GWAS; Mendelian randomization; anorexia; architecture; genetic; nervosa; pleiotropy; polygenic overlap; schizophrenia; Humans; Anorexia Nervosa/genetics; Schizophrenia/genetics; Genome-Wide Association Study; Multifactorial Inheritance; Mendelian Randomization Analysis; Psychiatry and Mental Health
Abstract :
[en] [en] 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.
Disciplines :
Psychiatry
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
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
Docampo Martínez, Elisa ; Université de Liège - ULiège > Département des sciences cliniques ; Centre Hospitalier Universitaire de Liège - CHU > > Service de génétique
Language :
English
Title :
Shared Genetic Architecture Between Schizophrenia and Anorexia Nervosa: A Cross-trait Genome-Wide Analysis.
CSC - Chinese Scholarship Council Sverige Vetenskapsrådet Swedish Research Council NIMH - National Institute of Mental Health Lundbeck Foundation
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 Vetenskapsrdet 2021-03126 (PI: Sarah E. Bergen). 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. Cynthia M. Bulik is supported by National Institute of Mental Health (NIMH) (R56MH129437, R01MH120170, R01MH124871, R01MH119084, R01MH118278, R01 MH124871); Swedish Research Council (Vetenskapsr\u00E5det, award: 538-2013-8864); Lundbeck Foundation (R276-2018-4581).This study was funded by the Chinese Scholarship Council (CSC202206010089) and Vetenskapsr\u00E5det 2021-03126 (PI: Sarah E. Bergen). 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. Cynthia M. Bulik is supported by National Institute of Mental Health (NIMH) (R56MH129437, R01MH120170, R01MH124871, R01MH119084, R01MH118278, R01 MH124871); Swedish Research Council (Vetenskapsr\u00E5det, award: 538-2013-8864); Lundbeck Foundation (R276-2018-4581).
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