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 men2,3,4, 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.
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The policy of the PGC is to make genome-wide summary results public. Genome-wide summary statistics for the meta-analysis are freely downloadable from the website of the PGC (http://www.med.unc.edu/pgc/results-and-downloads). Individual-level data are deposited in dbGaP (http://www.ncbi.nlm.nih.gov/gap) for ANGI-ANZ/SE/US (accession number phs001541.v1.p1) and CHOP/PFCG (accession number phs000679.v1.p1). ANGI-DK individual-level data are not available in dbGaP owing to Danish laws, but are available through collaboration with principal investigators of the Danish institutions. GCAN/WTCCC3 individual-level data are deposited in EGA (https://www.ebi.ac.uk/ega) (accession number EGAS00001000913) with the exception of the Netherlands and USA/Canada; data from these countries are available through collaboration with principal investigators of institutions in these countries. UK Biobank individual-level data can be applied for on the UK Biobank website (http://www.ukbiobank.ac.uk/register-apply).
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Grant support for ANGI, the PGC-ED and its component groups is shown in Supplementary Table 17. We thank all study volunteers, study coordinators and research staff who enabled this study. ANGI: The Anorexia Nervosa Genetics Initiative is an initiative of the Klarman Family Foundation. Additional support was offered by the National Institute of Mental Health. We are deeply grateful to all of the individuals who, through their participation, made ANGI a success. The goodwill that permeated the eating disorders community fueled by the enthusiasm of prominent bloggers, advocates, clinicians, treatment centers, scientists, organizations, families and especially those who have suffered from anorexia nervosa, yielded in an unprecedented and inspired global movement to complete this science. ANGI (United States): We thank Walden Behavioral Care, McCallum Place and the Renfrew Center for assisting with recruitment. We express our gratitude to J. Alexander (http://www.junealexander.com/) and C. Arnold (http://carriearnold.com/), who helped us disseminate information about ANGI. We acknowledge support from the North Carolina Translational and Clinical Sciences Institute (NC TraCS), the Carolina Data Warehouse and the Foundation of Hope, Raleigh, North Carolina. ANGI (Australia and New Zealand): We thank the Australia & and New Zealand Academy for Eating Disorders for assistance with recruitment and publicity. We thank VIVA! Communications for their efforts in promoting the study and the Butterfly Foundation for their ongoing support of anorexia nervosa research in Australia and EDANZ in New Zealand. We thank the QSkin Sun and Health Study for controls. We also acknowledge the assistance of S. Maguire and J. Russell (University of Sydney), P. Hay (Western Sydney University), S. Madden (Western Sydney University and the Sydney Children’s Hospital Network), S. Sawyer and E. Hughes (Royal Children’s Hospital, Melbourne), K. Fairweather-Schmidt (Flinders University), A. Fursland (Centre for Clinical Interventions and Curtin University), J. McCormack (Princess Margaret Hospital for Children), F. Wagg (Royal Hobart Hospital) and W. Ward (Royal Brisbane and Women’s Hospital) in recruitment. We also thank L. Nunn for validation work on the ED100Kv1 Questionnaire. Additionally, administrative support for data collection was received from the Australian Twin Registry, which is supported by an Enabling Grant (ID 310667) from the NHMRC administered by the University of Melbourne. In New Zealand, we also acknowledge assistance with recruitment from M. Roberts (University of Auckland), R. Lawson (South Island Eating Disorders Service), M. Meiklejohn (Auckland District Health Board) and R. Mysliwiec. Special thanks to those who provided their stories in relation to publicity about ANGI. ANGI (Sweden): We acknowledge the assistance of the Stockholm Centre for Eating Disorders (SCÄ) and thank the Swedish National Quality Register for Eating Disorders (Riksät) and Lifegene. We would also like to thank the research nurses and data collectors at the Department of Medical Epidemiology and Biostatistics who worked on ANGI. ANGI (Denmark): We thank the Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH). PGC: We are deeply indebted to the investigators who comprise the PGC and to the hundreds of thousands of individuals who have shared their life experiences with PGC investigators and the contributing studies. We are grateful to the Children’s Hospital of Philadelphia (CHOP), the Price Foundation Collaborative Group (PFCG), Genetic Consortium for Anorexia Nervosa (GCAN), Wellcome Trust Case-Control Consortium-3 (WTCCC-3), the UK Biobank and all PGC-ED members for their support in providing individual samples used in this study. We thank SURFsara (http://www.surf.nl) for support in using the Lisa Compute Cluster. We thank M. Lam for Ricopili consultation. This study also represents independent research partly funded by the English National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London and the NIHR BioResource. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the English Department of Health and Social Care. High performance computing facilities were funded with capital equipment grants from the GSTT Charity (TR130505) and Maudsley Charity (980). Research reported in this publication was also supported by the National Institute of Mental Health of the US National Institutes of Health under Award Numbers U01MH109528 and U01MH109514. The content is solely the responsibility of the authors and does not necessarily represent the official views of the US National Institutes of Health.
O.A.A. received a speaker’s honorarium from Lundbeck. G.B. received grant funding and consultancy fees in preclinical genetics from Eli Lilly, consultancy fees from Otsuka and has received honoraria from Illumina. C.M.B. is a grant recipient from Shire Pharmaceuticals and served on Shire Scientific Advisory Board; she receives author royalties from Pearson. D.D. served as a speaker and on advisory boards, and has received consultancy fees for participation in research from various pharmaceutical industry companies including: AstraZeneca, Boehringer, Bristol Myers Squibb, Eli Lilly, Genesis Pharma, GlaxoSmithKline, Janssen, Lundbeck, Organon, Sanofi, UniPharma and Wyeth; he has received unrestricted grants from Lilly and AstraZeneca as director of the Sleep Research Unit of Eginition Hospital (National and Kapodistrian University of Athens, Greece). J.I.H. has received grant support from Shire and Sunovion, and has received consulting fees from DiaMentis, Shire, and Sunovion. A.S.K. is a member of the Shire Canadian BED Advisory Board and is on the steering committee for the Shire B/educated Educational Symposium: 15–16 June 2018. J.L.K. served as an unpaid member of the scientific advisory board of AssurexHealth Inc. M.L. declares that, over the past 36 months, he has received lecture honoraria from Lundbeck and served as scientific consultant for EPID Research Oy, but has received no other equity ownership, profit-sharing agreements, royalties or patents. P.F.S. is on the Lundbeck advisory committee and is a Lundbeck grant recipient; he has served on the scientific advisory board for Pfizer, has received a consultation fee from Element Genomics, and a speaker reimbursement fee from Roche. J.T. has received an honorarium for participation in an EAP meeting and has received royalties from several books from Routledge, Wiley and Oxford University Press. T.W. has acted as a lecturer and scientific advisor to H. Lundbeck A/S. All other authors have no conflicts of interest to disclose.
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Watson, H.J., Yilmaz, Z., Thornton, L.M. et al. Genome-wide association study identifies eight risk loci and implicates metabo-psychiatric origins for anorexia nervosa. Nat Genet 51, 1207–1214 (2019). https://doi.org/10.1038/s41588-019-0439-2
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