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

[en] 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 PRSshared, PRSAN-specific, PRSOCS-specific, PRSMDD-specific, PRSSCZ-specific and PRSANX-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 PRSshared was associated with 9-39% excess risk of disease burden and psychiatric comorbidity, whereas the associations between PRSAN-specific and most clinical outcomes were statistically non-significant. +1 SD increase of PRSMDD-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.

Disciplines :

Genetics & genetic processes

Author, co-author :

Lu, Zheng-An; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden

Ploner, Alexander ; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden

Birgegård, Andreas ; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden

Eating Disorders Working Group of the Psychiatric Genomics Consortium

Landén, Mikael ; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden ; Institute of Neuroscience and Physiology, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden

Bulik, Cynthia M ; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden ; Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA ; Department of Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

Bergen, Sarah E ; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden. Sarah.Bergen@ki.se

Docampo Martínez, Elisa ; Université de Liège - ULiège > Département des sciences cliniques ; Centre Hospitalier Universitaire de Liège - CHU > > Service de génétique

Language :

English

Title :

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

Publication date :

23 September 2025

Journal title :

Molecular Psychiatry

ISSN :

1359-4184

eISSN :

1476-5578

Publisher :

Springer Nature, England

Peer reviewed :

Peer Reviewed verified by ORBi

Additional URL :

https://www.nature.com/articles/s41380-025-03264-x.pdf

Funding text :

Cynthia M. Bulik reports: Lundbeckfonden (grant recipient); Pearson (author, royalty recipient); Equip Health Inc. (Stakeholder Advisory Board). Other authors declare no conflict of interest.This study was funded by the Chinese Scholarship Council (CSC202206010089) and Vetenskapsr\u00E5det 2021-03126 (PI: Sarah E. Bergen). Cynthia M. Bulik is supported by NIMH (R56MH129437; R01MH120170; R01MH124871; R01MH119084; R01MH118278; R01MH124871); Swedish Research Council (Vetenskapsr\u00E5det, award: 538-2013-8864); Lundbeck Foundation (Grant no. R276-2018-4581). The Anorexia Nervosa Genetics Initiative (ANGI) was an initiative of the Klarman Family Foundation. We acknowledge and thank Stina Borg for her support on ANGI data extraction, as well as Ruyue Zhang for her analytic support and data curation. The computations and data handling were enabled by resources provided by the National Academic Infrastructure for Supercomputing in Sweden (NAISS) and the Swedish National Infrastructure for Computing (SNIC) at Uppsala Multidisciplinary Center for Advanced Computational Science (UPPMAX) partially funded by the Swedish Research Council through grant agreements no. 2022-06725 and no. 2018-05973. The funding organizations had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. Open access funding provided by Karolinska Institute.

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since 13 January 2026

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