The Eating Disorders Genetics Initiative 2 (EDGI2): study protocol

Natasha Berthold^#^{1

2

3}, Casey M MacDermod^#¹, Laura M Thornton¹, Richard Parker⁴, Shantal Anid Cortés Morales^{5

6}, Liv Hog⁷, Hannah L Kennedy⁸, Jerry Guintivano¹, Patrick F Sullivan^{1

7}, James J Crowley^{7

9}, Jessica S Johnson¹, Andreas Birgegård⁷, Bengt T Fundín⁷, Emma Frans⁷, Jiayi Xu¹⁰, Michaela Pettie Ngāti Pūkenga⁸, Allison L Miller⁸, Mariana Valdez Aguilar¹, Sarah Barakat¹¹, Mohamed Abdulkadir¹², Jennifer P White^{1

13}, Janne T Larsen¹², Elsie Trujillo⁵, Bertha Winterman⁵, Ruyue Zhang⁷, Rachel Lawson¹⁴, Stephen Wonderlich^{15

16}, Joseph Wonderlich¹⁵, Lauren M Schaefer¹⁵, Philip S Mehler¹⁷, Judy Oakes¹⁷, Marina Foster¹⁷, Jennifer Gaudiani¹⁸, Eva Trujillo Chi Vacuán^#^{5

6}, Emilio J Compte^#^{5

19}, Liselotte V Petersen^#¹², Zeynep Yilmaz^#^{1

12

20}, Nadia Micali^#^{21

22}, Jennifer Jordan^#^{23

24}, Martin A Kennedy^#⁶, Sarah Maguire^#^{11

25}, Laura M Huckins^#¹⁰, Yi Lu^#⁷, Lisa Dinkler^#⁷, Nicholas G Martin^#⁴, Cynthia M Bulik^#^{26

27

28}

Affiliations

¹ Department of Psychiatry, University of North Carolina at Chapel Hill, #7160, 101 Manning Drive, Chapel Hill, CBNC, 27599 - 7160, USA.
² School of Human Sciences, University of Western Australia, Crawley, WA, 6009, Australia.
³ Perron Research Institute, Nedlands, WA, 6009, Australia.
⁴ QIMR Berghofer Medical Research Institute, Royal Brisbane Hospital, Locked Bag 2000, Brisbane, QLD, 4029, Australia.
⁵ Research Department, Comenzar de Nuevo, Monterrey, Mexico.
⁶ Tecnologico de Monterrey, Escuela de Medicina y Ciencias de la Salud - , Monterrey, Mexico.
⁷ Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, 171 77, Stockholm, Sweden.
⁸ Department of Pathology and Biomedical Science, University of Otago, Christchurch, New Zealand.
⁹ Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.
¹⁰ Division of Molecular Psychiatry, Department of Psychiatry, Yale University, New Haven, CT, USA.
¹¹ Insideout Institute for Eating Disorders, The University of Sydney, Sydney, Australia.
¹² Department of Public Health, National Centre for Register-Based Research, Aarhus University, Aarhus, Denmark.
¹³ Department of Psychology, University of Albany, State University of New York, Albany, NY, USA.
¹⁴ South Island Eating Disorders Service, Health NZ Te Whatu Ora, Christchurch, New Zealand.
¹⁵ Center for Biobehavioral Research, Sanford Health, Fargo, ND, USA.
¹⁶ Department of Psychiatry and Behavioral Science, University of North Dakota School of Medicine and Health Sciences, Fargo, ND, USA.
¹⁷ ACUTE Center for Eating Disorders and Severe Malnutrition, Denver Health and Hospital Authority, Denver, CO, USA.
¹⁸ Gaudiani Clinic, Denver, CO, USA.
¹⁹ Eating Behavior Research Center, School of Psychology, Universidad Adolfo Ibáñez, Santiago, Chile.
²⁰ Department of Biomedicine, Aarhus University, Aarhus, Denmark.
²¹ Center for Eating and Feeding Disorders Research, Mental Health Services of the Capital Region of Denmark, Psychiatric Centre Ballerup, Copenhagen, Denmark.
²² Great Ormond Street Institute of Child Health, University College London, London, UK.
²³ Department of Psychological Medicine, University of Otago, Christchurch, New Zealand.
²⁴ Health NZ - Te Whatu Ora, Christchurch, New Zealand.
²⁵ Faculty of Medicine and Health, University of Sydney, Sydney, Australia.
²⁶ Department of Psychiatry, University of North Carolina at Chapel Hill, #7160, 101 Manning Drive, Chapel Hill, CBNC, 27599 - 7160, USA. cynthia_bulik@med.unc.edu.
²⁷ Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, 171 77, Stockholm, Sweden. cynthia_bulik@med.unc.edu.
²⁸ Department of Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA. cynthia_bulik@med.unc.edu.

^# Contributed equally.

PMID: 40419993
PMCID: PMC12105188
DOI: 10.1186/s12888-025-06777-5

The Eating Disorders Genetics Initiative 2 (EDGI2): study protocol

Natasha Berthold et al. BMC Psychiatry. 2025.

. 2025 May 26;25(1):532.

doi: 10.1186/s12888-025-06777-5.

Authors

Affiliations

¹ Department of Psychiatry, University of North Carolina at Chapel Hill, #7160, 101 Manning Drive, Chapel Hill, CBNC, 27599 - 7160, USA.
² School of Human Sciences, University of Western Australia, Crawley, WA, 6009, Australia.
³ Perron Research Institute, Nedlands, WA, 6009, Australia.
⁴ QIMR Berghofer Medical Research Institute, Royal Brisbane Hospital, Locked Bag 2000, Brisbane, QLD, 4029, Australia.
⁵ Research Department, Comenzar de Nuevo, Monterrey, Mexico.
⁶ Tecnologico de Monterrey, Escuela de Medicina y Ciencias de la Salud - , Monterrey, Mexico.
⁷ Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, 171 77, Stockholm, Sweden.
⁸ Department of Pathology and Biomedical Science, University of Otago, Christchurch, New Zealand.
⁹ Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.
¹⁰ Division of Molecular Psychiatry, Department of Psychiatry, Yale University, New Haven, CT, USA.
¹¹ Insideout Institute for Eating Disorders, The University of Sydney, Sydney, Australia.
¹² Department of Public Health, National Centre for Register-Based Research, Aarhus University, Aarhus, Denmark.
¹³ Department of Psychology, University of Albany, State University of New York, Albany, NY, USA.
¹⁴ South Island Eating Disorders Service, Health NZ Te Whatu Ora, Christchurch, New Zealand.
¹⁵ Center for Biobehavioral Research, Sanford Health, Fargo, ND, USA.
¹⁶ Department of Psychiatry and Behavioral Science, University of North Dakota School of Medicine and Health Sciences, Fargo, ND, USA.
¹⁷ ACUTE Center for Eating Disorders and Severe Malnutrition, Denver Health and Hospital Authority, Denver, CO, USA.
¹⁸ Gaudiani Clinic, Denver, CO, USA.
¹⁹ Eating Behavior Research Center, School of Psychology, Universidad Adolfo Ibáñez, Santiago, Chile.
²⁰ Department of Biomedicine, Aarhus University, Aarhus, Denmark.
²¹ Center for Eating and Feeding Disorders Research, Mental Health Services of the Capital Region of Denmark, Psychiatric Centre Ballerup, Copenhagen, Denmark.
²² Great Ormond Street Institute of Child Health, University College London, London, UK.
²³ Department of Psychological Medicine, University of Otago, Christchurch, New Zealand.
²⁴ Health NZ - Te Whatu Ora, Christchurch, New Zealand.
²⁵ Faculty of Medicine and Health, University of Sydney, Sydney, Australia.
²⁶ Department of Psychiatry, University of North Carolina at Chapel Hill, #7160, 101 Manning Drive, Chapel Hill, CBNC, 27599 - 7160, USA. cynthia_bulik@med.unc.edu.
²⁷ Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, 171 77, Stockholm, Sweden. cynthia_bulik@med.unc.edu.
²⁸ Department of Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA. cynthia_bulik@med.unc.edu.

^# Contributed equally.

PMID: 40419993
PMCID: PMC12105188
DOI: 10.1186/s12888-025-06777-5

Abstract

Background: The Eating Disorders Genetics Initiative 2 (EDGI2) is designed to explore the role of genes and environment in anorexia nervosa, bulimia nervosa, binge-eating disorder, and avoidant/restrictive food intake disorder (ARFID) with a focus on broad population representation and severe and/or longstanding illness.

Methods: A total of 20,000 new participants (18,700 cases and 1,300 controls) will be ascertained from the United States (US), Mexico (MX), Australia (AU), Aotearoa New Zealand (NZ), Sweden (SE), and Denmark (DK). Comprehensive phenotyping and genotyping will be performed for participants in US, MX, AU, NZ, and SE using the EDGI2 questionnaire battery and participant saliva samples. In DK, case identification and genotyping will be through the National Patient Register and bloodspots archived near birth. Case-control and case-case genome-wide association studies will be conducted within EDGI2 and enhanced via meta-analysis with external data from the Eating Disorders Working Group of the Psychiatric Genomics Consortium (PGC-ED). Additional analyses will explore genetic correlations between eating disorders (EDs) and other psychiatric and metabolic traits, calculate polygenic risk scores (PRS), and leverage functional biology to evaluate clinical outcomes. Moreover, analyzing PRS for patient stratification and linking identified risk loci to clinically relevant phenotypes highlight the potential of EDGI2 for clinical translation.

Discussion: EDGI2 is a global expansion of the EDGI study to increase sample size, increase participant representation across multiple ancestral backgrounds, and to include ARFID. ED genetics research has historically lagged behind other psychiatric disorders, and EDGI2 is designed to rapidly advance the study of the genetics of the major EDs. Exploring EDs at both the diagnostic level and the symptom level will provide an unprecedented look at the genetic architecture underlying EDs.

Trial registration: EDGI2 is a registered clinical trial: clinicaltrials.gov NCT06594913. https://clinicaltrials.gov/study/NCT06594913 (posted September 19, 2024).

Keywords: Anorexia nervosa; Avoidant/restrictive food intake disorder; Binge-eating disorder; Bulimia nervosa; Genome-wide association; Psychiatric genetics.

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Conflict of interest statement

Declarations. Ethics approvals and consent to participate: This study is being conducted in accordance with the Helsinki Declaration of 1975, as revised in 2008. Ethical approval for EDGI2 study was obtained by the University of North Carolina at Chapel Hill Biomedical Institutional Review Board (IRB) (Protocol #23–2887); Research Ethics Committee of the School of Medicine of the Monterrey Institute of Technology and Higher Studies (folio: P000552-EDGI-MX- 2021-CEIC-CR009; QIMR Berghofer Human Research Ethics Committee (QIMRB-HREC approval P3550), New Zealand Health and Disability Ethics Committees (Ethics Reference: HDEC20/CEN/1/HDEC20/CEN/1_ 2024 AM 9136), the Swedish Ethical Review Authority (DNR: 2023–00254 - 02), and Danish Scientific Ethics Committee, the Danish Health Data Authority, the Danish data protection agency and the Danish Neonatal Screening Biobank Steering Committee. All participants from US, MX, NZ, AU, and SE will provide informed consent prior to engaging in any study-related activities. The electronic consent process was approved by the ethical committees. Consent for publication: Not applicable. Competing interests: CM Bulik receives royalties from Pearson Education, Inc. PF Sullivan reports Neumora Therapeutics (advisory committee, shareholder). L Dinkler received personal fees from Baxter Medical AB and Fresenius Kabi AB. All other authors report no financial interests or potential conflicts of interest.

References

1. Bulik CM, Thornton LM, Parker R, Kennedy H, Baker JH, MacDermod C, et al. The Eating Disorders Genetics Initiative (EDGI): study protocol. BMC Psychiatry. 2021;21(1):234. - PMC - PubMed
1. Thornton L, Munn-Chernoff M, Baker J, Juréus A, Parker R, Henders A, et al. The Anorexia Nervosa Genetics Initiative (ANGI): Overview and methods. Contemp Clin Trials. 2018;74:61–9. - PMC - PubMed
1. Watson H, Yilmaz Z, Thornton L, Hübel C, Coleman J, Gaspar H, et al. Genome-wide association study identifies eight risk loci and implicates metabo-psychiatric origins for anorexia nervosa. Nat Genet. 2019;51:1207–14. - PMC - PubMed
1. Termorshuizen J, Davies H, Lee S, Huckins L, Bulik C, Breen G, et al. Genome-wide association studies of binge-eating behaviour and anorexia nervosa yield insights into the unique and shared biology of eating disorder phenotypes. medRxiv. 2025. 10.1101/2025.01.31.25321397.
1. Zickgraf HF, Ellis JM. Initial validation of the Nine Item Avoidant/Restrictive Food Intake disorder screen (NIAS): A measure of three restrictive eating patterns. Appetite. 2018;123:32–42. - PubMed

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The Eating Disorders Genetics Initiative 2 (EDGI2): study protocol

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The Eating Disorders Genetics Initiative 2 (EDGI2): study protocol

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Abstract

Conflict of interest statement

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