Shared Genetic Architecture Between Schizophrenia and Anorexia Nervosa: A Cross-trait Genome-Wide Analysis
Zheng-An Lu, Alexander Ploner, Andreas Birgegård, Roger A.H. Adan, Lars Alfredsson, Tetsuya Ando, Ole A. Andreassen, Jessica H. Baker, Andrew W. Bergen, Wade H. Berrettini, Andreas Birgegård, Joseph M. Boden, Ilka Boehm, Vesna Boraska Perica, Harry Brandt, Gerome Breen, Julien Bryois, Katharina Buehren, Cynthia M. Bulik, Roland Burghardt, Matteo Cassina, Sven Cichon, Jonathan R. I. Coleman, Roger D. Cone, Philippe Courtet, Steven Crawford, Scott J. Crow, James J. Crowley, Unna N. Danner, Oliver S. P. Davis, Martina de Zwaan, George Dedoussis, Janiece E. DeSocio, Danielle M. Dick, Dimitris Dikeos, Christian Dina, Monika Dmitrzak‐Węglarz, Elisa Docampo, Laramie E. Duncan, Karin Egberts, Stefan Ehrlich, Geòrgia Escaramís, Tõnu Esko, Xavier Estivill, Anne Farmer, Angela Favaro, Fernando Fernández‐Aranda, Krista Fischer, Manuel Föcker, Lenka Foretová, Andreas J. Forstner, Monica Forzan, Christopher S. Franklin, Steven Gallinger, Ina Giegling, Paola Giusti‐Rodríguez, Fragiskos Gonidakis, Scott D. Gordon, Philip Gorwood, Monica Gratacos Mayora, Jakob Grove, Sébastien Guillaume, Yiran Guo, Håkon Håkonarson, Katherine A. Halmi, Ken B. Hanscombe, Konstantinos Hatzikotoulas, Joanna Hauser, Johannes Hebebrand, Sietske G. Helder, Stefan Herms, Beate Herpertz‐Dahlmann, Wolfgang Herzog, Anke Hinney, L. John Horwood, Christopher Hübel, Laura M. Huckins, James I. Hudson, Hartmut Imgart, Hidetoshi Inoko, Vladimír Janout, Susana Jiménez‐Múrcia, Craig Johnson, Jennifer Jordan, Antonio Julià, Gursharan Kalsi, Deborah Kaminská, Allan S. Kaplan, Jaakko Kaprio, Leila Karhunen, Andreas Karwautz, Martien J. Kas, Walter H. Kaye, James L. Kennedy, Martin A. Kennedy, Anna Keski‐Rahkonen, Kirsty Kiezebrink, Youl‐Ri Kim, Lars Klareskog, Kelly L. Klump
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 <0.01. At conjFDR <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.