Eating disorders (EDs)-including anorexia nervosa (AN), bulimia nervosa, and binge-eating disorder-are clinically distinct, but exhibit high symptom overlap and comorbidity. Genomic analyses to date have only examined AN. We conducted the first genome-wide association meta-analysis of binge-eating behaviour (BE; 39,279 cases, 1,227,436 controls, all from European genetic ancestries), alongside new analyses of AN (24,223 cases, 1,243,971 controls, all from European genetic ancestries) and its subtypes. We implicated six genomic loci associated with BE, including known associations with higher body mass index (BMI) and impulse-control behaviours. BE and AN exhibit genetic similarity, including positive genetic correlation with psychiatric disorders, and genetic dissimilarity, including opposing genetic correlations with anthropometric traits. Genomic structural equation modelling analyses indicate that most genetic signal in EDs is independent of BMI. We have extended ED genomics beyond AN; work is underway to diversify further, incorporating multiple diagnoses and global genetic ancestries.

CMB receives royalties from Pearson Education Inc.

This overall study was funded by NIH grant R01MH124851. Research using the ALSPAC cohort was funded by the UK NIHR (CS/01/2008/014) and the US NIH (MH087786-01). Research using BioVU was funded by R01MH118233 to Lea K Davis. Research in the Estonian Biobank was supported by the European Union through the European Regional Development Fund (Project No. 2014-2020.4.01.15-0012), and Estonian Research Council grant No. PSG615. The FinnGen project is funded by two grants from Business Finland (HUS 4685/31/2016 and UH 4386/31/2016) and nine industry partners (AbbVie, AstraZeneca, Biogen, Celgene, Genentech, GSK, MSD, Pfizer, and Sanofi). The Janssen study was funded by Johnson & Johnson Pharmaceutical Research & Development, L.L.C. The Norwegian Mother, Father and Child Cohort Study is supported by the Norwegian Ministry of Health and Care Services and the Ministry of Education and Research. This research is part of the HARVEST collaboration, supported by the Research Council of Norway (#229624). We also thank the NORMENT Centre for providing genotype data, funded by the Research Council of Norway (#223273), South East Norway Health Authorities and Stiftelsen Kristian Gerhard Jebsen. We further thank the Center for Diabetes Research, the University of Bergen for providing genotype data and performing quality control and imputation of the data funded by the ERC AdG project SELECTionPREDISPOSED, Stiftelsen Kristian Gerhard Jebsen, Trond Mohn Foundation, the Research Council of Norway, the Novo Nordisk Foundation, the University of Bergen, and the Western Norway Health Authorities. Research in URGE was supported by grants of Netherlands Organisation for Scientific Research (NWO: 024.004.012, ALWOP.137 and OCENW.KLEIN.071) to Roger Adan. Research in GLAD and the NIHR Bioresource was supported by the National Institute of Health Research (NIHR) BioResource, NIHR Biomedical Research Centre [IS-BRC-1215-20018], HSC R&D Division, Public Health Agency [COM/5516/18], MRC Mental Health Data Pathfinder Award (MC_PC_17,217), and the National Centre for Mental Health funding through Health and Care Research Wales. Research in the Korean Study of Anorexia Nervosa was supported by the Korea Centers for Disease Control and Prevention Research Fund [grant number: 2016-ER6310-00, 2016]. No authors nor their institutions at any time received payment or services from a third party for any aspect of the submitted work (including but not limited to grants, data monitoring board, study design, manuscript preparation, statistical analysis, etc.)

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

Price Foundation Collaborative Group and Children's Hospital of Philadelphia (CHOP): Ethical approval was obtained by each of the individual study sites (Cornell University, University of California at Los Angeles, University of Pittsburgh, University of Toronto, University of London, and University of Munich.). For the CHOP controls, CHOP's Research Ethics Board approved the study, and informed consent was obtained from all participants or their parents. Anorexia Nervosa Genetics Initiative (ANGI): ANGI-Australia and New Zealand (ANGI-ANZ) and Queensland Skin Study (QSkin): For ANGI-ANZ, all participants provided informed consent. Ethical approval for the Australian arm of the study was obtained by the QIMR Berfhoger Human Research Ethics Committee; for New Zealand, this was provided by the Health and Disability Ethics Committee of the New Zealand Ministry of Health. For QSkin, ethical approval was obtained by the QIMR Berghofer Human Research Ethics Committee (QIMR-HEC approval P1339). ANGI-Denmark (ANGI-DK) and the The Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH): Participants from ANGI-DK and the iPSYCH study did not provide written informed consent, as an exemption from consent was provided by the Danish Scientific Ethics Committee (Videnskabsetisk Komité). Additional Danish cases: All participants provided written informed consent before participating in the study. The study was approved by the Capital Region of Denmark's Committees on Health Research Ethics (De Videnskabsetiske Komiteer for Region Hovedstaden) (approval number H-KF-01-024/01). ANGI-United States of America (ANGI-US): ANGI-US was approved by the Institutional Review Board of the University of North Carolina at Chapel Hill (IRB: 13-0081). All participants were broadly consented for research. ANGI-Sweden and Binge-Eating Genetics Initiative (BEGIN): This project has been approved by the ethical review board in Sweden. The fundament of the ethical permit comes from ANGI Sweden (dnr 2013/112-31/2) which has later been amended to also include individuals with another diagnosis than AN (dnr 2014/1563) and to change the study name to BEGIN (dnr 2016/1852-32). Australian Genetics of Depression Study: Ethics approval for all aspects of the project was obtained from the QIMR Berghofer Human Research Ethics Committee (P2118 & P3434). Avon Longitudinal Study of Parents and Children (ALSPAC): Ethical approval for the study was obtained from the ALSPAC Ethics and Law Committee and the Local Research Ethics Committees. Informed consent for the use of data collected via questionnaires and clinics was obtained from participants following the recommendations of the ALSPAC Ethics and Law Committee at the time. The main caregiver initially provided consent for child participation, and from the age of 16 years, the offspring themselves have provided informed written consent. The Vanderbilt University biorepository (BioVU): The study was approved by the Vanderbilt University Medical Center Institutional Review Board (IRB #201609). The Estonian Biobank: The research project has obtained approval from the Estonian Council on Bioethics and Human Research (1.1-12/624). The Finnish Study of Genetics (FinnGEN): Written informed consent was obtained from all the study participants. For the Finnish Institute of Health and Welfare (THL)-driven FinnGen preparatory project and FinnGen project, all patients and control subjects had provided informed consent for biobank research, based on the Finnish Biobank Act. Alternatively, the North Karelia Project (FINRISK) and Health 2000 cohorts were based on study specific consents and later transferred to the THL Biobank after approval by Valvira, the National Supervisory Authority for Welfare and Health. Recruitment protocols followed the biobank protocols approved by Valvira. Jannsen: The CAPSS220BED clinical study (ClinicalTrials.gov ID: NCT00210808) was conducted by Johnson & Johnson Pharmaceutical Research & Development, L.L.C., and was approved by the appropriate ethical review boards and followed the principles outlined in the Declaration of Helsinki for all human investigations. In addition, informed consent has been obtained from the study participants. The Norwegian Mother, Father and Child Cohort Study (MoBa): The establishment of MoBa and initial data collection was based on a licence from the Norwegian Data Protection Agency and approval from The Regional Committees for Medical and Health Research Ethics. The MoBa cohort is currently regulated by the Norwegian Health Registry Act. The current study was approved by The Regional Committees for Medical and Health Research Ethics (20311). Utrecht Research Group Eating Disorders (URGE) cohort: Informed consent was obtained from all patients who provided DNA. The Biobank Ethics Committee of the University of Utrecht gave ethical approval for this work. UK Biobank: UK Biobank is registered as a Research Tissue Bank (North West - Haydock Research Ethics Committee, 21/NW/0157). All data and sample applications may use this ethical clearance to conduct their research. Separate Research Ethics Committee or other ethical clearance is not required. This research was conducted under application 82087 (PI: Jonathan Coleman). Charlotte's Helix: Charlotte's Helix participants were recruited using ethics approval provided by the Research Ethics Committee South Central Oxford C (15/SC/0388). The Genetic Links to Anxiety and Depression (GLAD) Study , and the National Institute for Health Research (NIHR) Bioresource: The GLAD Study was approved by the London - Fulham Research Ethics Committee on 21st August 2018 (REC reference: 18/LO/1218) following a full review by the committee. The NIHR BioResource has been approved as a Research Tissue Bank by the East of England - Cambridge Central Committee (REC reference: 17/EE/0025). Korean Study of Anorexia Nervosa: The study was approved by the Institutional Review Board of Inje University (INJE 2016-01-003-002). Genetics Consortium for Anorexia Nervosa: Each study site (Medical University of Vienna, Toronto General Hospital, Charles University, University of Helsinki, Institut National de la Santé et de la Recherche Médicale, University of Pittsburgh, University of North Carolina at Chapel Hill, Roseneck Hospital for Behavioral Medicine, University of Munich, Kings College London, Laureate Psychiatric Hospital, Weill Cornell Medical College, Sheppard Pratt Health System, Neuropsychiatric Research Institute Fargo, University of California at Los Angeles, University of Pennsylvania, University of Birmingham, University of Duisburg-Essen, GlaxoSmithKline Leeds, Athens University, Medical School, Padua/Verona/Treviso/Vicenza/Portogruaro hospitals, University Medical Center Utrecht, Altrecht in Zeist, Poznan University of Medical Sciences, Center for Genomic Regulation Barcelona, Department of Psychiatry University Hospital of Bellvitge, Karolinska Institutet, McLean Hospital/Harvard Medical School, Vanderbilt University School of Medicine) obtained informed consent from all participants, as well as permission from local ethical committees.

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

Individual level genotype data and summary statistics used in this study are available to bona fide researchers working in collaboration with a member of the PGC Eating Disorders Working Group via secondary analysis proposals (https://pgc.unc.edu/for-researchers/data-access-committee/data-access-information/). Summary statistics from this work will be made available via Figshare and the PGC website on publication (https://pgc.unc.edu/for-researchers/download-results/).