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Nat Genet. 2019 Aug;51(8):1207-1214. doi: 10.1038/s41588-019-0439-2. Epub 2019 Jul 15.

Genome-wide association study identifies eight risk loci and implicates metabo-psychiatric origins for anorexia nervosa.

Watson HJ1,2,3, Yilmaz Z1,4, Thornton LM1, Hübel C5,6, Coleman JRI5,7, Gaspar HA5,7, Bryois J6, Hinney A8, Leppä VM6, Mattheisen M9,10,11,12, Medland SE13, Ripke S14,15,16, Yao S6, Giusti-Rodríguez P4; Anorexia Nervosa Genetics Initiative, Hanscombe KB17, Purves KL5; Eating Disorders Working Group of the Psychiatric Genomics Consortium, Adan RAH18,19,20, Alfredsson L21, Ando T22, Andreassen OA23, Baker JH1, Berrettini WH24, Boehm I25, Boni C26, Perica VB27,28, Buehren K29, Burghardt R30, Cassina M31, Cichon S32, Clementi M31, Cone RD33, Courtet P34, Crow S35, Crowley JJ4,10, Danner UN19, Davis OSP36,37, de Zwaan M38, Dedoussis G39, Degortes D40, DeSocio JE41, Dick DM42, Dikeos D43, Dina C44, Dmitrzak-Weglarz M45, Docampo E46,47,48, Duncan LE49, Egberts K50, Ehrlich S25, Escaramís G46,47,48, Esko T51,52, Estivill X46,47,48,53, Farmer A5, Favaro A40, Fernández-Aranda F54,55, Fichter MM56,57, Fischer K51, Föcker M8, Foretova L58, Forstner AJ32,59,60,61,62, Forzan M31, Franklin CS27, Gallinger S63, Giegling I64, Giuranna J8, Gonidakis F65, Gorwood P26,66, Mayora MG46,47,48, Guillaume S34, Guo Y67, Hakonarson H67,68, Hatzikotoulas K27,69, Hauser J70, Hebebrand J8, Helder SG5,71, Herms S32,60,62, Herpertz-Dahlmann B29, Herzog W72, Huckins LM27,73, Hudson JI74, Imgart H75, Inoko H76, Janout V77, Jiménez-Murcia S54,55, Julià A78, Kalsi G5, Kaminská D79, Kaprio J80,81, Karhunen L82, Karwautz A83, Kas MJH18,84, Kennedy JL85,86,87, Keski-Rahkonen A80, Kiezebrink K88, Kim YR89, Klareskog L90, Klump KL91, Knudsen GPS92, La Via MC1, Le Hellard S93,94,95, Levitan RD85,86,87, Li D67, Lilenfeld L96, Lin BD18, Lissowska J97, Luykx J18, Magistretti PJ98,99, Maj M100, Mannik K51,101, Marsal S78, Marshall CR102, Mattingsdal M23, McDevitt S103,104, McGuffin P5, Metspalu A51,105, Meulenbelt I106, Micali N107,108,109, Mitchell K110, Monteleone AM100, Monteleone P111, Munn-Chernoff MA1, Nacmias B112, Navratilova M58, Ntalla I39, O'Toole JK113, Ophoff RA18,114, Padyukov L90, Palotie A52,81,115, Pantel J26, Papezova H79, Pinto D73, Rabionet R116,117,118, Raevuori A80, Ramoz N26, Reichborn-Kjennerud T92,119, Ricca V112,120, Ripatti S52,80,121, Ritschel F25,122, Roberts M5,123,124, Rotondo A125, Rujescu D56,64, Rybakowski F126, Santonastaso P127, Scherag A128, Scherer SW129, Schmidt U7,130, Schork NJ131, Schosser A132, Seitz J29, Slachtova L133, Slagboom PE106, Slof-Op 't Landt MCT134,135, Slopien A136, Sorbi S112,137, Świątkowska B138, Szatkiewicz JP4, Tachmazidou I27, Tenconi E40, Tortorella A139,140, Tozzi F141, Treasure J7,130, Tsitsika A142, Tyszkiewicz-Nwafor M136, Tziouvas K143, van Elburg AA19,144, van Furth EF134,135, Wagner G83, Walton E25, Widen E81, Zeggini E27,69, Zerwas S1, Zipfel S145, Bergen AW146,147, Boden JM148, Brandt H149, Crawford S149, Halmi KA150, Horwood LJ148, Johnson C151, Kaplan AS85,86,87, Kaye WH152, Mitchell JE153, Olsen CM13, Pearson JF154, Pedersen NL6, Strober M155,156, Werge T157, Whiteman DC13, Woodside DB86,87,158,159, Stuber GD1,160, Gordon S13, Grove J9,161,162,163, Henders AK164, Juréus A6, Kirk KM13, Larsen JT161,165,166, Parker R13, Petersen L161,165,166, Jordan J123,167, Kennedy M168, Montgomery GW13,164,169, Wade TD170, Birgegård A10,11, Lichtenstein P6, Norring C10,11, Landén M6,171, Martin NG13, Mortensen PB161,165,166, Sullivan PF1,4,6, Breen G5,7, Bulik CM172,173,174.

Author information

1
Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
2
School of Psychology, Curtin University, Perth, Western Australia, Australia.
3
School of Paediatrics and Child Health, University of Western Australia, Perth, Western Australia, Australia.
4
Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
5
Institute of Psychiatry, Psychology and Neuroscience, Social, Genetic and Developmental Psychiatry (SGDP) Centre, King's College London, London, UK.
6
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
7
National Institute for Health Research Biomedical Research Centre, King's College London and South London and Maudsley National Health Service Foundation Trust, London, UK.
8
Department of Child and Adolescent Psychiatry, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
9
Department of Biomedicine, Aarhus University, Aarhus, Denmark.
10
Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
11
Center for Psychiatry Research, Stockholm Health Care Services, Stockholm City Council, Stockholm, Sweden.
12
Department of Psychiatry, Psychosomatics and Psychotherapy, University of Würzburg, Würzburg, Germany.
13
QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
14
Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.
15
Stanley Center for Psychiatric Research, Broad Institute of the Massachusetts Institute of Technology and Harvard University, Cambridge, MA, USA.
16
Department of Psychiatry and Psychotherapy, Charité - Universitätsmedizin, Berlin, Germany.
17
Department of Medical and Molecular Genetics, King's College London, Guy's Hospital, London, UK.
18
Brain Center Rudolf Magnus, Department of Translational Neuroscience, University Medical Center Utrecht, Utrecht, the Netherlands.
19
Center for Eating Disorders Rintveld, Altrecht Mental Health Institute, Zeist, the Netherlands.
20
Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
21
Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
22
Department of Behavioral Medicine, National Institute of Mental Health, National Center of Neurology and Psychiatry, Tokyo, Japan.
23
NORMENT KG Jebsen Centre, Division of Mental Health and Addiction, University of Oslo, Oslo University Hospital, Oslo, Norway.
24
Department of Psychiatry, Center for Neurobiology and Behavior, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
25
Division of Psychological and Social Medicine and Developmental Neurosciences, Faculty of Medicine, Technische Universität Dresden, Dresden, Germany.
26
INSERM 1266, Institute of Psychiatry and Neuroscience of Paris, Paris, France.
27
Wellcome Sanger Institute, Hinxton, UK.
28
Department of Medical Biology, School of Medicine, University of Split, Split, Croatia.
29
Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, RWTH Aachen University, Aachen, Germany.
30
Department of Child and Adolescent Psychiatry, Klinikum Frankfurt/Oder, Frankfurt, Germany.
31
Clinical Genetics Unit, Department of Woman and Child Health, University of Padova, Padova, Italy.
32
Institute of Medical Genetics and Pathology, University Hospital Basel, Basel, Switzerland.
33
Life Sciences Institute and Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA.
34
Department of Emergency Psychiatry and Post-Acute Care, CHRU Montpellier, University of Montpellier, Montpellier, France.
35
Department of Psychiatry, University of Minnesota, Minneapolis, MN, USA.
36
MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK.
37
School of Social and Community Medicine, University of Bristol, Bristol, UK.
38
Department of Psychosomatic Medicine and Psychotherapy, Hannover Medical School, Hannover, Germany.
39
Department of Nutrition and Dietetics, Harokopio University, Athens, Greece.
40
Department of Neurosciences, University of Padova, Padova, Italy.
41
College of Nursing, Seattle University, Seattle, WA, USA.
42
Department of Psychology, Virginia Commonwealth University, Richmond, VA, USA.
43
Department of Psychiatry, Athens University Medical School, Athens University, Athens, Greece.
44
L'institut du thorax, INSERM, CNRS, UNIV Nantes, CHU Nantes, Nantes, France.
45
Department of Psychiatric Genetics, Poznan University of Medical Sciences, Poznan, Poland.
46
Barcelona Institute of Science and Technology, Barcelona, Spain.
47
Universitat Pompeu Fabra, Barcelona, Spain.
48
Centro de Investigación Biomédica en Red en Epidemiología y Salud Pública (CIBERESP), Barcelona, Spain.
49
Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, USA.
50
Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University Hospital of Würzburg, Centre for Mental Health, Würzburg, Germany.
51
Estonian Genome Center, University of Tartu, Tartu, Estonia.
52
Program in Medical and Population Genetics, Broad Institute of the Massachusetts Institute of Technology and Harvard University, Cambridge, MA, USA.
53
Genomics and Disease, Bioinformatics and Genomics Programme, Centre for Genomic Regulation, Barcelona, Spain.
54
Department of Psychiatry, University Hospital of Bellvitge -IDIBELL and CIBERobn, Barcelona, Spain.
55
Department of Clinical Sciences, School of Medicine, University of Barcelona, Barcelona, Spain.
56
Department of Psychiatry and Psychotherapy, Ludwig-Maximilians-University (LMU), Munich, Germany.
57
Schön Klinik Roseneck affiliated with the Medical Faculty of the University of Munich (LMU), Munich, Germany.
58
Department of Cancer, Epidemiology and Genetics, Masaryk Memorial Cancer Institute, Brno, Czech Republic.
59
Institute of Human Genetics, University of Bonn, School of Medicine & University Hospital Bonn, Bonn, Germany.
60
Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany.
61
Department of Psychiatry (UPK), University of Basel, Basel, Switzerland.
62
Department of Biomedicine, University of Basel, Basel, Switzerland.
63
Department of Surgery, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
64
Department of Psychiatry, Psychotherapy and Psychosomatics, Martin Luther University of Halle-Wittenberg, Halle, Germany.
65
First Psychiatric Department, National and Kapodistrian University of Athens, Medical School, Eginition Hospital, Athens, Greece.
66
CMME, Hôpital Sainte-Anne (GHU Paris Psychiatrie et Neurosciences), Paris Descartes University, Paris, France.
67
Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
68
Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
69
Institute of Translational Genomics, Helmholtz Zentrum München, Neuherberg, Germany.
70
Department of Adult Psychiatry, Poznan University of Medical Sciences, Poznan, Poland.
71
Zorg op Orde, Leidschendam, the Netherlands.
72
Department of General Internal Medicine and Psychosomatics, Heidelberg University Hospital, Heidelberg University, Heidelberg, Germany.
73
Department of Psychiatry, and Genetics and Genomics Sciences, Division of Psychiatric Genomics, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
74
Biological Psychiatry Laboratory, McLean Hospital/Harvard Medical School, Boston, MA, USA.
75
Eating Disorders Unit, Parklandklinik, Bad Wildungen, Germany.
76
Department of Molecular Life Science, Division of Basic Medical Science and Molecular Medicine, School of Medicine, Tokai University, Isehara, Japan.
77
Faculty of Health Sciences, Palacky University, Olomouc, Czech Republic.
78
Rheumatology Research Group, Vall d'Hebron Research Institute, Barcelona, Spain.
79
Department of Psychiatry, First Faculty of Medicine, Charles University, Prague, Czech Republic.
80
Department of Public Health, University of Helsinki, Helsinki, Finland.
81
Institute for Molecular Medicine Finland, Helsinki Institute of Life Science, University of Helsinki, Helsinki, Finland.
82
Institute of Public Health and Clinical Nutrition, Department of Clinical Nutrition, University of Eastern Finland, Kuopio, Finland.
83
Eating Disorders Unit, Department of Child and Adolescent Psychiatry, Medical University of Vienna, Vienna, Austria.
84
Groningen Institute for Evolutionary Life Sciences, University of Groningen, Groningen, the Netherlands.
85
Centre for Addiction and Mental Health, Toronto, Ontario, Canada.
86
Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada.
87
Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada.
88
Institute of Applied Health Sciences, University of Aberdeen, Aberdeen, UK.
89
Department of Psychiatry, Seoul Paik Hospital, Inje University, Seoul, Korea.
90
Rheumatology Unit, Department of Medicine, Center for Molecular Medicine, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.
91
Department of Psychology, Michigan State University, East Lansing, MI, USA.
92
Department of Mental Disorders, Norwegian Institute of Public Health, Oslo, Norway.
93
Department of Clinical Science, K.G. Jebsen Centre for Psychosis Research, Norwegian Centre for Mental Disorders Research (NORMENT), University of Bergen, Bergen, Norway.
94
Dr. Einar Martens Research Group for Biological Psychiatry, Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway.
95
Department of Clinical Medicine, Laboratory Building, Haukeland University Hospital, Bergen, Norway.
96
American School of Professional Psychology, Argosy University, Northern Virginia, Arlington, VA, USA.
97
Department of Cancer Epidemiology and Prevention, M Skłodowska-Curie Cancer Center - Oncology Center, Warsaw, Poland.
98
BESE Division, King Abdullah University of Science and Technology, Thuwal, Saudi Arabia.
99
Department of Psychiatry, University of Lausanne-University Hospital of Lausanne (UNIL-CHUV), Lausanne, Switzerland.
100
Department of Psychiatry, University of Campania "Luigi Vanvitelli", Naples, Italy.
101
Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland.
102
Department of Paediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, Ontario, Canada.
103
Department of Psychiatry, University College Cork, Cork, Ireland.
104
HSE National Clinical Programme for Eating Disorders, Cork, Ireland.
105
Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia.
106
Department of Biomedical Data Science, Leiden University Medical Centre, Leiden, the Netherlands.
107
Department of Psychiatry, Faculty of Medicine, University of Geneva, Geneva, Switzerland.
108
Division of Child and Adolescent Psychiatry, Geneva University Hospital, Geneva, Switzerland.
109
Great Ormond Street Institute of Child Health, University College London, London, UK.
110
National Center for PTSD, VA Boston Healthcare System, Department of Psychiatry, Boston University School of Medicine, Boston, MA, USA.
111
Department of Medicine, Surgery and Dentistry "Scuola Medica Salernitana", University of Salerno, Salerno, Italy.
112
Department of Neuroscience, Psychology, Drug Research and Child Health (NEUROFARBA), University of Florence, Florence, Italy.
113
Kartini Clinic, Portland, OR, USA.
114
Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, University of California Los Angeles, Los Angeles, CA, USA.
115
Center for Human Genome Research at the Massachusetts General Hospital, Boston, MA, USA.
116
Saint Joan de Déu Research Institute, Saint Joan de Déu Barcelona Children's Hospital, Barcelona, Spain.
117
Institute of Biomedicine (IBUB), University of Barcelona, Barcelona, Spain.
118
Department of Genetics, Microbiology and Statistics, University of Barcelona, Barcelona, Spain.
119
Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
120
Department of Health Science, University of Florence, Florence, Italy.
121
Institute for Molecular Medicine Finland (FIMM), HiLIFE Unit, University of Helsinki, Helsinki, Finland.
122
Eating Disorders Research and Treatment Center, Department of Child and Adolescent Psychiatry, Faculty of Medicine, Technische Universität Dresden, Dresden, Germany.
123
Department of Psychological Medicine, University of Otago, Christchurch, New Zealand.
124
Faculty of Medicine & Health Sciences, University of Aukland, Aukland, New Zealand.
125
Department of Psychiatry, Neurobiology, Pharmacology, and Biotechnologies, University of Pisa, Pisa, Italy.
126
Department of Psychiatry, Poznan University of Medical Sciences, Poznan, Poland.
127
Department of Neurosciences, Padua Neuroscience Center, University of Padova, Padova, Italy.
128
Institute of Medical Statistics, Computer and Data Sciences, Jena University Hospital, Jena, Germany.
129
Department of Genetics and Genomic Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.
130
Institute of Psychiatry, Psychology and Neuroscience, Department of Psychological Medicine, King's College London, London, UK.
131
J. Craig Venter Institute (JCVI), La Jolla, CA, USA.
132
Department of Psychiatry and Psychotherapy, Medical University of Vienna, Vienna, Austria.
133
Department of Pediatrics and Center of Applied Genomics, First Faculty of Medicine, Charles University, Prague, Czech Republic.
134
Center for Eating Disorders Ursula, Rivierduinen, Leiden, the Netherlands.
135
Department of Psychiatry, Leiden University Medical Centre, Leiden, the Netherlands.
136
Department of Child and Adolescent Psychiatry, Poznan University of Medical Sciences, Poznan, Poland.
137
IRCSS Fondazione Don Carlo Gnocchi, Florence, Italy.
138
Department of Environmental Epidemiology, Nofer Institute of Occupational Medicine, Lodz, Poland.
139
Department of Psychiatry, University of Naples SUN, Naples, Italy.
140
Department of Psychiatry, University of Perugia, Perugia, Italy.
141
Brain Sciences Department, Stremble Ventures, Limassol, Cyprus.
142
Adolescent Health Unit, Second Department of Pediatrics, "P. & A. Kyriakou" Children's Hospital, University of Athens, Athens, Greece.
143
Pediatric Intensive Care Unit, "P. & A. Kyriakou" Children's Hospital, University of Athens, Athens, Greece.
144
Faculty of Social and Behavioral Sciences, Utrecht University, Utrecht, the Netherlands.
145
Department of Internal Medicine VI, Psychosomatic Medicine and Psychotherapy, University Medical Hospital Tuebingen, Tuebingen, Germany.
146
BioRealm, LLC, Walnut, CA, USA.
147
Oregon Research Institute, Eugene, OR, USA.
148
Christchurch Health and Development Study, University of Otago, Christchurch, New Zealand.
149
The Center for Eating Disorders at Sheppard Pratt, Baltimore, MD, USA.
150
Department of Psychiatry, Weill Cornell Medical College, New York, NY, USA.
151
Eating Recovery Center, Denver, CO, USA.
152
Department of Psychiatry, University of California San Diego, San Diego, CA, USA.
153
Department of Psychiatry and Behavioral Science, University of North Dakota School of Medicine and Health Sciences, Fargo, ND, USA.
154
Biostatistics and Computational Biology Unit, University of Otago, Christchurch, New Zealand.
155
Department of Psychiatry and Biobehavioral Science, Semel Institute for Neuroscience and Human Behavior, University of California Los Angeles, Los Angeles, CA, USA.
156
David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.
157
Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark.
158
Centre for Mental Health, University Health Network, Toronto, Ontario, Canada.
159
Program for Eating Disorders, University Health Network, Toronto, Ontario, Canada.
160
Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
161
The Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), Aarhus, Denmark.
162
Centre for Integrative Sequencing, iSEQ, Aarhus University, Aarhus, Denmark.
163
Bioinformatics Research Centre, Aarhus University, Aarhus, Denmark.
164
Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia.
165
National Centre for Register-Based Research, Aarhus BSS, Aarhus University, Aarhus, Denmark.
166
Centre for Integrated Register-based Research (CIRRAU), Aarhus University, Aarhus, Denmark.
167
Canterbury District Health Board, Christchurch, New Zealand.
168
Department of Pathology and Biomedical Science, University of Otago, Christchurch, New Zealand.
169
Queensland Brain Institute, University of Queensland, Brisbane, Queensland, Australia.
170
School of Psychology, Flinders University, Adelaide, South Australia, Australia.
171
Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
172
Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. cynthia_bulik@med.unc.edu.
173
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden. cynthia_bulik@med.unc.edu.
174
Department of Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. cynthia_bulik@med.unc.edu.

Abstract

Characterized primarily by a low body-mass index, anorexia nervosa is a complex and serious illness1, affecting 0.9-4% of women and 0.3% of men2-4, with twin-based heritability estimates of 50-60%5. Mortality rates are higher than those in other psychiatric disorders6, and outcomes are unacceptably poor7. Here we combine data from the Anorexia Nervosa Genetics Initiative (ANGI)8,9 and the Eating Disorders Working Group of the Psychiatric Genomics Consortium (PGC-ED) and conduct a genome-wide association study of 16,992 cases of anorexia nervosa and 55,525 controls, identifying eight significant loci. The genetic architecture of anorexia nervosa mirrors its clinical presentation, showing significant genetic correlations with psychiatric disorders, physical activity, and metabolic (including glycemic), lipid and anthropometric traits, independent of the effects of common variants associated with body-mass index. These results further encourage a reconceptualization of anorexia nervosa as a metabo-psychiatric disorder. Elucidating the metabolic component is a critical direction for future research, and paying attention to both psychiatric and metabolic components may be key to improving outcomes.

PMID:
31308545
DOI:
10.1038/s41588-019-0439-2

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