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Cross-Disease Analysis of Depression, Ataxia and Dystonia University of Groningen Cross-disease analysis of depression, ataxia and dystonia highlights a role for synaptic plasticity and the cerebellum in the pathophysiology of these comorbid diseases Huang, Miaozhen; de Koning, Tom J; Tijssen, Marina A J; Verbeek, Dineke S Published in: Biochimica et biophysica acta-Molecular basis of disease DOI: 10.1016/j.bbadis.2020.165976 IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite from it. Please check the document version below. Document Version Publisher's PDF, also known as Version of record Publication date: 2021 Link to publication in University of Groningen/UMCG research database Citation for published version (APA): Huang, M., de Koning, T. J., Tijssen, M. A. J., & Verbeek, D. S. (2021). Cross-disease analysis of depression, ataxia and dystonia highlights a role for synaptic plasticity and the cerebellum in the pathophysiology of these comorbid diseases. Biochimica et biophysica acta-Molecular basis of disease, 1867(1), [165976]. https://doi.org/10.1016/j.bbadis.2020.165976 Copyright Other than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons). The publication may also be distributed here under the terms of Article 25fa of the Dutch Copyright Act, indicated by the “Taverne” license. More information can be found on the University of Groningen website: https://www.rug.nl/library/open-access/self-archiving-pure/taverne- amendment. Take-down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons the number of authors shown on this cover page is limited to 10 maximum. BBA - Molecular Basis of Disease 1867 (2021) 165976 Contents lists available at ScienceDirect BBA - Molecular Basis of Disease journal homepage: www.elsevier.com/locate/bbadis Cross-disease analysis of depression, ataxia and dystonia highlights a role for T synaptic plasticity and the cerebellum in the pathophysiology of these comorbid diseases ⁎ Miaozhen Huanga, Tom J. de Koninga,b,c, Marina A.J. Tijssenb, Dineke S. Verbeeka, a Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands b Department of Neurology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands c Pediatrics, Department of Clinical Sciences, Lund University, Sweden ARTICLE INFO ABSTRACT Keywords: Background: There is growing evidence that the neuropsychiatric and neurological disorders depression, ataxia Cross-disease analysis and dystonia share common biological pathways. We therefore aimed to increase our understanding of their Depression shared pathophysiology by investigating their shared biological pathways and molecular networks. Ataxia Methods: We constructed gene sets for depression, ataxia, and dystonia using the Human Phenotype Ontology Dystonia database and genome-wide association studies, and identified shared genes between the three diseases. Wethen Synaptic plasticity assessed shared genes in terms of functional enrichment, pathway analysis, molecular connectivity, expression Cerebellum comorbidity profiles and brain-tissue-specific gene co-expression networks. Results: The 33 genes shared by depression, ataxia and dystonia are enriched in shared biological pathways and connected through molecular complexes in protein–protein interaction networks. Biological processes common/ shared to all three diseases were identified across different brain tissues, highlighting roles for synaptic trans- mission, synaptic plasticity and nervous system development. The average expression of shared genes was sig- nificantly higher in the cerebellum compared to other brain regions, suggesting these genes have distinctcer- ebellar functions. Several shared genes also showed high expression in the cerebellum during prenatal stages, pointing to a functional role during development. Conclusions: The shared pathophysiology of depression, ataxia and dystonia seems to converge onto the cere- bellum that maybe particularly vulnerable to changes in synaptic transmission, regulation of synaptic plasticity and nervous system development. Consequently, in addition to regulating motor coordination and motor function, the cerebellum may likely play a role in mood processing. 1. Introduction genes associated with depression. Many of these genes were linked to synaptic structures and neurotransmission, and an integrative func- Depression is a disabling neuropsychiatric disease that affects more tional genomic analysis revealed that the origins of neuropsychiatric than 264 million people worldwide [1]. Current estimates are that disorders, including depression, are closely related to genes involved in ~20% of the general population will experience at least one episode of the development of the human brain [9]. None-the-less, the causal re- depression in their lifetime [2]. At present, fewer than half of patients lationships between genome-wide association study (GWAS) variants/ with depressive symptoms receive effective treatment, in part because genes and depression remain to be determined. the pathophysiology of depression is not fully understood [3]. Comorbid depression is also frequently seen in patients suffering Neuroanatomical and imaging studies in patients have shown that from ataxia and dystonia [10–15], neurological disorders that affect depression is a disease with a complex pathophysiology that seems to motor movement and motor function. For ataxia this is due to dys- involve multiple brain regions, including the hippocampus, prefrontal function of the cerebellum, while dystonia has been linked to dys- cortex and cerebellum [4–7]. A recently published genome-wide meta- function of the basal ganglia [16,17]. The anatomical structures in- analysis further illustrated the complexity of the genetic background of volved in both ataxia and dystonia are not strictly separated, because depression [8]. In this study, hundreds of independent variants and there is growing evidence that the cerebellum has a role in dystonia as ⁎ Corresponding author at: University Medical Center Groningen, Department of Genetics, Antonius Deusinglaan 1, 9700RB Groningen, the Netherlands. E-mail address: [email protected] (D.S. Verbeek). https://doi.org/10.1016/j.bbadis.2020.165976 Received 10 July 2020; Accepted 15 September 2020 Available online 02 October 2020 0925-4439/ © 2020 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/BY/4.0/). M. Huang, et al. BBA - Molecular Basis of Disease 1867 (2021) 165976 well [18]. Many disease genes have been identified for both disorders, (PPI) using the following databases: BioGrid, InWeb_IM and OmniPath. and ataxia and dystonia have a profoundly shared genetic background The enrichment network was visualized by Cytoscape (v3.7.2) [25]. converging into shared molecular pathways [19],which may also con- The related enrichment terms were manually clustered and marked tribute to comorbid depression. Common biochemical etiologies are with different colors. suggested to underlie the motor and psychiatric symptoms in cervical dystonia [20], but the severity of the motor symptoms severity not 2.4. Brain-tissue-specific gene co-expression network analysis necessarily correlates with the severity of non-motor symptoms sug- gesting that the depression is not the directly linked to the motor Gene co-expression network analysis of multiple brain tissues was symptoms or the cause of the motor symptoms. Patients with dystonia performed using NetworkAnalyst (assessed May 2019) [28]. We gen- can have mild motor symptoms but significant psychiatric/depression erated tissue-specific gene co-expression networks for cerebellum, symptoms. And this is not only the case in dystonia, a higher risk for cortex, nucleus accumbens/basal ganglia and hippocampus. Networ- depression was correlated with the severity of disease in dominantly kAnalyst uses data from the TCSBN, a database of tissue- and cancer- inherited cerebellar ataxias [21]. So more and more data becomes specific biological networks for 46 tissues and 17 cancers [29]. The available over depression in dystonia and ataxia, however the common intersecting pathways between the brain-tissue-specific gene co-ex- pathophysiological mechanisms underlying the comorbidity of these pression networks of the shared genes were plotted using the R-Package disorders remain unknown. UpSetR (v1.4.0) [30], and the analyses were performed in R (v3.5.2) The comorbidity between depression, ataxia and dystonia and the using RStudio (v1.1.463). profound shared genetic basis of ataxia and dystonia, motivated us to carry out a cross-disease analysis to discover their shared pathophy- 2.5. Protein-protein interaction network siological mechanisms. We identified the similarities and differences among the distinct disease gene sets associated with all three diseases, The STRING database (v11.0) [31] was used to obtain PPIs between and we then explored the function of gene shared between all three 163AD and 497Dep. The interactions are based on associated evidence, diseases
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