Leveraging transdiagnostic genetic liability to psychiatric disorders to dissect clinical outcomes of anorexia nervosa

Anorexia nervosa (AN) has extensive genetic correlations with other psychiatric disorders, and genetic risk for different psychiatric disorders was associated with distinct clinical courses in AN. Uncovering associations between transdiagnostic psychiatric genetic liability and AN outcomes can facilitate its personalized treatment. In this study, we investigated the associations between transdiagnostic psychiatric genetic liability and outcomes of AN. Genomic structural equation models were fitted to genome-wide association data for AN and psychiatric disorders with high genetic correlations with AN (obsessive-compulsive symptoms [OCS], major depressive disorder [MDD], schizophrenia, and anxiety disorders) to extract one shared and five trait-specific genetic components. Next, we calculated the polygenic risk scores (PRS) for these components, including PRS<sub>shared</sub>, PRS<sub>AN-specific</sub>, PRS<sub>OCS-specific</sub>, PRS<sub>MDD-specific</sub>, PRS<sub>SCZ-specific</sub> and PRS<sub>ANX-specific</sub>, which index the shared genetic liability to all five psychiatric traits, and genetic liability specific to AN, OCS, MDD, SCZ and ANX, respectively. We then tested associations between these PRSs and clinical outcomes reported between 1997 and 2018 among AN cases from the Anorexia Nervosa Genetics Initiative (ANGI), linked to Swedish National Registers. The clinical outcomes included cumulative disease burden (i.e., number of diagnoses, medication prescriptions, and inpatient days), risks of psychiatric comorbidities, and AN symptomatology. Among 4028 included AN cases, the mean (SD) birth year was 1985 (9), and 3947 (98.0%) were female. Within AN, +1 SD increase of PRS<sub>shared</sub> was associated with 9-39% excess risk of disease burden and psychiatric comorbidity, whereas the associations between PRS<sub>AN-specific</sub> and most clinical outcomes were statistically non-significant. +1 SD increase of PRS<sub>MDD-specific</sub> was associated with 3-29% increased risk of AN disease burden. Our findings show that shared psychiatric liability is associated with more adverse AN outcomes, whereas AN-specific liability is not a good indicator for its clinical course. This study provides a novel perspective on factors influencing heterogeneity in AN clinical course.

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Journal
Molecular Psychiatry
Published
2025-09-23
DOI
https://doi.org/10.1038/s41380-025-03264-x
Primary Topic
Eating Disorders and Behaviors
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article
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0.00

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article

Leveraging transdiagnostic genetic liability to psychiatric disorders to dissect clinical outcomes of anorexia nervosa

Stefan Ehrlich, Hartmut Imgart, Beata Świątkowska, André Scherag et al.
Molecular Psychiatry
Eating Disorders and Behaviors
article

Leveraging transdiagnostic genetic liability to psychiatric disorders to dissect clinical outcomes of anorexia nervosa

Stefan Ehrlich, Hartmut Imgart, Beata Świątkowska, André Scherag, Jolanta Lissowska, Joanna Hauser, Jaakko A. Kaprio, Cynthia Marie Bulik, Ted Reichborn‐Kjennerud, Anke Hinney, Fernando Fernández‐Aranda, Kirsty Kiezebrink, Annemarie van Elburg, Laura M. Huckins, Zeynep Yılmaz, Tōnu Esko, Janet Treasure, Gudrun Wagner, Gerome D. Breen, Karen S. Mitchell, Nicolás Ramoz, Oliver S. P. Davis, Anjali K. Henders, Stéphanie Le Hellard, Virpi Leppä, Beate Herpertz‐Dahlmann, Janne Tidselbak Larsen, Alexander Ploner, Héléna A. Gaspar, Sandro Sorbi, Nancy L. Pedersen, Sarah Elizabeth Medland, Jennifer Jordan, Nicholas G. Martin, Vladimír Bencko, Katherine M. Kirk, Leila Karhunen, L. John Horwood, Yiran Guo, Steven Gallinger, Preben Bo Mortensen, Lisa Lilenfeld, Katherine A. Halmi, Sara McDevitt, Leonid Padyukov, Sarah Maguire, Jin Szatkiewicz, Danielle M. Dick, D. Blake Woodside, Alfonso Tortorella, Jurjen J. Luykx, Maria C. La Via, Roel A. Ophoff, Manfred M. Fichter, Mikael Landén, Monica Forzan, Nadia Micali, Laramie E. Duncan, Andreas Birgegård, Triinu Peters, Harry Brandt, David C. Whiteman, Άρτεμις Τσίτσικα, Andreas Karwautz, Hunna J. Watson, Sébastien Guillaume, Xavier Estivill, Eleftheria Zeggini, Philibert Duriez, Stefan Herms, Roger A.H. Adan, Christian Dina, Angela Favaro, Samuli Ripatti, Sara Marsal, Pierre Julius Magistretti, Monika Dmitrzak‐Węglarz, Philip A. P. M. Gorwood, Johannes Hebebrand, Nicole Soranzo, Anna Keski‐Rahkonen, Kirstin L. Purves, Wolfgang Herzog, Palmiero Monteleone, Stephan Ripke, Grant W. Montgomery, Lenka Foretová, Konstantinos Hatzikotoulas, Marta Tyszkiewicz‐Nwafor, Giovanni Gambaro, Catherine M. Olsen, Susana Jiménez‐Múrcia, Ιωάννα Ντάλλα, Paul Lichtenstein, Deborah Kaminská, Sarah E. Bergen, Garret D. Stuber, Joseph M. Boden, Martin Alexander Kennedy, Andreas J. Forstner, Stephen W. Scherer, Jakob Grove, James J. Crowley, Scott J. Crow, Daniela Degortes, Thomas Werge, Hidetoshi Inoko, Monica Gratacos Mayora, Roger D. Cone, Gursharan Kalsi, Lenka Šlachtová, Christian R. Marshall, James L. Kennedy, Martien J. Kas, Astri J. Lundervold, Vladimí­r Janout, Eric F. van Furth, Valdo Ricca, Elisa Docampo, Benedetta Nacmias, Ken B. Hanscombe, Jochen Seitz, Krista Fischer, Karin Egberts, Janiece DeSocio, Laura Carlberg, Alessio Maria Monteleone, Youl‐Ri Kim, Antonio Julià, Elisabeth Widén, Richard Anthony Parker, Scott D. Gordon, Matteo Cassina, Anu Raevuori, Martina DeZwaan, Lars S. Alfredsson, Julien Bryois, Melissa A. Munn‐Chernoff, P. Eline Slagboom, Lars Klareskog, Steven Crawford, Hana Papežová, James I. Hudson, Walter H. Kaye, Fragiskos Gonidakis, Manuel Föcker, Laura M. Thornton, Vesna Boraska Perica, Nicholas J. Schork, Christopher Hübel, Jonathan R. I. Coleman, Bochao Danae Lin, Andres Metspalu, Roland Burghardt, Friederike I. Tam, Andrew W. Bergen, Paolo Santonastaso, Liselotte Vogdrup Petersen, Aarno V. Palotie, Unna N. Danner, Alexandra Schosser, Morten Mattingsdal, Jiayi Xu, Dalila Pinto, John F. Pearson, Jessica Johnson, H.N. Aschauer, Manuel Mattheisen, Jessica H. Baker, Lorraine Southam, Katrin Männik, John C. Mitchell, Zheng-An Lu, Dong Li, Wade H. Berrettini, Ingrid Meulenbelt, Ilka Boehm, Tetsuya Ando, Alessandro Rotondo, Kelly L. Klump, Mario Maj, Maurizio Clementi, Konstantinos Tziouvas, Ina Giegling, Patrick F. Sullivan, Paola Giusti-Rodríquez, Sven Cichon, Michael Strober, Philippe Courtet, Thomas Espeseth, Gun Peggy Knudsen, Dan Rujescu, Federica Tozzi, Shuyang Yao, Christopher S. Franklin, Sietske G. Helder, Geòrgia Escaramís, Jacques Pantel, Ulrike Schmidt, Stephan Zipfel, Agnieszka Slopien, Tracey D. Wade, Filip Rybakowski, H‐Erich Wichmann, Craig Johnson, Marion Roberts, Dimitris Dikeos, Marie Navratilova, Elena Tenconi, Vidar W. Steen, Peter McGuffin, Ioanna Tachmazidou, Julie O’Toole, Anne Farmer, Hakon Hakonarson, Allan S. Kaplan, George Dedoussis, James Floyd, Stephanie Zerwas, Ole A. Andreassen, Margarita C. T. Slof-Op’t
article en

Abstract

Anorexia nervosa (AN) has extensive genetic correlations with other psychiatric disorders, and genetic risk for different psychiatric disorders was associated with distinct clinical courses in AN. Uncovering associations between transdiagnostic psychiatric genetic liability and AN outcomes can facilitate its personalized treatment. In this study, we investigated the associations between transdiagnostic psychiatric genetic liability and outcomes of AN. Genomic structural equation models were fitted to genome-wide association data for AN and psychiatric disorders with high genetic correlations with AN (obsessive-compulsive symptoms [OCS], major depressive disorder [MDD], schizophrenia, and anxiety disorders) to extract one shared and five trait-specific genetic components. Next, we calculated the polygenic risk scores (PRS) for these components, including PRS<sub>shared</sub>, PRS<sub>AN-specific</sub>, PRS<sub>OCS-specific</sub>, PRS<sub>MDD-specific</sub>, PRS<sub>SCZ-specific</sub> and PRS<sub>ANX-specific</sub>, which index the shared genetic liability to all five psychiatric traits, and genetic liability specific to AN, OCS, MDD, SCZ and ANX, respectively. We then tested associations between these PRSs and clinical outcomes reported between 1997 and 2018 among AN cases from the Anorexia Nervosa Genetics Initiative (ANGI), linked to Swedish National Registers. The clinical outcomes included cumulative disease burden (i.e., number of diagnoses, medication prescriptions, and inpatient days), risks of psychiatric comorbidities, and AN symptomatology. Among 4028 included AN cases, the mean (SD) birth year was 1985 (9), and 3947 (98.0%) were female. Within AN, +1 SD increase of PRS<sub>shared</sub> was associated with 9-39% excess risk of disease burden and psychiatric comorbidity, whereas the associations between PRS<sub>AN-specific</sub> and most clinical outcomes were statistically non-significant. +1 SD increase of PRS<sub>MDD-specific</sub> was associated with 3-29% increased risk of AN disease burden. Our findings show that shared psychiatric liability is associated with more adverse AN outcomes, whereas AN-specific liability is not a good indicator for its clinical course. This study provides a novel perspective on factors influencing heterogeneity in AN clinical course.

Molecular PsychiatryVol. 31(3)
Broad Institute (US), University of Pisa (IT), Boston University (US), University of North Carolina at Chapel Hill (US), Poznan University of Medical Sciences (PL), University of Copenhagen (DK), National Health Service (GB), Oslo University Hospital (NO), Centre National de la Recherche Scientifique (FR), The University of Sydney (AU), J. Craig Venter Institute (US), University of Minnesota (US), Tokai University (JP), University of Salerno (IT), Oregon Research Institute (US), University Health Network (CA), Norwegian Institute of Public Health (NO), Karolinska University Hospital (SE), Children's Hospital of Philadelphia (US), University of Helsinki (FI), Centre for Addiction and Mental Health (CA), University of Bonn (DE), Harvard University (US), University of Padua (IT), Inserm (FR), Philipps University of Marburg (DE), University of California, Los Angeles (US), The University of Queensland (AU), University of Groningen (NL), Flinders University (AU), Universitat Pompeu Fabra (ES), Forschungszentrum Jülich (DE), University of Eastern Finland (FI), The University of Western Australia (AU), King's College London (GB), Virginia Commonwealth University (US), University of Oslo (NO), University of Basel (CH), University of Toronto (CA), Utrecht University (NL), University of Aberdeen (GB), University of Campania "Luigi Vanvitelli" (IT), Université de Montpellier (FR), National and Kapodistrian University of Athens (GR), Aarhus University (DK), Université Paris Cité (FR), Curtin University (AU), Cornell University (US), Nofer Institute of Occupational Medicine (PL), Charles University (CZ), QIMR Berghofer Medical Research Institute (AU), Heidelberg University (DE), University of Münster (DE), University of Cambridge (GB), University of North Dakota (US), University of Würzburg (DE), University of Perugia (IT), University College Cork (IE), University of Michigan (US), University Hospital Bonn (DE), Leiden University Medical Center (NL), Helsinki University Hospital (FI), Sankt Hans Hospital (DK), Sheppard and Enoch Pratt Hospital (US), Haukeland University Hospital (NO), Mental Health Services (DK), McLean Hospital (US), Hospital for Sick Children (CA), VA Boston Healthcare System (US), Stockholm County Council (SE), Erasmus MC (NL), Bellvitge University Hospital (ES), University Hospital Heidelberg (DE), Centre Hospitalier Universitaire Vaudois (CH), Wellcome Sanger Institute (GB), University Hospital of Basel (CH), TUM Klinikum (DE), Center for Environmental Health (US), Karolinska Institutet (SE), Helmholtz Zentrum München (DE), University Medical Center Utrecht (NL), British Heart Foundation (GB), Harokopio University of Athens (GR), Yale University (US), Medizinische Hochschule Hannover (DE), National Institute for Health and Care Research (GB), University of Bristol (GB), University of California San Diego (US), Health Service Executive (IE), Institut d'Investigació Biomédica de Bellvitge (ES), Ospedale Maggiore (IT), Massachusetts General Hospital (US), Schön Klinik Roseneck (DE), Vall d'Hebron Institut de Recerca (ES), National Center of Neurology and Psychiatry (JP), National Center for PTSD (US), Oregon Clinic (US), BioRealm (United States) (US), Masaryk Memorial Cancer Institute (CZ), James J. Peters VA Medical Center (US), Don Carlo Gnocchi Foundation (IT), Klinikum Frankfurt Höchst (DE), The Recovery Center (US), Mental Illness Research, Education and Clinical Centers (US), Universitätsklinikum Würzburg (DE), GGZ Rivierduinen (NL), Lundbeck Foundation (DK), Oslo Nye Høyskole (NO), The Alan Turing Institute (GB), Institut de Psychiatrie et Neurosciences de Paris (FR), Barcelona Institute of Science and Technology (ES), Institute for Molecular Medicine Finland (FI), Jena University Hospital (DE), Stockholm Health Care Services (SE), Centre for Genomic Regulation (ES), Eginition Hospital (GR), Institut du Thorax (FR), FHU Neurovasc (FR), STZ eyetrial (DE), The Maria Sklodowska-Curie National Research Institute of Oncology (PL), Werner-Wicker-Klinik (DE), Genomics (United Kingdom) (GB), Altrecht GGZ (NL), Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública (ES), MRC Epidemiology Unit (GB), Panagiotis & Aglaia Kyriakou Children's Hospital (GR), Canterbury District Health Board (NZ), National Institute of Mental Health (JP), Inje University Seoul Paik Hospital (KR), University of Bergen (NO), University of Florence (IT), University of Tartu (EE), Seattle University (US), University of Duisburg-Essen (DE), Technical University of Munich (DE), Martin Luther University Halle-Wittenberg (DE), Palacký University Olomouc (CZ), King Abdullah University of Science and Technology (SA), Universitat de Barcelona (ES), Medical University of Vienna (AT), Technische Universität Dresden (DE), Charité - Universitätsmedizin Berlin (DE), University of Pennsylvania (US), University of Otago (NZ), University of Tübingen (DE), Ludwig-Maximilians-Universität München (DE), Michigan State University (US), University of Gothenburg (SE), RWTH Aachen University (DE), The Chicago School (US), University of Split (HR), Stanford University (US), University of Lausanne (CH), Icahn School of Medicine at Mount Sinai (US)
Lundbeckfonden, Karolinska Institutet, Vetenskapsrådet, China Scholarship Council, H. Lundbeck A/S, Uppsala Multidisciplinary Center for Advanced Computational Science, National Institute of Mental Health
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