TY - JOUR
T1 - Leveraging transdiagnostic genetic liability to psychiatric disorders to dissect clinical outcomes of anorexia nervosa
AU - Lu, Zheng An
AU - Ploner, Alexander
AU - Birgegård, Andreas
AU - Maguire, Sarah L.
AU - Zipfel, Stephan
AU - Zeggini, Eleftheria
AU - Woodside, D. Blake
AU - Wichmann, H. Erich
AU - Werge, Thomas
AU - Watson, Hunna J.
AU - Wade, Tracey D.
AU - van Elburg, Annemarie
AU - Tziouvas, Konstantinos
AU - Tsitsika, Artemis
AU - Tozzi, Federica
AU - Tortorella, Alfonso
AU - Tam, Friederike I.
AU - Świątkowska, Beata
AU - Stuber, Garret D.
AU - Strober, Michael
AU - Steen, Vidar W.
AU - Soranzo, Nicole
AU - Slopien, Agnieszka
AU - Tyszkiewicz-Nwafor, Marta
AU - van Furth, Eric F.
AU - Slof-Op’t, Margarita C.T.
AU - Slachtova, Lenka
AU - Schosser, Alexandra
AU - Schork, Nicholas J.
AU - Treasure, Janet
AU - Schmidt, Ulrike
AU - Scherer, Stephen W.
AU - Scherag, André
AU - Santonastaso, Paolo
AU - Rybakowski, Filip
AU - Rotondo, Alessandro
AU - Ripke, Stephan
AU - Ripatti, Samuli
AU - Ricca, Valdo
AU - Reichborn-Kjennerud, Ted
AU - Raevuori, Anu
AU - Pearson, John F.
AU - Pantel, Jacques
AU - Palotie, Aarno
AU - O’Toole, Julie
AU - Ophoff, Roel A.
AU - Kas, Martien J.H.
AU - Adan, Roger A.H.
AU - Luykx, Jurjen
AU - Lin, Bochao Danae
N1 - Publisher Copyright:
© The Author(s) 2025.
PY - 2026/3
Y1 - 2026/3
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/105018071077
U2 - 10.1038/s41380-025-03264-x
DO - 10.1038/s41380-025-03264-x
M3 - Article
C2 - 40983652
AN - SCOPUS:105018071077
SN - 1359-4184
VL - 31
SP - 1475
EP - 1484
JO - Molecular Psychiatry
JF - Molecular Psychiatry
IS - 3
ER -