italy.
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authors: Eating Disorders Unit, Department of Child and Adolescent Psychiatry, Medical University of Vienna, Vienna, Austria.
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authors: The Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
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authors: The Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
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authors: Department of Molecular and Experimental Medicine and The Scripps Translational Science Institute, The Scripps Research Institute, La Jolla, CA, USA.
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authors: Centre de Psychiatrie et Neurosciences - Inserm U894, Paris, France.
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authors: Department of Genetics, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
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authors: Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
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authors: 1] Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, King's College London, London, UK [2] Department of Genetics, Evolution and Environment, University College London, UCL Genetics Institute, London, UK.
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authors: Davis
authors: Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, King's College London, London, UK.
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authors: Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University Clinics RWTH Aachen, Aachen, Germany.
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authors: Bühren
authors: Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, Charité, Berlin, Germany.
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authors: de Zwaan
authors: Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University Würzburg, Würzburg, Germany.
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authors: 1] Department of Child and Adolescent Psychiatry, University Hospital Carl Gustav Carus, Dresden University of Technology, Dresden, Germany [2] Athinoula A. Martinos Center for Biomedical Imaging, Psychiatric Neuroimaging Research Program, Massachusetts General Hospital/Harvard Medical School, Charlestown, MA, USA.
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authors: Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University Clinics RWTH Aachen, Aachen, Germany.
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authors: Herpertz-Dahlmann
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authors: Imgart
authors: Institute for Medical Informatics, Biometry and Epidemiology, Universitätsklinikum Essen, University of Duisburg-Essen, Essen, Germany.
authors: A
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authors: Scherag
authors: Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, Universitätsklinikum Essen, University of Duisburg-Essen, Essen, Germany.
authors: S
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authors: Scherag
authors: Department of Internal Medicine VI, Psychosomatic Medicine and Psychotherapy, University Medical Hospital Tübingen, Tübingen, Germany.
authors: S
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authors: INSERM U894, Centre of Psychiatry and Neuroscience, Paris, France.
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authors: INSERM U894, Centre of Psychiatry and Neuroscience, Paris, France.
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authors: Ramoz
authors: INSERM U894, Centre of Psychiatry and Neuroscience, Paris, France.
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authors: Versini
authors: 1] Brain Center Rudolf Magnus, Department of Translational Neuroscience, University Medical Center Utrecht, Utrecht, The Netherlands [2] Altrecht Eating Disorders Rintveld, Zeist, The Netherlands.
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authors: Brandys
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authors: Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
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authors: Brain Center Rudolf Magnus, Department of Translational Neuroscience, University Medical Center Utrecht, Utrecht, The Netherlands.
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authors: Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
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authors: R A
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authors: Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
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authors: Clinical Genetics Unit, Department of Woman and Child Health, University of Padova, Padova, Italy.
authors: A
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authors: Clinical Genetics Unit, Department of Woman and Child Health, University of Padova, Padova, Italy.
authors: M
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authors: Clementi
authors: Department of Neurosciences, University of Padova, Padova, Italy.
authors: D
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authors: Degortes
authors: Clinical Genetics Unit, Department of Woman and Child Health, University of Padova, Padova, Italy.
authors: M
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authors: Forzan
authors: Department of Neurosciences, University of Padova, Padova, Italy.
authors: E
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authors: G
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authors: Jiménez-Murcia
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authors: J
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authors: A
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authors: N
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authors: Szeszenia-Dabrowska
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authors: Hauser
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authors: L
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authors: Karhunen
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authors: I
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authors: P E
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authors: Slagboom
authors: Department of Psychiatry, University of Naples SUN, Naples, Italy.
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authors: Tortorella
authors: Department of Psychiatry, University of Naples SUN, Naples, Italy.
authors: M
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authors: Maj
authors: Department of Nutrition and Dietetics, Harokopio University, Athens, Greece.
authors: G
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authors: Dedoussis
authors: 1st Department of Psychiatry, Athens University Medical School, Athens, Greece.
authors: D
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authors: Dikeos
authors: Eating Disorders Unit, 1st Department of Psychiatry, Athens University Medical School, Athens, Greece.
authors: F
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authors: Gonidakis
authors: Department of Nutrition and Dietetics, Harokopio University, Athens, Greece.
authors: K
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authors: Tziouvas
authors: Adolescent Health Unit (A.H.U.), 2nd Department of Pediatrics - Medical School, University of Athens 'P. & A. Kyriakou' Children's Hospital, Athens, Greece.
authors: A
authors: A
authors: Tsitsika
authors: Department of Psychiatry, 1st Faculty of Medicine, Charles University, Prague, Czech Republic.
authors: H
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authors: Papezova
authors: Department of Pediatrics, 1st Faculty of Medicine, Charles University, Prague, Czech Republic.
authors: L
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authors: Slachtova
authors: Department of Psychiatry, 1st Faculty of Medicine, Charles University, Prague, Czech Republic.
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authors: 1] Centre for Addiction and Mental Health, Toronto, ON, Canada [2] Department of Psychiatry, University of Toronto, Toronto, ON, Canada.
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authors: 1] Centre for Addiction and Mental Health, Toronto, ON, Canada [2] Department of Psychiatry, University of Toronto, Toronto, ON, Canada.
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authors: 1] Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA [2] Centre for Addiction and Mental Health, Toronto, ON, Canada.
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authors: Yilmaz
authors: Eating Disorders Unit, Department of Child and Adolescent Psychiatry, Medical University of Vienna, Vienna, Austria.
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authors: Eating Disorders Unit, Department of Child and Adolescent Psychiatry, Medical University of Vienna, Vienna, Austria.
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authors: Eating Disorders Unit, Department of Child and Adolescent Psychiatry, Medical University of Vienna, Vienna, Austria.
authors: E
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authors: G
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authors: Wagner
authors: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
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authors: Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, King's College London, London, UK.
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authors: Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, King's College London, London, UK.
authors: S
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authors: Cohen-Woods
authors: Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, King's College London, London, UK.
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authors: Farmer
authors: Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, King's College London, London, UK.
authors: P
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authors: McGuffin
authors: 1] Department of Genomics, Life & Brain Center, Institute of Human Genetics, University of Bonn, Bonn, Germany [2] Institute of Neuroscience and Medicine (INM-1), Research Center Jülich, Jülich, Germany [3] Division of Medical Genetics, Department of Biomedicine, University of Basel, Basel, Switzerland.
authors: S
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authors: Cichon
authors: Klinikum der Medizinischen Fakultät, Martin-Luther-Universität Halle-Wittenberg, Halle/Saale, Germany.
authors: I
authors: I
authors: Giegling
authors: 1] Department of Genomics, Life & Brain Center, Institute of Human Genetics, University of Bonn, Bonn, Germany [2] Division of Medical Genetics, Department of Biomedicine, University of Basel, Basel, Switzerland.
authors: S
authors: S
authors: Herms
authors: Klinikum der Medizinischen Fakultät, Martin-Luther-Universität Halle-Wittenberg, Halle/Saale, Germany.
authors: D
authors: D
authors: Rujescu
authors: Institute of Clinical Molecular Biology, University of Kiel, Kiel, Germany.
authors: S
authors: S
authors: Schreiber
authors: 1] Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany [2] Institute of Medical Informatics, Biometry and Epidemiology, Ludwig-Maximilians-University, Munich, Germany.
authors: H-E
authors: HE
authors: Wichmann
authors: CNRS 8090-Institute of Biology, Pasteur Institute, Lille, France.
authors: C
authors: C
authors: Dina
authors: McGill University and Genome Quebec Innovation Centre, Montreal, QC, Canada.
authors: R
authors: R
authors: Sladek
authors: Division of Nephrology, Department of Internal Medicine and Medical Specialties, Columbus-Gemelly Hospitals, Catholic University, Rome, Italy.
authors: G
authors: G
authors: Gambaro
authors: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK.
authors: N
authors: N
authors: Soranzo
authors: Unitat de Recerca de Reumatologia (URR), Institut de Recerca Hospital Universitari Vall d'Hebron, Barcelona, Spain.
authors: A
authors: A
authors: Julia
authors: Unitat de Recerca de Reumatologia (URR), Institut de Recerca Hospital Universitari Vall d'Hebron, Barcelona, Spain.
authors: S
authors: S
authors: Marsal
authors: 1] Genomics and Disease Group, Centre for Genomic Regulation (CRG), Barcelona, Spain [2] Universitat Pompeu Fabra (UPF), Barcelona, Spain [3] Centro de Investigación Biomédica en Red en Epidemiología y Salud Pública (CIBERESP), Barcelona, Spain [4] Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain.
authors: R
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authors: Rabionet
authors: Genetic Epidemiology Group, International Agency for Research on Cancer (IARC), Lyon, France.
authors: V
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authors: Gaborieau
authors: Virginia Institute for Psychiatric and Behavioral Genetics, Department of Psychiatry, Virginia Commonwealth University, Richmond, VA, USA.
authors: D M
authors: DM
authors: Dick
authors: 1] Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK [2] The Finnish Institute of Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland [3] The Program for Human and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
authors: A
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authors: Palotie
authors: 1] The Finnish Institute of Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland [2] Finnish Institute of Occupational Health, Helsinki, Finland.
authors: S
authors: S
authors: Ripatti
authors: 1] The Finnish Institute of Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland [2] Finnish Institute of Occupational Health, Helsinki, Finland.
authors: E
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authors: Widén
authors: 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.
authors: O A
authors: OA
authors: Andreassen
authors: 1] 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 [2] Department of Psychology, University of Oslo, Oslo, Norway.
authors: T
authors: T
authors: Espeseth
authors: 1] Department of Biological and Medical Psychology, University of Bergen, Bergen, Norway [2] Kavli Research Centre for Aging and Dementia, Haraldsplass Deaconess Hospital, Bergen, Norway [3] K.G. Jebsen Centre for Research on Neuropsychiatric Disorders, University of Bergen, Bergen, Norway.
authors: A
authors: A
authors: Lundervold
authors: Department of Psychology, University of Oslo, Oslo, Norway.
authors: I
authors: I
authors: Reinvang
authors: 1] Department of Clinical Science, K.G. Jebsen Centre for Psychosis Research, Norwegian Centre For Mental Disorders Research (NORMENT), University of Bergen, Bergen, Norway [2] Dr Einar Martens Research Group for Biological Psychiatry, Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway.
authors: V M
authors: VM
authors: Steen
authors: 1] Department of Clinical Science, K.G. Jebsen Centre for Psychosis Research, Norwegian Centre For Mental Disorders Research (NORMENT), University of Bergen, Bergen, Norway [2] Dr Einar Martens Research Group for Biological Psychiatry, Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway.
authors: S
authors: S
authors: Le Hellard
authors: 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.
authors: M
authors: M
authors: Mattingsdal
authors: Department of Nutrition and Dietetics, Harokopio University, Athens, Greece.
authors: I
authors: I
authors: Ntalla
authors: Institute of Hygiene and Epidemiology, 1st Faculty of Medicine, Charles University, Prague, Czech Republic.
authors: V
authors: V
authors: Bencko
authors: Department of Cancer Epidemiology and Genetics, Masaryk Memorial Cancer Institute, Brno, Czech Republic.
authors: L
authors: L
authors: Foretova
authors: Palacky University, Olomouc, Czech Republic.
authors: V
authors: V
authors: Janout
authors: Department of Cancer Epidemiology and Genetics, Masaryk Memorial Cancer Institute, Brno, Czech Republic.
authors: M
authors: M
authors: Navratilova
authors: 1] University Health Network, Toronto General Hospital, Toronto, ON, Canada [2] Mount Sinai Hospital, Samuel Lunenfeld Research Institute, Toronto, ON, Canada.
authors: S
authors: S
authors: Gallinger
authors: Departments of Psychiatry, and Genetics and Genomic Sciences, Seaver Autism Center, and the Mindich Child Health and Development Institute, Mount Sinai School of Medicine, New York, NY, USA.
authors: D
authors: D
authors: Pinto
authors: The Centre for Applied Genomics and Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON, Canada.
authors: S W
authors: SW
authors: Scherer
authors: Department of Psychiatry and Psychotherapy, Medical University of Vienna, Vienna, Austria.
authors: H
authors: H
authors: Aschauer
authors: Department of Psychiatry and Psychotherapy, Medical University of Vienna, Vienna, Austria.
authors: L
authors: L
authors: Carlberg
authors: Department of Psychiatry and Psychotherapy, Medical University of Vienna, Vienna, Austria.
authors: A
authors: A
authors: Schosser
authors: The Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
authors: L
authors: L
authors: Alfredsson
authors: The Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
authors: B
authors: B
authors: Ding
authors: Rheumatology Unit, Department of Medicine at the Karolinska University Hospital, Solna, Sweden.
authors: L
authors: L
authors: Klareskog
authors: Rheumatology Unit, Department of Medicine at the Karolinska University Hospital, Solna, Sweden.
authors: L
authors: L
authors: Padyukov
authors: 1] Inserm, U1061, Université Montpellier 1, Montpellier, France [2] Department of Emergency Psychiatry, CHU Montpellier, Montpellier, France.
authors: P
authors: P
authors: Courtet
authors: 1] Inserm, U1061, Université Montpellier 1, Montpellier, France [2] Department of Emergency Psychiatry, CHU Montpellier, Montpellier, France.
authors: S
authors: S
authors: Guillaume
authors: 1] Inserm, U1061, Université Montpellier 1, Montpellier, France [2] Department of Emergency Psychiatry, CHU Montpellier, Montpellier, France.
authors: I
authors: I
authors: Jaussent
authors: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK.
authors: C
authors: C
authors: Finan
authors: Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, King's College London, London, UK.
authors: G
authors: G
authors: Kalsi
authors: Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, King's College London, London, UK.
authors: M
authors: M
authors: Roberts
authors: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK.
authors: D W
authors: DW
authors: Logan
authors: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK.
authors: L
authors: L
authors: Peltonen
authors: 1] Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK [2] European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge.
authors: G R S
authors: GR
authors: Ritchie
authors: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK.
authors: J C
authors: JC
authors: Barrett
authors: 1] Genomics and Disease Group, Centre for Genomic Regulation (CRG), Barcelona, Spain [2] Universitat Pompeu Fabra (UPF), Barcelona, Spain [3] Centro de Investigación Biomédica en Red en Epidemiología y Salud Pública (CIBERESP), Barcelona, Spain [4] Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain.
authors: X
authors: X
authors: Estivill
authors: Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, Universitätsklinikum Essen, University of Duisburg-Essen, Essen, Germany.
authors: A
authors: A
authors: Hinney
authors: 1] Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA [2] Department of Genetics, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors: P F
authors: PF
authors: Sullivan
authors: 1] Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, King's College London, London, UK [2] Eli Lilly and Company, Erl Wood Manor, Windlesham, UK.
authors: D A
authors: DA
authors: Collier
authors: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK.
authors: E
authors: E
authors: Zeggini
authors: 1] Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA [2] Department of Nutrition, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors: C M
authors: CM
authors: Bulik
mesh_terms: D000856:Anorexia Nervosa / Q000235:genetics*; D044466:Asian People / Q000235:genetics; D019703:Calcineurin / Q000235:genetics; D002352:Carrier Proteins / Q000235:genetics; D016022:Case-Control Studies; D044842:Cullin Proteins / Q000235:genetics; D005260:Female; D055106:Genome-Wide Association Study; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics; D006801:Humans; D007564:Japan; D008297:Male; D015201:Meta-Analysis as Topic; D009687:Nuclear Proteins / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D044465:White People / Q000235:genetics
chemical_list: C503645:CUL3 protein, human; D002352:Carrier Proteins; D044842:Cullin Proteins; C581900:FAM124B protein, human; D020662:Guanine Nucleotide Exchange Factors; D009687:Nuclear Proteins; C525704:SPATA13 protein, human; D019703:Calcineurin; C525673:PPP3CA protein, human