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

Zheng An Lu; Alexander Ploner; Andreas Birgegård; Eating Disorders Working Group of the Psychiatric Genomics Consortium; Tracey D. Wade; Mikael Landén; Cynthia M. Bulik; Sarah E. Bergen

doi:10.1038/s41380-025-03264-x

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

Zheng An Lu, Alexander Ploner, Andreas Birgegård, Eating Disorders Working Group of the Psychiatric Genomics Consortium, Tracey D. Wade, Mikael Landén, Cynthia M. Bulik, Sarah E. Bergen

College of Education, Psychology and Social Work

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Number of pages	10
Journal	MOLECULAR PSYCHIATRY
DOIs	https://doi.org/10.1038/s41380-025-03264-x
Publication status	E-pub ahead of print - 23 Sept 2025

Keywords

Genetics
Psychiatric disorders

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10.1038/s41380-025-03264-xLicence: CC BY

Final published versionFinal published version, 1.89 MBLicence: CC BY

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Lu, Z. A., Ploner, A., Birgegård, A., Eating Disorders Working Group of the Psychiatric Genomics Consortium, Wade, T. D., Landén, M., Bulik, C. M., & Bergen, S. E. (2025). Leveraging transdiagnostic genetic liability to psychiatric disorders to dissect clinical outcomes of anorexia nervosa. MOLECULAR PSYCHIATRY. Advance online publication. https://doi.org/10.1038/s41380-025-03264-x

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title = "Leveraging transdiagnostic genetic liability to psychiatric disorders to dissect clinical outcomes of anorexia nervosa",

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 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.",

keywords = "Genetics, Psychiatric disorders",

author = "Lu, {Zheng An} and Alexander Ploner and Andreas Birgeg{\aa}rd and {Eating Disorders Working Group of the Psychiatric Genomics Consortium} and Maguire, {Sarah L.} and Stephan Zipfel and Eleftheria Zeggini and Woodside, {D. Blake} and Wichmann, {H. Erich} and Thomas Werge and Watson, {Hunna J.} and Wade, {Tracey D.} and {van Elburg}, Annemarie and Konstantinos Tziouvas and Artemis Tsitsika and Federica Tozzi and Alfonso Tortorella and Tam, {Friederike I.} and Beata {\'S}wi{\c a}tkowska and Stuber, {Garret D.} and Michael Strober and Steen, {Vidar W.} and Nicole Soranzo and Agnieszka Slopien and Marta Tyszkiewicz-Nwafor and {van Furth}, {Eric F.} and Slof-Op{\textquoteright}t, {Margarita C.T.} and Lenka Slachtova and Alexandra Schosser and Schork, {Nicholas J.} and Janet Treasure and Ulrike Schmidt and Scherer, {Stephen W.} and Andr{\'e} Scherag and Paolo Santonastaso and Filip Rybakowski and Alessandro Rotondo and Stephan Ripke and Samuli Ripatti and Valdo Ricca and Ted Reichborn-Kjennerud and Anu Raevuori and Pearson, {John F.} and Jacques Pantel and Aarno Palotie and Julie O{\textquoteright}Toole and Ophoff, {Roel A.} and Olsen, {Catherine M.} and Whiteman, {David C.} and Sandro Sorbi and Benedetta Nacmias and Montgomery, {Grant W.} and Palmiero Monteleone and Karen Mitchell and James Mitchell and Nadia Micali and Ingrid Meulenbelt and Slagboom, {P. Eline} and Andres Metspalu and Sara McDevitt and Manuel Mattheisen and Marshall, {Christian R.} and Katrin Mannik and Mario Maj and Monteleone, {Alessio Maria} and Magistretti, {Pierre J.} and Lundervold, {Astri J.} and Jolanta Lissowska and Lisa Lilenfeld and {Le Hellard}, Stephanie and Mortensen, {Preben Bo} and Petersen, {Liselotte V.} and Larsen, {Janne T.} and Knudsen, {Gun Peggy S.} and Klump, {Kelly L.} and Leonid Padyukov and Lars Klareskog and Richard Parker and Medland, {Sarah E.} and Kirk, {Katherine M.} and Kim, {Youl Ri} and Kirsty Kiezebrink and Anna Keski-Rahkonen and Kennedy, {Martin A.} and Kaye, {Walter H.} and Kas, {Martien J.H.} and Gudrun Wagner and Andreas Karwautz and Leila Karhunen and Elisabeth Widen and Jaakko Kaprio and Kennedy, {James L.} and Kaplan, {Allan S.} and Deborah Kaminsk{\'a} and Hana Papezova and Antonio Juli{\`a} and Sara Marsal and Jennifer Jordan and Craig Johnson and Vladimir Janout and Hidetoshi Inoko and Hartmut Imgart and Hudson, {James I.} and Dalila Pinto and Huckins, {Laura M.} and Johnson, {Jessica S.} and Jiayi Xu and Zeynep Yilmaz and Christopher H{\"u}bel and Wolfgang Herzog and Jochen Seitz and Beate Herpertz-Dahlmann and Anjali Henders and Helder, {Sietske G.} and Anke Hinney and Triinu Peters and Johannes Hebebrand and Joanna Hauser and Konstantinos Hatzikotoulas and Lorraine Southam and Halmi, {Katherine A.} and Hakon Hakonarson and Dong Li and Yiran Guo and Jakob Grove and Martin, {Nicholas G.} and Scott Gordon and Dan Rujescu and Ina Giegling and Giovanni Gambaro and Steven Gallinger and Marie Navratilova and Lenka Foretova and Manuel F{\"o}cker and Floyd, {James A.B.} and Fichter, {Manfred M.} and Susana Jim{\'e}nez-Murcia and Fernando Fern{\'a}ndez-Aranda and Xavier Estivill and Thomas Espeseth and T{\~o}nu Esko and Krista Fischer and Karin Egberts and Nicolas Ramoz and Philip Gorwood and Philibert Duriez and Duncan, {Laramie E.} and Mayora, {Monica Gratacos} and Ge{\`o}rgia Escaram{\'i}s and Elisa Docampo and Monika Dmitrzak-Weglarz and Christian Dina and Fragiskos Gonidakis and Dimitris Dikeos and Dick, {Danielle M.} and DeSocio, {Janiece E.} and Elena Tenconi and Daniela Degortes and Angela Favaro and Ioanna Ntalla and George Dedoussis and Martina deZwaan and Davis, {Oliver S.P.} and Sullivan, {Patrick F.} and Crowley, {James J.} and Szatkiewicz, {Jin P.} and Paola Giusti-Rodr{\'i}quez and Scott Crow and S{\'e}bastien Guillaume and Philippe Courtet and Cone, {Roger D.} and Forstner, {Andreas J.} and Stefan Herms and Sven Cichon and Monica Forzan and Matteo Cassina and Maurizio Clementi and Laura Carlberg and Roland Burghardt and Hanscombe, {Ken B.} and Purves, {Kirstin L.} and Marion Roberts and Coleman, {Jonathan R.I.} and Gaspar, {H{\'e}l{\'e}na A.} and Gerome Breen and Gursharan Kalsi and Peter McGuffin and Anne Farmer and Harry Brandt and Steven Crawford and Perica, {Vesna Boraska} and Ioanna Tachmazidou and Franklin, {Christopher S.} and Stefan Ehrlich and Ilka Boehm and Horwood, {L. John} and Boden, {Joseph M.} and Berrettini, {Wade H.} and Bergen, {Andrew W.} and Vladimir Bencko and Harald Aschauer and Morten Mattingsdal and Andreassen, {Ole A.} and Tetsuya Ando and Lars Alfredsson and Danner, {Unna N.} and Adan, {Roger A.H.} and Jurjen Luykx and Lin, {Bochao Danae} and Munn-Chernoff, {Melissa A.} and {La Via}, {Maria C.} and Thornton, {Laura M.} and Stephanie Zerwas and Baker, {Jessica H.} and Paul Lichtenstein and Lepp{\"a}, {Virpi M.} and Julien Bryois and Shuyang Yao and Pedersen, {Nancy L.} and Mikael Land{\'e}n and Bulik, {Cynthia M.} and Bergen, {Sarah E.}",

year = "2025",

month = sep,

day = "23",

doi = "10.1038/s41380-025-03264-x",

language = "English",

journal = "MOLECULAR PSYCHIATRY",

issn = "1359-4184",

publisher = "Nature",

}

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 - Eating Disorders Working Group of the Psychiatric Genomics Consortium

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 - Olsen, Catherine M.

AU - Whiteman, David C.

AU - Sorbi, Sandro

AU - Nacmias, Benedetta

AU - Montgomery, Grant W.

AU - Monteleone, Palmiero

AU - Mitchell, Karen

AU - Mitchell, James

AU - Micali, Nadia

AU - Meulenbelt, Ingrid

AU - Slagboom, P. Eline

AU - Metspalu, Andres

AU - McDevitt, Sara

AU - Mattheisen, Manuel

AU - Marshall, Christian R.

AU - Mannik, Katrin

AU - Maj, Mario

AU - Monteleone, Alessio Maria

AU - Magistretti, Pierre J.

AU - Lundervold, Astri J.

AU - Lissowska, Jolanta

AU - Lilenfeld, Lisa

AU - Le Hellard, Stephanie

AU - Mortensen, Preben Bo

AU - Petersen, Liselotte V.

AU - Larsen, Janne T.

AU - Knudsen, Gun Peggy S.

AU - Klump, Kelly L.

AU - Padyukov, Leonid

AU - Klareskog, Lars

AU - Parker, Richard

AU - Medland, Sarah E.

AU - Kirk, Katherine M.

AU - Kim, Youl Ri

AU - Kiezebrink, Kirsty

AU - Keski-Rahkonen, Anna

AU - Kennedy, Martin A.

AU - Kaye, Walter H.

AU - Kas, Martien J.H.

AU - Wagner, Gudrun

AU - Karwautz, Andreas

AU - Karhunen, Leila

AU - Widen, Elisabeth

AU - Kaprio, Jaakko

AU - Kennedy, James L.

AU - Kaplan, Allan S.

AU - Kaminská, Deborah

AU - Papezova, Hana

AU - Julià, Antonio

AU - Marsal, Sara

AU - Jordan, Jennifer

AU - Johnson, Craig

AU - Janout, Vladimir

AU - Inoko, Hidetoshi

AU - Imgart, Hartmut

AU - Hudson, James I.

AU - Pinto, Dalila

AU - Huckins, Laura M.

AU - Johnson, Jessica S.

AU - Xu, Jiayi

AU - Yilmaz, Zeynep

AU - Hübel, Christopher

AU - Herzog, Wolfgang

AU - Seitz, Jochen

AU - Herpertz-Dahlmann, Beate

AU - Henders, Anjali

AU - Helder, Sietske G.

AU - Hinney, Anke

AU - Peters, Triinu

AU - Hebebrand, Johannes

AU - Hauser, Joanna

AU - Hatzikotoulas, Konstantinos

AU - Southam, Lorraine

AU - Halmi, Katherine A.

AU - Hakonarson, Hakon

AU - Li, Dong

AU - Guo, Yiran

AU - Grove, Jakob

AU - Martin, Nicholas G.

AU - Gordon, Scott

AU - Rujescu, Dan

AU - Giegling, Ina

AU - Gambaro, Giovanni

AU - Gallinger, Steven

AU - Navratilova, Marie

AU - Foretova, Lenka

AU - Föcker, Manuel

AU - Floyd, James A.B.

AU - Fichter, Manfred M.

AU - Jiménez-Murcia, Susana

AU - Fernández-Aranda, Fernando

AU - Estivill, Xavier

AU - Espeseth, Thomas

AU - Esko, Tõnu

AU - Fischer, Krista

AU - Egberts, Karin

AU - Ramoz, Nicolas

AU - Gorwood, Philip

AU - Duriez, Philibert

AU - Duncan, Laramie E.

AU - Mayora, Monica Gratacos

AU - Escaramís, Geòrgia

AU - Docampo, Elisa

AU - Dmitrzak-Weglarz, Monika

AU - Dina, Christian

AU - Gonidakis, Fragiskos

AU - Dikeos, Dimitris

AU - Dick, Danielle M.

AU - DeSocio, Janiece E.

AU - Tenconi, Elena

AU - Degortes, Daniela

AU - Favaro, Angela

AU - Ntalla, Ioanna

AU - Dedoussis, George

AU - deZwaan, Martina

AU - Davis, Oliver S.P.

AU - Sullivan, Patrick F.

AU - Crowley, James J.

AU - Szatkiewicz, Jin P.

AU - Giusti-Rodríquez, Paola

AU - Crow, Scott

AU - Guillaume, Sébastien

AU - Courtet, Philippe

AU - Cone, Roger D.

AU - Forstner, Andreas J.

AU - Herms, Stefan

AU - Cichon, Sven

AU - Forzan, Monica

AU - Cassina, Matteo

AU - Clementi, Maurizio

AU - Carlberg, Laura

AU - Burghardt, Roland

AU - Hanscombe, Ken B.

AU - Purves, Kirstin L.

AU - Roberts, Marion

AU - Coleman, Jonathan R.I.

AU - Gaspar, Héléna A.

AU - Breen, Gerome

AU - Kalsi, Gursharan

AU - McGuffin, Peter

AU - Farmer, Anne

AU - Brandt, Harry

AU - Crawford, Steven

AU - Perica, Vesna Boraska

AU - Tachmazidou, Ioanna

AU - Franklin, Christopher S.

AU - Ehrlich, Stefan

AU - Boehm, Ilka

AU - Horwood, L. John

AU - Boden, Joseph M.

AU - Berrettini, Wade H.

AU - Bergen, Andrew W.

AU - Bencko, Vladimir

AU - Aschauer, Harald

AU - Mattingsdal, Morten

AU - Andreassen, Ole A.

AU - Ando, Tetsuya

AU - Alfredsson, Lars

AU - Danner, Unna N.

AU - Adan, Roger A.H.

AU - Luykx, Jurjen

AU - Lin, Bochao Danae

AU - Munn-Chernoff, Melissa A.

AU - La Via, Maria C.

AU - Thornton, Laura M.

AU - Zerwas, Stephanie

AU - Baker, Jessica H.

AU - Lichtenstein, Paul

AU - Leppä, Virpi M.

AU - Bryois, Julien

AU - Yao, Shuyang

AU - Pedersen, Nancy L.

AU - Landén, Mikael

AU - Bulik, Cynthia M.

AU - Bergen, Sarah E.

PY - 2025/9/23

Y1 - 2025/9/23

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.

KW - Genetics

KW - Psychiatric disorders

UR - http://www.scopus.com/inward/record.url?scp=105018071077&partnerID=8YFLogxK

U2 - 10.1038/s41380-025-03264-x

DO - 10.1038/s41380-025-03264-x

M3 - Article

C2 - 40983652

AN - SCOPUS:105018071077

SN - 1359-4184

JO - MOLECULAR PSYCHIATRY

JF - MOLECULAR PSYCHIATRY

ER -

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

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