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Mol Psychiatry. 2014 Oct;19(10):1085-94. doi: 10.1038/mp.2013.187. Epub 2014 Feb 11.

A genome-wide association study of anorexia nervosa.

Boraska V1, Franklin CS2, Floyd JA3, Thornton LM4, Huckins LM2, Southam L2, Rayner NW5, Tachmazidou I2, Klump KL6, Treasure J7, Lewis CM8, Schmidt U7, Tozzi F4, Kiezebrink K9, Hebebrand J10, Gorwood P11, Adan RA12, Kas MJ13, Favaro A14, Santonastaso P14, Fernández-Aranda F15, Gratacos M16, Rybakowski F17, Dmitrzak-Weglarz M18, Kaprio J19, Keski-Rahkonen A20, Raevuori A21, Van Furth EF22, Slof-Op 't Landt MC23, Hudson JI24, Reichborn-Kjennerud T25, Knudsen GP26, Monteleone P27, Kaplan AS28, Karwautz A29, Hakonarson H30, Berrettini WH31, Guo Y32, Li D32, Schork NJ33, Komaki G34, Ando T35, Inoko H36, Esko T37, Fischer K37, Männik K38, Metspalu A39, Baker JH4, Cone RD40, Dackor J41, DeSocio JE42, Hilliard CE4, O'Toole JK43, Pantel J44, Szatkiewicz JP41, Taico C4, Zerwas S4, Trace SE4, Davis OS45, Helder S8, Bühren K46, Burghardt R47, de Zwaan M48, Egberts K49, Ehrlich S50, Herpertz-Dahlmann B46, Herzog W51, Imgart H52, Scherag A53, Scherag S10, Zipfel S54, Boni C55, Ramoz N55, Versini A55, Brandys MK12, Danner UN56, de Kovel C57, Hendriks J13, Koeleman BP57, Ophoff RA58, Strengman E57, van Elburg AA59, Bruson A60, Clementi M60, Degortes D14, Forzan M60, Tenconi E14, Docampo E16, Escaramís G16, Jiménez-Murcia S15, Lissowska J61, Rajewski A62, Szeszenia-Dabrowska N62, Slopien A18, Hauser J18, Karhunen L63, Meulenbelt I64, Slagboom PE65, Tortorella A66, Maj M66, Dedoussis G67, Dikeos D68, Gonidakis F69, Tziouvas K67, Tsitsika A70, Papezova H71, Slachtova L72, Martaskova D71, Kennedy JL28, Levitan RD28, Yilmaz Z73, Huemer J29, Koubek D29, Merl E29, Wagner G29, Lichtenstein P74, Breen G8, Cohen-Woods S8, Farmer A8, McGuffin P8, Cichon S75, Giegling I76, Herms S77, Rujescu D76, Schreiber S78, Wichmann HE79, Dina C80, Sladek R81, Gambaro G82, Soranzo N2, Julia A83, Marsal S83, Rabionet R16, Gaborieau V84, Dick DM85, Palotie A86, Ripatti S87, Widén E87, Andreassen OA88, Espeseth T89, Lundervold A90, Reinvang I91, Steen VM92, Le Hellard S92, Mattingsdal M88, Ntalla I67, Bencko V93, Foretova L94, Janout V95, Navratilova M94, Gallinger S96, Pinto D97, Scherer SW98, Aschauer H99, Carlberg L99, Schosser A99, Alfredsson L100, Ding B100, Klareskog L101, Padyukov L101, Courtet P102, Guillaume S102, Jaussent I102, Finan C2, Kalsi G8, Roberts M8, Logan DW2, Peltonen L2, Ritchie GR103, Barrett JC2; Wellcome Trust Case Control Consortium 3, Estivill X16, Hinney A10, Sullivan PF104, Collier DA105, Zeggini E2, Bulik CM106.

Author information

1
1] Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK [2] University of Split School of Medicine, Split, Croatia.
2
Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK.
3
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.
4
Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
5
1] Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK [2] Wellcome Trust Centre for Human Genetics (WTCHG), University of Oxford, Oxford, UK [3] Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), Oxford, UK.
6
Department of Psychology, Michigan State University, East Lansing, MI, USA.
7
Section of Eating Disorders, Institute of Psychiatry, King's College London, London, UK.
8
Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, King's College London, London, UK.
9
Health Services Research Unit, University of Aberdeen, Aberdeen, UK.
10
Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, Universitätsklinikum Essen, University of Duisburg-Essen, Essen, Germany.
11
1] INSERM U894, Centre of Psychiatry and Neuroscience, Paris, France [2] Sainte-Anne Hospital (CMME), University of Paris-Descartes, Paris, France.
12
1] Brain Center Rudolf Magnus, Department of Translational Neuroscience, University Medical Center Utrecht, Utrecht, The Netherlands [2] Altrecht Eating Disorders Rintveld, Zeist, The Netherlands.
13
Brain Center Rudolf Magnus, Department of Translational Neuroscience, University Medical Center Utrecht, Utrecht, The Netherlands.
14
Department of Neurosciences, University of Padova, Padova, Italy.
15
1] Department of Psychiatry and CIBERON, University Hospital of Bellvitge-IDIBELL, Barcelona, Spain [2] Department of Clinical Sciences, School of Medicine, University of Barcelona, Barcelona, Spain.
16
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.
17
Department of Child and Adolescent Psychiatry, Institute of Psychiatry and Neurology, Warsaw, Poland.
18
Department of Psychiatry, Poznan University of Medical Sciences, Poznan, Poland.
19
1] Hjelt Institute, University of Helsinki, Helsinki, Finland [2] Institute of Molecular Medicine, University of Helsinki, Helsinki, Finland [3] Department of Mental Health and Substance Abuse Services, National Institute for Health and Welfare, Helsinki, Finland.
20
Hjelt Institute, University of Helsinki, Helsinki, Finland.
21
1] Hjelt Institute, University of Helsinki, Helsinki, Finland [2] Department of Adolescent Psychiatry, Helsinki University Central Hospital, Helsinki, Finland.
22
1] Center for Eating Disorders Ursula, Leidschendam, The Netherlands [2] Department of Psychiatry, Leiden University Medical Centre, Leiden, The Netherlands.
23
1] Center for Eating Disorders Ursula, Leidschendam, The Netherlands [2] Molecular Epidemiology Section, Department of Medical Statistics, Leiden University Medical Centre, Leiden, The Netherlands.
24
Department of Psychiatry, McLean Hospital/Harvard Medical School, Belmont, MA, USA.
25
1] Department of Genetics, Environment and Mental Health, Norwegian Institute of Public Health, Oslo, Norway [2] Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
26
Department of Genetics, Environment and Mental Health, Norwegian Institute of Public Health, Oslo, Norway.
27
1] Department of Psychiatry, University of Naples SUN, Naples, Italy [2] Chair of Psychiatry, University of Salerno, Salerno, Italy.
28
1] Centre for Addiction and Mental Health, Toronto, ON, Canada [2] Department of Psychiatry, University of Toronto, Toronto, ON, Canada.
29
Eating Disorders Unit, Department of Child and Adolescent Psychiatry, Medical University of Vienna, Vienna, Austria.
30
1] The Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA [2] The Division of Human Genetics, Department of Pediatrics, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
31
Department of Psychiatry, University of Pennsylvania, Philadelphia, PA, USA.
32
The Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
33
Department of Molecular and Experimental Medicine and The Scripps Translational Science Institute, The Scripps Research Institute, La Jolla, CA, USA.
34
1] Department of Psychosomatic Research, National Institute of Mental Health, NCNP, Tokyo, Japan [2] School of Health Sciences at Fukuoka, International University of Health and Welfare, Fukuoka, Japan.
35
Department of Psychosomatic Research, National Institute of Mental Health, NCNP, Tokyo, Japan.
36
Department of Molecular Life Sciences, Tokai University School of Medicine, Kanagawa, Japan.
37
Estonian Genome Center, University of Tartu, Tartu, Estonia.
38
1] Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia [2] Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland.
39
1] Estonian Genome Center, University of Tartu, Tartu, Estonia [2] Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia.
40
Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN, USA.
41
Department of Genetics, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
42
Seattle University College of Nursing, Seattle, WA, USA.
43
Kartini Clinic, Portland, OR, USA.
44
Centre de Psychiatrie et Neurosciences - Inserm U894, Paris, France.
45
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.
46
Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University Clinics RWTH Aachen, Aachen, Germany.
47
Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, Charité, Berlin, Germany.
48
1] Department of Psychosomatic Medicine and Psychotherapy, Hannover Medical School, Hannover, Germany [2] Department of Psychosomatic Medicine and Psychotherapy, University of Erlangen-Nuremberg, Erlangen, Germany.
49
Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University Würzburg, Würzburg, Germany.
50
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.
51
Departments of Psychosocial and Internal Medicine, Heidelberg University, Heidelberg, Germany.
52
Parklandklinik, Bad Wildungen, Germany.
53
Institute for Medical Informatics, Biometry and Epidemiology, Universitätsklinikum Essen, University of Duisburg-Essen, Essen, Germany.
54
Department of Internal Medicine VI, Psychosomatic Medicine and Psychotherapy, University Medical Hospital Tübingen, Tübingen, Germany.
55
INSERM U894, Centre of Psychiatry and Neuroscience, Paris, France.
56
Altrecht Eating Disorders Rintveld, Zeist, The Netherlands.
57
Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
58
1] Center for Neurobehavioral Genetics, University of California, Los Angeles, Los Angeles, CA, USA [2] Department of Psychiatry, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands.
59
1] Altrecht Eating Disorders Rintveld, Zeist, The Netherlands [2] Department of Child and Adolescent Psychiatry, University Medical Center Utrecht, Utrecht, The Netherlands.
60
Clinical Genetics Unit, Department of Woman and Child Health, University of Padova, Padova, Italy.
61
M. Sklodowska-Curie Cancer Center and Institute of Oncology, Warsaw, Poland.
62
Department of Epidemiology, Institute of Occupational Medicine, Department of Epidemiology, Lodz, Poland.
63
Department of Clinical Nutrition, Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland.
64
Molecular Epidemiology Section, Department of Medical Statistics, Leiden University Medical Centre, Leiden, The Netherlands.
65
1] Molecular Epidemiology Section, Department of Medical Statistics, Leiden University Medical Centre, Leiden, The Netherlands [2] Netherlands Consortium for Healthy Ageing, Leiden University Medical Center, Leiden, The Netherlands.
66
Department of Psychiatry, University of Naples SUN, Naples, Italy.
67
Department of Nutrition and Dietetics, Harokopio University, Athens, Greece.
68
1st Department of Psychiatry, Athens University Medical School, Athens, Greece.
69
Eating Disorders Unit, 1st Department of Psychiatry, Athens University Medical School, Athens, Greece.
70
Adolescent Health Unit (A.H.U.), 2nd Department of Pediatrics - Medical School, University of Athens 'P. & A. Kyriakou' Children's Hospital, Athens, Greece.
71
Department of Psychiatry, 1st Faculty of Medicine, Charles University, Prague, Czech Republic.
72
Department of Pediatrics, 1st Faculty of Medicine, Charles University, Prague, Czech Republic.
73
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.
74
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
75
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.
76
Klinikum der Medizinischen Fakultät, Martin-Luther-Universität Halle-Wittenberg, Halle/Saale, Germany.
77
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.
78
Institute of Clinical Molecular Biology, University of Kiel, Kiel, Germany.
79
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.
80
CNRS 8090-Institute of Biology, Pasteur Institute, Lille, France.
81
McGill University and Genome Quebec Innovation Centre, Montreal, QC, Canada.
82
Division of Nephrology, Department of Internal Medicine and Medical Specialties, Columbus-Gemelly Hospitals, Catholic University, Rome, Italy.
83
Unitat de Recerca de Reumatologia (URR), Institut de Recerca Hospital Universitari Vall d'Hebron, Barcelona, Spain.
84
Genetic Epidemiology Group, International Agency for Research on Cancer (IARC), Lyon, France.
85
Virginia Institute for Psychiatric and Behavioral Genetics, Department of Psychiatry, Virginia Commonwealth University, Richmond, VA, USA.
86
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.
87
1] The Finnish Institute of Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland [2] Finnish Institute of Occupational Health, Helsinki, Finland.
88
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.
89
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.
90
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.
91
Department of Psychology, University of Oslo, Oslo, Norway.
92
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.
93
Institute of Hygiene and Epidemiology, 1st Faculty of Medicine, Charles University, Prague, Czech Republic.
94
Department of Cancer Epidemiology and Genetics, Masaryk Memorial Cancer Institute, Brno, Czech Republic.
95
Palacky University, Olomouc, Czech Republic.
96
1] University Health Network, Toronto General Hospital, Toronto, ON, Canada [2] Mount Sinai Hospital, Samuel Lunenfeld Research Institute, Toronto, ON, Canada.
97
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.
98
The Centre for Applied Genomics and Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON, Canada.
99
Department of Psychiatry and Psychotherapy, Medical University of Vienna, Vienna, Austria.
100
The Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
101
Rheumatology Unit, Department of Medicine at the Karolinska University Hospital, Solna, Sweden.
102
1] Inserm, U1061, Université Montpellier 1, Montpellier, France [2] Department of Emergency Psychiatry, CHU Montpellier, Montpellier, France.
103
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.
104
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.
105
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.
106
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.

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.

PMID:
24514567
PMCID:
PMC4325090
DOI:
10.1038/mp.2013.187
[Indexed for MEDLINE]
Free PMC Article

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