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Mol Psychiatry. 2018 May;23(5):1169-1180. doi: 10.1038/mp.2017.88. Epub 2017 Jul 25.

Investigation of common, low-frequency and rare genome-wide variation in anorexia nervosa.

Collaborators (190)

Adan RAH, Alfredsson L, Ando T, Andreassen OA, Aschauer H, Baker JH, Barrett JC, Bencko V, Bergen AW, Berrettini WH, Birgegard A, Boni C, Boraska Perica V, Brandt H, Breen G, Bulik CM, Carlberg L, Cassina M, Cichon S, Clementi M, Cohen-Woods S, Coleman J, Cone RD, Courtet P, Crawford S, Crow S, Crowley J, Danner UN, Davis OSP, de Zwaan M, Dedoussis G, Degortes D, DeSocio JE, Dick DM, Dikeos D, Dina C, Ding B, Dmitrzak-Weglarz M, Docampo E, Duncan L, Egberts K, Ehrlich S, Escaramís G, Esko T, Espeseth T, Estivill X, Favaro A, Fernández-Aranda F, Fichter MM, Finan C, Fischer K, Floyd JAB, Foretova L, Forzan M, Franklin CS, Gallinger S, Gambaro G, Gaspar HA, Giegling I, Gonidakis F, Gorwood P, Gratacos M, Guillaume S, Guo Y, Hakonarson H, Halmi KA, Hatzikotoulas K, Hauser J, Hebebrand J, Helder S, Herms S, Herpertz-Dahlmann B, Herzog W, Hilliard CE, Hinney A, Hübel C, Huckins LM, Hudson JI, Huemer J, Inoko H, Janout V, Jiménez-Murcia S, Johnson C, Julià A, Juréus A, Kalsi G, Kaminska D, Kaplan AS, Kaprio J, Karhunen L, Karwautz A, Kas MJH, Kaye W, Kennedy JL, Keski-Rahkonen A, Kiezebrink K, Klareskog L, Klump KL, Knudsen GPS, Koeleman BPC, Koubek D, La Via MC, Landén M, Le Hellard S, Levitan RD, Li D, Lichtenstein P, Lilenfeld L, Lissowska J, Lundervold A, Magistretti P, Maj M, Mannik K, Marsal S, Martin N, Mattingsdal M, McDevitt S, McGuffin P, Merl E, Metspalu A, Meulenbelt I, Micali N, Mitchell J, Mitchell K, Monteleone P, Monteleone AM, Mortensen P, Munn-Chernoff MA, Navratilova M, Nilsson I, Norring C, Ntalla I, Ophoff RA, O'Toole JK, Palotie A, Pante J, Papezova H, Pinto D, Rabionet R, Raevuori A, Rajewski A, Ramoz N, Rayner NW, Reichborn-Kjennerud T, Ripatti S, Roberts M, Rotondo A, Rujescu D, Rybakowski F, Santonastaso P, Scherag A, Scherer SW, Schmidt U, Schork NJ, Schosser A, Slachtova L, Sladek R, Slagboom PE, Slof-Op 't Landt MCT, Slopien A, Soranzo N, Southam L, Steen VM, Strengman E, Strober M, Sullivan PF, Szatkiewicz JP, Szeszenia-Dabrowska N, Tachmazidou I, Tenconi E, Thornton LM, Tortorella A, Tozzi F, Treasure J, Tsitsika A, Tziouvas K, van Elburg AA, van Furth EF, Wagner G, Walton E, Watson H, Wichmann HE, Widen E, Woodside DB, Yanovski J, Yao S, Yilmaz Z, Zeggini E, Zerwas S, Zipfel S.

Author information

1
Department of Human Genetics, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK.
2
Division of Psychiatric Genomics, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
3
Department of Psychiatry and Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
4
Section of Eating Disorders, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
5
NIHR BRC SLaM BioResource for Mental Health, SGDP Centre & Centre for Neuroimaging Sciences, Section of Eating Disorders, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
6
Klinik für Kinder- und Jugendpsychiatrie, Psychotherapie und Psychosomatik Klinikum Frankfurt, Frankfurt, Germany.
7
Division of Psychological and Social Medicine and Developmental Neurosciences, Faculty of Medicine, TU Dresden, Dresden, Germany.
8
Eating Disorders Research and Treatment Center, Department of Child and Adolescent Psychiatry, Faculty of Medicine, TU Dresden, Dresden, Germany.
9
Department of Child and Adolescent Psychiatry and Psychotherapy, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
10
Helmholtz Zentrum München, Deutsches Forschungszentrum für Gesundheit und Umwelt, Neuherberg, Germany.
11
Division of Psychological & Social Medicine and Developmental Neurosciences, Technische Universität Dresden, Faculty of Medicine, University Hospital C.G. Carus, Dresden, Germany.
12
Department of Psychology, Georgia State University, Atlanta, GA, USA.
13
Erasmus University Medical Center, Rotterdam, The Netherlands.
14
Center for Human Genome Research at the Massachusetts General Hospital, Boston, MA, USA.
15
Department of Public Health & Institute for Molecular Medicine FIMM, University of Helsinki, Helsinki, Finland.
16
Brain Center Rudolf Magnus, Department of Neuroscience and Pharmacology, University Medical Center Utrecht, Utrecht, The Netherlands.
17
INSERM U984, Centre of Psychiatry and Neuroscience, Paris, France.
18
Mary Sue Coleman Director, Life Sciences Institute, Professor of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA.
19
Department of Dietetics-Nutrition, Harokopio University, Athens, Greece.
20
Rivierduinen Eating Disorders Ursula, Leiden, Zuid-Holland, The Netherlands.
21
Eating Disorders Unit, 1st Department of Psychiatry, National and Kapodistrian University of Athens, Medical School, Athens, Greece.
22
Department of Psychiatry, McLean Hospital/Harvard Medical School, Belmont, MA, USA.
23
Groningen Institute for Evolutionary Life Sciences, University of Groningen, Groningen, The Netherlands.
24
Department of Public Health, Clinicum, University of Helsinki, Helsinki, Finland.
25
Institute of Applied Health Sciences, University of Aberdeen, Aberdeen, UK.
26
Health Data and Digitalisation, Norwegian Institute of Public Health, Oslo, Norway.
27
Department of Psychiatry, University of Naples SUN, Naples, Italy.
28
Department of Medicine and Surgery, Section of Neurosciences, University of Salerno, Salerno, Italy.
29
Department of Genetics, Environment and Mental Health, Norwegian Institute of Public Health, Oslo, Norway.
30
eHealth Lab-Computer Science Department, University of Cyprus, Nicosia, Cyprus.
31
Adolescent Health Unit (A.H.U.), 2nd Department of Pediatrics - Medical School, University of Athens "P. & A. Kyriakou" Children's Hospital, Athens, Greece.
32
Center for Eating Disorders Rintveld, University of Utrecht, Utrecht, The Netherlands.
33
Eli Lilly and Company, Erl Wood Manor, Windlesham, UK.
34
Departments of Genetics and Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
35
Department of Medical Epidemiology and Biostatistics, Karolinksa Institutet, Stockholm, Sweden.
36
Social Genetic and Developmental Psychiatry, King's College London, London, UK.

Abstract

Anorexia nervosa (AN) is a complex neuropsychiatric disorder presenting with dangerously low body weight, and a deep and persistent fear of gaining weight. To date, only one genome-wide significant locus associated with AN has been identified. We performed an exome-chip based genome-wide association studies (GWAS) in 2158 cases from nine populations of European origin and 15 485 ancestrally matched controls. Unlike previous studies, this GWAS also probed association in low-frequency and rare variants. Sixteen independent variants were taken forward for in silico and de novo replication (11 common and 5 rare). No findings reached genome-wide significance. Two notable common variants were identified: rs10791286, an intronic variant in OPCML (P=9.89 × 10-6), and rs7700147, an intergenic variant (P=2.93 × 10-5). No low-frequency variant associations were identified at genome-wide significance, although the study was well-powered to detect low-frequency variants with large effect sizes, suggesting that there may be no AN loci in this genomic search space with large effect sizes.

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