Genome-wide association study identifies eight risk loci and implicates metabo-psychiatric origins for anorexia nervosa
Open accessAbstract
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. Genome-wide analyses identify eight independent loci associated with anorexia nervosa. Genetic correlations implicate both psychiatric and metabolic components in the etiology of this disorder, even after adjusting for the effects of common variants associated with body mass index.
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Self-citation
- Authors
- Initiative, A. N. G., Watson, H. J., Eating Disorders Working Group of the Psychiatric Genomics Consortium, Yilmaz, Z., Thornton, L. M., Hübel, C., Coleman, J. R. I., Gaspar, H. A., Bryois, J., Hinney, A., Leppä, V. M., Mattheisen, M., Medland, S. E., Ripke, S., Yao, S., Giusti-Rodríguez, P., Hanscombe, K. B., Purves, K. L., Adan, R. A. H., Alfredsson, L., Ando, T., Andreassen, O. A., Baker, J. H., Berrettini, W. H., Boehm, I., Boni, C., Perica, V. B., Buehren, K., Burghardt, R., Cassina, M., Cichon, S., Clementi, M., Cone, R. D., Courtet, P., Crow, S., Crowley, J. J., Danner, U. N., Davis, O. S. P., de Zwaan, M., Dedoussis, G., Degortes, D., DeSocio, J. E., Dick, D. M., Dikeos, D., Dina, C., Dmitrzak-Weglarz, M., Docampo, E., Duncan, L. E., Egberts, K., Ehrlich, S., Escaramís, G., Esko, T., Estivill, X., Farmer, A., Favaro, A., Fernández-Aranda, F., Fichter, M. M., Fischer, K., Föcker, M., Foretova, L., Forstner, A. J., Forzan, M., Franklin, C. S., Gallinger, S., Giegling, I., Giuranna, J., Gonidakis, F., Gorwood, P., Mayora, M. G., Guillaume, S., Guo, Y., Hakonarson, H., Hatzikotoulas, K., Hauser, J., Hebebrand, J., Helder, S. G., Herms, S., Herpertz-Dahlmann, B., Herzog, W., Huckins, L. M., Hudson, J. I., Imgart, H., Inoko, H., Janout, V., Jiménez-Murcia, S., Julià, A., Kalsi, G., Kaminská, D., Kaprio, J., Karhunen, L., Karwautz, A., Kas, M. J. H., Kennedy, J. L., Keski-Rahkonen, A., Kiezebrink, K., Kim, Y.-R., Klareskog, L., Klump, K. L., Knudsen, G. P. S., La Via, M. C., Le Hellard, S., Levitan, R. D., Li, D., Lilenfeld, L., Lin, B. D., Lissowska, J., Luykx, J., Magistretti, P. J., Maj, M., Mannik, K., Marsal, S., Marshall, C. R., Mattingsdal, M., McDevitt, S., McGuffin, P., Metspalu, A., Meulenbelt, I., Micali, N., Mitchell, K., Monteleone, A. M., Monteleone, P., Munn-Chernoff, M. A., Nacmias, B., Navratilova, M., Ntalla, I., O’Toole, J. K., Ophoff, R. A., Padyukov, L., Palotie, A., Pantel, J., Papezova, H., Pinto, D., Rabionet, R., Raevuori, A., Ramoz, N., Reichborn-Kjennerud, T., Ricca, V., Ripatti, S., Ritschel, F., Roberts, M., Rotondo, A., Rujescu, D., Rybakowski, F., Santonastaso, P., Scherag, A., Scherer, S. W., Schmidt, U., Schork, N. J., Schosser, A., Seitz, J., Slachtova, L., Slagboom, P. E., Slof-Op ‘t Landt, M. C. T., Slopien, A., Sorbi, S., Świątkowska, B., Szatkiewicz, J. P., Tachmazidou, I., Tenconi, E., Tortorella, A., Tozzi, F., Treasure, J., Tsitsika, A., Tyszkiewicz-Nwafor, M., Tziouvas, K., van Elburg, A. A., van Furth, E. F., Wagner, G., Walton, E., Widen, E., Zeggini, E., Zerwas, S., Zipfel, S., Bergen, A. W., Boden, J. M., Brandt, H., Crawford, S., Halmi, K. A., Horwood, L. J., Johnson, C., Kaplan, A. S., Kaye, W. H., Mitchell, J. E., Olsen, C. M., Pearson, J. F., Pedersen, N. L., Strober, M., Werge, T., Whiteman, D. C., Woodside, D. B., Stuber, G. D., Gordon, S., Grove, J., Henders, A. K., Juréus, A., Kirk, K. M., Larsen, J. T., Parker, R., Petersen, L., Jordan, J., Kennedy, M., Montgomery, G. W., Wade, T. D., Birgegård, A., Lichtenstein, P., Norring, C., Landén, M., Martin, N. G., Mortensen, P. B., Sullivan, P. F., Breen, G., & Bulik, C. M.
- Affiliations
- University of North Carolina at Chapel Hill (US)
- King's College London (GB)
- National Health Service (GB)
- Karolinska Institutet (SE)
- Aarhus University (DK)
- QIMR Berghofer Medical Research Institute (AU)
- Broad Institute (US)
- Guy's Hospital (GB)
- Oslo University Hospital (NO)
- Technische Universität Dresden (DE)
- Inserm (FR)
- Wellcome Sanger Institute (GB)
- RWTH Aachen University (DE)
- University of Padua (IT)
- Université de Montpellier (FR)
- University of Minnesota (US)
- University of Bristol (GB)
- Medizinische Hochschule Hannover (DE)
- Virginia Commonwealth University (US)
- Centre National de la Recherche Scientifique (FR)
- Universitat Pompeu Fabra (ES)
- Universitätsklinikum Würzburg (DE)
- Barcelona Institute of Science and Technology (ES)
- Schön Klinik Roseneck (DE)
- Essen University Hospital (DE)
- Masaryk Memorial Cancer Institute (CZ)
- University of Bonn (DE)
- University of Toronto (CA)
- National and Kapodistrian University of Athens (GR)
- Children's Hospital of Philadelphia (US)
- Poznan University of Medical Sciences (PL)
- Heidelberg University (DE)
- Harvard University (US)
- Tokai University (JP)
- University of Helsinki (FI)
- University of Eastern Finland (FI)
- University Medical Center Utrecht (NL)
- Centre for Addiction and Mental Health (CA)
- University of Aberdeen (GB)
- Karolinska University Hospital (SE)
- Norwegian Institute of Public Health (NO)
- Argosy University (US)
- University of Campania "Luigi Vanvitelli" (IT)
- Hospital for Sick Children (CA)
- Leiden University Medical Center (NL)
- University of Geneva (CH)
- Boston University (US)
- University of Salerno (IT)
- Harokopio University of Athens (GR)
- Hospital Sant Joan de Déu Barcelona (ES)
- University of Pisa (IT)
- J. Craig Venter Institute (US)
- Medical University of Vienna (AT)
- Charles University (CZ)
- Nofer Institute of Occupational Medicine (PL)
- University of Perugia (IT)
- Universitätsklinikum Tübingen (DE)
- Oregon Research Institute (US)
- Sheppard and Enoch Pratt Hospital (US)
- Weill Cornell Medicine (US)
- University of Otago (NZ)
- University of North Dakota (US)
- University of California, Los Angeles (US)
- University of Copenhagen (DK)
- The University of Queensland (AU)
- Canterbury District Health Board (NZ)
- Flinders University (AU)
- Corresponding author
- Bulik, Cynthia M.
- ORCID
- Watson, Hunna J.
- Hübel, Christopher
- Coleman, Jonathan R. I.
- Gaspar, Héléna A.
- Bryois, Julien
- Hinney, Anke
- Leppä, Virpi M.
- Mattheisen, Manuel
- Medland, Sarah E.
- Ripke, Stephan
- Yao, Shuyang
- Hanscombe, Ken B.
- Purves, Kirstin L.
- Adan, Roger A. H.
- Alfredsson, Lars
- Ando, Tetsuya
- Andreassen, Ole A.
- Baker, Jessica H.
- Boehm, Ilka
- Perica, Vesna Boraska
- Burghardt, Roland
- Cassina, Matteo
- Cichon, Sven
- Clementi, Maurizio
- Cone, Roger D.
- Courtet, Philippe
- Crow, Scott
- Crowley, James J.
- Danner, Unna N.
- Davis, Oliver S. P.
- Dedoussis, George
- Dick, Danielle M.
- Dikeos, Dimitris
- Duncan, Laramie E.
- Egberts, Karin
- Ehrlich, Stefan
- Escaramís, Geòrgia
- Esko, Tõnu
- Estivill, Xavier
- Favaro, Angela
- Fischer, Krista
- Föcker, Manuel
- Forstner, Andreas J.
- Forzan, Monica
- Giegling, Ina
- Gonidakis, Fragiskos
- Gorwood, Philip
- Guillaume, Sébastien
- Guo, Yiran
- Hakonarson, Hakon
- Hatzikotoulas, Konstantinos
- Hauser, Joanna
- Hebebrand, Johannes
- Herms, Stefan
- Herzog, Wolfgang
- Huckins, Laura M.
- Hudson, James I.
- Imgart, Hartmut
- Inoko, Hidetoshi
- Julià, Antonio
- Kalsi, Gursharan
- Kaminská, Deborah
- Kaprio, Jaakko
- Karhunen, Leila
- Karwautz, Andreas
- Kas, Martien J. H.
- Kennedy, James L.
- Kiezebrink, Kirsty
- Kim, Youl-Ri
- Klareskog, Lars
- Klump, Kelly L.
- Knudsen, Gun Peggy S.
- Li, Dong
- Lilenfeld, Lisa
- Lin, Bochao Danae
- Lissowska, Jolanta
- Luykx, Jurjen
- Magistretti, Pierre J.
- Maj, Mario
- Marsal, Sara
- Marshall, Christian R.
- Mattingsdal, Morten
- McDevitt, Sara
- Metspalu, Andres
- Micali, Nadia
- Mitchell, Karen
- Monteleone, Alessio Maria
- Monteleone, Palmiero
- Nacmias, Benedetta
- Ophoff, Roel A.
- Padyukov, Leonid
- Palotie, Aarno
- Pantel, Jacques
- Pinto, Dalila
- Rabionet, Raquel
- Raevuori, Anu
- Ricca, Valdo
- Ripatti, Samuli
- Ritschel, Franziska
- Roberts, Marion
- Rujescu, Dan
- Rybakowski, Filip
- Santonastaso, Paolo
- Scherag, André
- Scherer, Stephen W.
- Schmidt, Ulrike
- Schork, Nicholas J.
- Schosser, Alexandra
- Seitz, Jochen
- Slachtova, Lenka
- Slagboom, P. Eline
- Sorbi, Sandro
- Świątkowska, Beata
- Tenconi, Elena
- Tortorella, Alfonso
- Treasure, Janet
- Tziouvas, Konstantinos
- Wagner, Gudrun
- Walton, Esther
- Zeggini, Eleftheria
- Zerwas, Stephanie
- Bergen, Andrew W.
- Boden, Joseph M.
- Crawford, Steven
- Halmi, Katherine A.
- Horwood, L. John
- Kaplan, Allan S.
- Kaye, Walter H.
- Mitchell, James E.
- Olsen, Catherine M.
- Pearson, John F.
- Pedersen, Nancy L.
- Werge, Thomas
- Whiteman, David C.
- Woodside, D. Blake
- Stuber, Garret D.
- Gordon, Scott
- Grove, Jakob
- Henders, Anjali K.
- Juréus, Anders
- Kirk, Katherine M.
- Larsen, Janne T.
- Parker, Richard
- Petersen, Liselotte
- Jordan, Jennifer
- Kennedy, Martin
- Montgomery, Grant W.
- Wade, Tracey D.
- Birgegård, Andreas
- Lichtenstein, Paul
- Norring, Claes
- Landén, Mikael
- Martin, Nicholas G.
- Mortensen, Preben Bo
- Sullivan, Patrick F.
- Breen, Gerome
- Bulik, Cynthia M.
- Venue
- Nature Genetics
- Published
- 2019-07-15
- Volume
- 51
- Issue
- 8
- Pages
- 1207-1214
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- PMC
- PMC6779477
- OpenAlex
- W2960372990
- Cited by
- 1,109
- References
- 57
- Citations by year
- 2026: 125 · 2025: 189 · 2024: 199 · 2023: 137 · 2022: 165 · 2021: 149 · 2020: 111 · 2019: 30 · 2018: 1 · 2016: 1
- FWCI
- 134.60
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Nature Genetics (publishedVersion, other-oa)
- Research at the University of Copenhagen (University of Copenhagen) (publishedVersion, other-oa)
- UWA Profiles and Research Repository (UWA) (publishedVersion, other-oa)
- PubMed (publishedVersion)
- Bristol Research (University of Bristol) (publishedVersion, other-oa)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (acceptedVersion, other-oa)
- PubMed Central (acceptedVersion)
- Aberdeen University Research Archive (Aberdeen University) (acceptedVersion)
- Archive ouverte UNIGE (University of Geneva) (acceptedVersion, other-oa)
- Pure (University of Bath) (submittedVersion, other-oa)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- HAL (submittedVersion)
- Leiden Repository (Leiden University) (submittedVersion)
- Aberdeen University Research Archive (Aberdeen University) (submittedVersion)
- Dipòsit Digital de la Universitat de Barcelona (Universitat de Barcelona) (submittedVersion, public-domain)
- Utrecht University Repository (Utrecht University) (submittedVersion, other-oa)
- eScholarship (California Digital Library) (submittedVersion)
- Archivio Istituzionale della Ricerca - Università degli Studi della Campania "Luigi Vanvitelli" (submittedVersion)
- IRIS (submittedVersion)
- Research Portal (King's College London) (submittedVersion, other-oa)
- ORBi (University of Liège) (submittedVersion)
- RWTH Publications (RWTH Aachen) (submittedVersion)
- PuSH - Publication Server of Helmholtz Zentrum München (submittedVersion)
- King Abdullah University of Science and Technology Repository (King Abdullah University of Science and Technology) (submittedVersion)
- SERVAL (Université de Lausanne) (submittedVersion)
- Archive ouverte UNIGE (University of Geneva) (submittedVersion, cc-by)
- Padua Research Archive (University of Padova) (submittedVersion, other-oa)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion, other-oa)
- Utrecht University Repository (Utrecht University) (submittedVersion)
- Funders
- Bristol-Myers Squibb
- Eli Lilly and Company
- Pfizer
- AstraZeneca
- GlaxoSmithKline
- Sanofi
- Children's Hospital of Philadelphia
- Louis and Harold Price Foundation
- Sunovion
- Wellcome Trust
- Maudsley Charity (TR130505)
- Academy for Eating Disorders
- Auckland District Health Board
- Foundation of Hope for Research and Treatment of Mental Illness
- National Institute for Health and Care Research (NF-SI-0616-10075)
- Department of Health and Social Care
- King's College London
- Flinders University
- Curtin University of Technology
- Lundbeckfonden (R208-2015-3951, R248‐2017‐2003, R276-2017-4581)
- Shire
- National and Kapodistrian University of Athens
- Genesis Pharma
- H. Lundbeck A/S
- Western Sydney University
- National Institutes of Health
- NIHR BioResource
- Medical Research Council (1668713)
- National Health and Medical Research Council (310667)
- National Institute on Alcohol Abuse and Alcoholism (K01AA025113)
- National Institute of Mental Health (R01MH092793, U01MH109514, K01MH109772, K01MH109782, K01MH106675, U01MH109528, R21MH104831, U01MH109536, R21MH115397, R01MH106611)
- National Human Genome Research Institute (U01HG006830)
- North Carolina Translational and Clinical Sciences Institute, University of North Carolina at Chapel Hill
- Topics
- Social Sciences › Psychology › Clinical Psychology › Eating Disorders and Behaviors
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Mapping and Diversity in Plants and Animals
- Keywords
- anorexia nervosa, genetic susceptibility loci, genetic correlation, eating disorders, body mass index, glycemic traits, lipid traits, anthropometric traits, physical activity, mental illness, genetic architecture
- MeSH terms
- Adult, Anorexia Nervosa, Mental Disorders, Female, Humans, Male, Metabolic Diseases, Phenotype, Prognosis, Body Mass Index, Case-Control Studies, Genetic Predisposition to Disease, Genomics, Quantitative Trait Loci, Genome-Wide Association Study
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