Shared Genetic Architecture Between Schizophrenia and Anorexia Nervosa: A Cross-trait Genome-Wide Analysis
Authors: Lu Zheng-An , Ploner Alexander , Birgegård Andreas ,   Eating Disorders Working Group of the Psychiatric Genomics Consortium, Adan Roger , Alfredsson Lars , Ando Tetsuya , Andreassen Ole , Baker Jessica , Bergen Andrew , Berrettini Wade , Birgegård Andreas , Boden Joseph , Boehm Ilka , Perica Vesna Boraska , Brandt Harry , Breen Gerome , Bryois Julien , Buehren Katharina , Bulik Cynthia , Burghardt Roland , Cassina Matteo , Cichon Sven , Coleman Jonathan , Cone Roger , Courtet Philippe , Crawford Steven , Crow Scott , Crowley James , Danner Unna , Davis Oliver , de Zwaan Martina , Dedoussis George , DeSocio Janiece , Dick Danielle , Dikeos Dimitris , Dina Christian , Dmitrzak-Weglarz Monika , Docampo Elisa , Duncan Laramie , Egberts Karin , Ehrlich Stefan , Escaramís Geòrgia , Esko Tõnu , Estivill Xavier , Farmer Anne , Favaro Angela , Fernández-Aranda Fernando , Fischer Krista , Föcker Manuel , Foretova Lenka , Forstner Andreas , Forzan Monica , Franklin Christopher , Gallinger Steven , Giegling Ina , Giusti-Rodríguez Paola , Gonidakis Fragiskos , Gordon Scott , Gorwood Philip , Mayora Monica Gratacos , Grove Jakob , Guillaume Sébastien , Guo Yiran , Hakonarson Hakon , Halmi Katherine , Hanscombe Ken , Hatzikotoulas Konstantinos , Hauser Joanna , Hebebrand Johannes , Helder Sietske , Herms Stefan , Herpertz-Dahlmann Beate , Herzog Wolfgang , Hinney Anke , Horwood L John , Hübel Christopher , Huckins Laura , Hudson James , Imgart Hartmut , Inoko Hidetoshi , Janout Vladimir , Jiménez-Murcia Susana , Johnson Craig , Jordan Jennifer , Julià Antonio , Kalsi Gursharan , Kaminská Deborah , Kaplan Allan , Kaprio Jaakko , Karhunen Leila , Karwautz Andreas , Kas Martien , Kaye Walter , Kennedy James , Kennedy Martin , Keski-Rahkonen Anna , Kiezebrink Kirsty , Kim Youl-Ri , Klareskog Lars , Klump Kelly , Landén Mikael , Larsen Janne , Le Hellard Stephanie , Leppä Virpi , Li Dong , Lichtenstein Paul , Lilenfeld Lisa , Lin Bochao Danae , Lissowska Jolanta , Luykx Jurjen , Maj Mario , Marsal Sara , Martin Nicholas , Mattheisen Manuel , Mattingsdal Morten , Medland Sarah , Metspalu Andres , Meulenbelt Ingrid , Micali Nadia , Mitchell Karen , Mitchell James , Monteleone Alessio Maria , Monteleone Palmiero , Mortensen Preben Bo , Munn-Chernoff Melissa , Nacmias Benedetta , Navratilova Marie , Ntalla Ioanna , Olsen Catherine , Ophoff Roel , Padyukov Leonid , Pantel Jacques , Papezova Hana , Parker Richard , Pearson John , Pedersen Nancy , Petersen Liselotte , Pinto Dalila , Purves Kirstin , Raevuori Anu , Ramoz Nicolas , Reichborn-Kjennerud Ted , Ricca Valdo , Ripatti Samuli , Ripke Stephan , Ritschel Franziska , Roberts Marion , Rujescu Dan , Rybakowski Filip , Santonastaso Paolo , Scherag André , Scherer Stephen , Schmidt Ulrike , Schork Nicholas , Schosser Alexandra , Seitz Jochen , Slachtova Lenka , Slagboom P Eline , Landt Margarita Slof-Op 't , Slopien Agnieszka , Sorbi Sandro , Strober Michael , Sullivan Patrick , Świątkowska Beata , Szatkiewicz Jin , Tenconi Elena , Thornton Laura , Tortorella Alfonso , Treasure Janet , Tsitsika Artemis , Tyszkiewicz-Nwafor Marta , van Elburg Annemarie , van Furth Eric , Wade Tracey , Wagner Gudrun , Watson Hunna , Werge Thomas , Whiteman David , Widen Elisabeth , Woodside D Blake , Yao Shuyang , Yilmaz Zeynep , Zeggini Eleftheria , Zerwas Stephanie , Zipfel Stephan , Breen Gerome , Bulik Cynthia , Bulik Cynthia M , Bergen Sarah E 
Published: June 2024

Abstract

Background and Hypothesis
Schizophrenia (SCZ) and anorexia nervosa (AN) are 2 severe and highly heterogeneous disorders showing substantial familial co-aggregation. Genetic factors play a significant role in both disorders, but the shared genetic etiology between them is yet to be investigated.

Study Design
Using summary statistics from recent large genome-wide association studies on SCZ (Ncases = 53 386) and AN (Ncases = 16 992), a 2-sample Mendelian randomization analysis was conducted to explore the causal relationship between SCZ and AN. MiXeR was employed to quantify their polygenic overlap. A conditional/conjunctional false discovery rate (condFDR/conjFDR) framework was adopted to identify loci jointly associated with both disorders. Functional annotation and enrichment analyses were performed on the shared loci.

Study Results
We observed a cross-trait genetic enrichment, a suggestive bidirectional causal relationship, and a considerable polygenic overlap (Dice coefficient = 62.2%) between SCZ and AN. The proportion of variants with concordant effect directions among all shared variants was 69.9%. Leveraging overlapping genetic associations, we identified 6 novel loci for AN and 33 novel loci for SCZ at condFDR &lt;0.01. At conjFDR &lt;0.05, we identified 10 loci jointly associated with both disorders, implicating multiple genes highly expressed in the cerebellum and pituitary and involved in synapse organization. Particularly, high expression of the shared genes was observed in the hippocampus in adolescence and orbitofrontal cortex during infancy.

Conclusions
This study provides novel insights into the relationship between SCZ and AN by revealing a shared genetic component and offers a window into their complex etiology.