Leveraging transdiagnostic genetic liability to psychiatric disorders to dissect clinical outcomes of anorexia nervosa
Year: 2025
Type: article
Study design: Observational Study
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 shared , PRS AN-specific , PRS OCS-specific , PRS MDD-specific , PRS SCZ-specific and PRS ANX-specific , 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 shared was associated with 9–39% excess risk of disease burden and psychiatric comorbidity, whereas the associations between PRS AN-specific and most clinical outcomes were statistically non-significant. +1 SD increase of PRS MDD-specific 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.
Source: Molecular Psychiatry
Authors: Zheng-An Lu, Alexander Ploner, Andreas Birgegård, Nancy L. Pedersen, Shuyang Yao, Julien Bryois, Virpi M. Leppä, Paul Lichtenstein, Jessica H. Baker, Stephanie Zerwas, Laura M. Thornton, Maria C. La Via, Melissa A. Munn-Chernoff, Bochao Danae Lin, Jurjen Luykx, Roger A. H. Adan, Unna N. Danner, Lars Alfredsson, Tetsuya Ando, Ole A. Andreassen, Morten Mattingsdal, Harald Aschauer, Vladimir Bencko, Andrew W. Bergen, Wade H. Berrettini, Joseph M. Boden, L. John Horwood, Ilka Boehm, Stefan Ehrlich, Christopher S. Franklin, Ioanna Tachmazidou, Vesna Boraska Perica, Steven Crawford, Harry Brandt, Anne Farmer, Peter McGuffin, Gursharan Kalsi, Gerome Breen, Héléna A. Gaspar, Jonathan R. I. Coleman, Marion Roberts, Kirstin L. Purves, Ken B. Hanscombe, Roland Burghardt, Laura Carlberg, Maurizio Clementi, Matteo Cassina, Monica Forzan, Sven Cichon, Stefan Herms, Andreas J. Forstner, Roger D. Cone, Philippe Courtet, Sébastien Guillaume, Scott Crow, Paola Giusti-Rodríquez, Jin P. Szatkiewicz, James J. Crowley, Patrick F. Sullivan, Oliver S. P. Davis, Martina deZwaan, George Dedoussis, Ioanna Ntalla, Angela Favaro, Daniela Degortes, Elena Tenconi, Janiece E. DeSocio, Danielle M. Dick, Dimitris Dikeos, Fragiskos Gonidakis, Christian Dina, Monika Dmitrzak-Weglarz, Elisa Docampo, Geòrgia Escaramís, Monica Gratacos Mayora, Laramie E. Duncan, Philibert Duriez, Philip Gorwood, Nicolas Ramoz, Karin Egberts, Krista Fischer, Tõnu Esko, Thomas Espeseth, Xavier Estivill, Fernando Fernández-Aranda, Susana Jiménez-Murcia, Manfred M. Fichter, James A. B. Floyd, Manuel Föcker, Lenka Foretova, Marie Navratilova, Steven Gallinger, Giovanni Gambaro, Ina Giegling, Dan Rujescu, Scott Gordon, Nicholas G. Martin, Jakob Grove, Yiran Guo, Dong Li, Hakon Hakonarson, Katherine A. Halmi, Lorraine Southam, Konstantinos Hatzikotoulas, Joanna Hauser, Johannes Hebebrand, Triinu Peters, Anke Hinney, Sietske G. Helder, Anjali Henders, Beate Herpertz-Dahlmann, Jochen Seitz, Wolfgang Herzog, Christopher Hübel, Zeynep Yilmaz, Jiayi Xu, Jessica S. Johnson, Laura M. Huckins, Dalila Pinto, James I. Hudson, Hartmut Imgart, Hidetoshi Inoko, Vladimir Janout, Craig Johnson, Jennifer Jordan, Sara Marsal, Antonio Julià, Hana Papezova, Deborah Kaminská, Allan S. Kaplan, James L. Kennedy, Jaakko Kaprio, Elisabeth Widen, Leila Karhunen, Andreas Karwautz, Gudrun Wagner, Martien J. H. Kas, Walter H. Kaye, Martin A. Kennedy, Anna Keski-Rahkonen, Kirsty Kiezebrink, Youl-Ri Kim, Katherine M. Kirk, Sarah E. Medland, Richard Parker, Lars Klareskog, Leonid Padyukov, Kelly L. Klump, Gun Peggy S. Knudsen, Janne T. Larsen, Liselotte V. Petersen, Preben Bo Mortensen, Stephanie Le Hellard, Lisa Lilenfeld, Jolanta Lissowska, Astri J. Lundervold, Pierre J. Magistretti, Alessio Maria Monteleone, Mario Maj, Katrin Mannik, Christian R. Marshall, Manuel Mattheisen, Sara McDevitt, Andres Metspalu, P. Eline Slagboom, Ingrid Meulenbelt, Nadia Micali, James Mitchell, Karen Mitchell, Palmiero Monteleone, Grant W. Montgomery, Benedetta Nacmias, Sandro Sorbi, David C. Whiteman, Catherine M. Olsen, Roel A. Ophoff, Julie O’Toole, Aarno Palotie, Jacques Pantel, John F. Pearson, Anu Raevuori, Ted Reichborn-Kjennerud, Valdo Ricca, Samuli Ripatti, Stephan Ripke, Alessandro Rotondo, Filip Rybakowski, Paolo Santonastaso, André Scherag, Stephen W. Scherer, Ulrike Schmidt, Janet Treasure, Nicholas J. Schork, Alexandra Schosser, Lenka Slachtova, Margarita C. T. Slof-Op’t, Eric F. van Furth, Marta Tyszkiewicz-Nwafor, Agnieszka Slopien, Nicole Soranzo, Vidar W. Steen, Michael Strober, Garret D. Stuber, Beata Świątkowska, Friederike I. Tam, Alfonso Tortorella, Federica Tozzi, Artemis Tsitsika, Konstantinos Tziouvas, Annemarie van Elburg, Tracey D. Wade, Hunna J. Watson, Thomas Werge, H-Erich Wichmann, D. Blake Woodside, Eleftheria Zeggini, Stephan Zipfel, Sarah L. Maguire, Mikael Landén, Cynthia M. Bulik, Sarah E. Bergen
Institutions: Karolinska Institutet, University of North Carolina at Chapel Hill, University Medical Center Utrecht, Altrecht GGZ, University of Gothenburg, National Center of Neurology and Psychiatry, National Institute of Mental Health, Oslo University Hospital, University of Oslo, Charles University, Oregon Research Institute, BioRealm (United States), University of Pennsylvania, University of Otago, Technische Universität Dresden, Wellcome Sanger Institute, University of Split, Sheppard and Enoch Pratt Hospital, King's College London, National Health Service, National Institute for Health and Care Research, Medical University of Vienna, University of Padua, Forschungszentrum Jülich, University of Basel, University Hospital of Basel, University of Bonn, Philipps University of Marburg, University Hospital Bonn, University of Michigan, Université de Montpellier, Centre Hospitalier Universitaire de Montpellier, University of Minnesota, University of Bristol, The Alan Turing Institute, MRC Integrative Epidemiology Unit, Medizinische Hochschule Hannover, Harokopio University of Athens, Seattle University, Virginia Commonwealth University, National and Kapodistrian University of Athens, Eginition Hospital, Centre National de la Recherche Scientifique, Inserm, Institut du Thorax, Nantes Université, Poznan University of Medical Sciences, Universitat Pompeu Fabra, Barcelona Institute of Science and Technology, Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública, Stanford Medicine, Stanford University, Université Paris Cité, Institut de Psychiatrie et Neurosciences de Paris, Université Paris Descartes, Universitätsklinikum Würzburg, University of Tartu, Broad Institute, Harvard University, Massachusetts Institute of Technology, Oslo Nye Høyskole, Centre for Genomic Regulation, Bellvitge University Hospital, Institut d'Investigació Biomédica de Bellvitge, Universitat de Barcelona, Schön Klinik Roseneck, Ludwig-Maximilians-Universität München, Genomics (United Kingdom), University of Münster, Masaryk Memorial Cancer Institute, University of Toronto, Martin Luther University Halle-Wittenberg, QIMR Berghofer Medical Research Institute, Aarhus University, Lundbeck Foundation, Children's Hospital of Philadelphia, Weill Cornell Medicine, Helmholtz Munich, Essen University Hospital, University of Duisburg-Essen, The University of Queensland, Institute for Molecular Bioscience, RWTH Aachen University, Heidelberg University, University Hospital Heidelberg, Yale University, Icahn School of Medicine at Mount Sinai, James J. Peters VA Medical Center, Mental Illness Research, Education and Clinical Centers, McLean Hospital, Tokai University, Palacký University Olomouc, Canterbury District Health Board, Vall d'Hebron Institut de Recerca, Centre for Addiction and Mental Health, University of Helsinki, University of Eastern Finland, Institute for Molecular Medicine Finland, HiLIFE – Elämäntieteiden Instituutti, University of Groningen, University of California San Diego, University of Aberdeen, Inje University Seoul Paik Hospital, Karolinska University Hospital, Michigan State University, Norwegian Institute of Public Health, Haukeland University Hospital, The Chicago School, The Maria Sklodowska-Curie National Research Institute of Oncology, University of Bergen, Centre Hospitalier Universitaire Vaudois, King Abdullah University of Science and Technology, University of Lausanne, University of Campania "Luigi Vanvitelli", Hospital for Sick Children, University of Würzburg, Stockholm Health Care Services, University College Cork, Health Service Executive, Leiden University Medical Center, Sankt Hans Hospital, Mental Health Services, Copenhagen University Hospital, University of North Dakota, Boston University, VA Boston Healthcare System, University of Salerno, Don Carlo Gnocchi Foundation, University of Florence, University of California, Los Angeles, Erasmus MC, Massachusetts General Hospital, Health and Functional Exposomics, Helsinki University Hospital, Stanley Center for Psychiatric Research, Charité – Universitätsmedizin Berlin, University of Pisa, Jena University Hospital, J. Craig Venter Institute, University of Cambridge, British Heart Foundation, Nofer Institute of Occupational Medicine, University of Perugia, Panagiotis & Aglaia Kyriakou Children's Hospital, Utrecht University, Flinders University, The University of Western Australia, Curtin University, University of Copenhagen, University Health Network, TUM Klinikum, Technical University of Munich, Universitätsklinikum Tübingen, University of Tübingen, The University of Sydney
Language: English
Subfield: Clinical Psychology
Field: Psychology
Domain: Social Sciences
Open Access status: hybrid
Estimated APC paid: $5,490
Funders: Klarman Family Foundation, Children's Hospital of Philadelphia, Massachusetts Institute of Technology, University of Pennsylvania, Harvard University, Aarhus Universitet, Virginia Commonwealth University, QIMR Berghofer Medical Research Institute, Broad Institute, Universitat Pompeu Fabra, Institut National de la Santé et de la Recherche Médicale, Lundbeckfonden, University of Toronto, Karolinska Institutet, Vetenskapsrådet, China Scholarship Council, Centre National de la Recherche Scientifique, Westfälische Wilhelms-Universität Münster, National and Kapodistrian University of Athens, Universitetet i Oslo, Université Paris Descartes, Universitat de Barcelona, RWTH Aachen University, Tartu Ülikool, Universität Duisburg-Essen, Uniwersytet Medyczny im. Karola Marcinkowskiego w Poznaniu, H. Lundbeck A/S, Weill Cornell Medical College, Perelman School of Medicine, University of Pennsylvania, Helmholtz Zentrum München, Institute for Molecular Bioscience, University Of Queensland, Uppsala Multidisciplinary Center for Advanced Computational Science, National Institute of Mental Health
Awards: G103800658, G1181994271, G1375331873, Eating Disorders Genetics Initiative (EDGI), G211885902, Leveraging shared genetic risk for schizophrenia and anorexia nervosa to understand clinical heterogeneity, G2417586468, G2953470886, G303339423, G3197369316, G3298186876, G3321450376, G3964009410, G4034426326, Predicting Binge and Purge Episodes from Passive and Active Apple Watch Data Using a Dynamical Systems Approach, G4377315820, G4670273794, G5012122282, G5197328387, Genetic Architecture of Avoidant/Restrictive Food Intake Disorder, G5408826359, G5663011202, G5680944848, G6235201806, G6830658824, G712881263, G7209062417, G796431723, Predicting the multi-omic impact of psychiatric GWAS associations, G8819238061, NAISS, 1/7 PGC: Advancing Discovery and Impact
OpenAlex ID: W4414446769