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Separable neural mechanisms for the pleiotropic association of copy number variants with neuropsychiatric traits

22q11.2, 15q13.3, and 1q21.1 microdeletions attract considerable interest by conferring high risk for a range of neuropsychiatric disorders, including schizophrenia and autism. A fundamental open question is whether divergent or convergent neural mechanisms mediate this genetic pleiotropic associati...

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Autores principales: Reinwald, Jonathan R., Sartorius, Alexander, Weber-Fahr, Wolfgang, Sack, Markus, Becker, Robert, Didriksen, Michael, Stensbøl, Tine B., Schwarz, Adam J., Meyer-Lindenberg, Andreas, Gass, Natalia
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7069945/
https://www.ncbi.nlm.nih.gov/pubmed/32170065
http://dx.doi.org/10.1038/s41398-020-0771-4
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author Reinwald, Jonathan R.
Sartorius, Alexander
Weber-Fahr, Wolfgang
Sack, Markus
Becker, Robert
Didriksen, Michael
Stensbøl, Tine B.
Schwarz, Adam J.
Meyer-Lindenberg, Andreas
Gass, Natalia
author_facet Reinwald, Jonathan R.
Sartorius, Alexander
Weber-Fahr, Wolfgang
Sack, Markus
Becker, Robert
Didriksen, Michael
Stensbøl, Tine B.
Schwarz, Adam J.
Meyer-Lindenberg, Andreas
Gass, Natalia
author_sort Reinwald, Jonathan R.
collection PubMed
description 22q11.2, 15q13.3, and 1q21.1 microdeletions attract considerable interest by conferring high risk for a range of neuropsychiatric disorders, including schizophrenia and autism. A fundamental open question is whether divergent or convergent neural mechanisms mediate this genetic pleiotropic association with the same behavioral phenotypes. We use a combination of rodent microdeletion models with high-field neuroimaging to perform a comparative whole-brain characterization of functional and structural mechanisms linked to high-risk states. Resting-state functional and structural magnetic resonance imaging data were acquired on mice carrying heterozygous microdeletions in 22q11.2 (N = 12), 15q13.3 (N = 11), and 1q21.1 (N = 11) loci. We performed network-based statistic, graph, and morphometric analyses. The three microdeletions did not share significant systems-level features. Instead, morphometric analyses revealed microcephaly in 1q21.1 and macrocephaly in 15q13.3 deletions, whereas cerebellar volume was specifically reduced in 22q11.2 deletion. In function, 22q11.2 deletion mice showed widespread cortical hypoconnectivity, accompanied by opposing hyperconnectivity in dopaminergic pathways, which was confirmed by graph analysis. 1q21.1 exhibited distinct changes in posterior midbrain morphology and function, especially in periaqueductal gray, whereas 15q13.3 demonstrated alterations in auditory/striatal system. The combination of cortical hypoconnectivity and dopaminergic hyperconnectivity and reduced cerebellum in 22q11.2 deletion mirrors key neurodevelopmental features of schizophrenia, whereas changes in midbrain and auditory/striatal morphology and topology in 1q21.1 and 15q13.3 rather indicate focal processes possibly linked to the emergence of abnormal salience perception and hallucinations. In addition to insights into pathophysiological processes in these microdeletions, our results establish the general point that microdeletions might increase risk for overlapping neuropsychiatric phenotypes through separable neural mechanisms.
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spelling pubmed-70699452020-03-19 Separable neural mechanisms for the pleiotropic association of copy number variants with neuropsychiatric traits Reinwald, Jonathan R. Sartorius, Alexander Weber-Fahr, Wolfgang Sack, Markus Becker, Robert Didriksen, Michael Stensbøl, Tine B. Schwarz, Adam J. Meyer-Lindenberg, Andreas Gass, Natalia Transl Psychiatry Article 22q11.2, 15q13.3, and 1q21.1 microdeletions attract considerable interest by conferring high risk for a range of neuropsychiatric disorders, including schizophrenia and autism. A fundamental open question is whether divergent or convergent neural mechanisms mediate this genetic pleiotropic association with the same behavioral phenotypes. We use a combination of rodent microdeletion models with high-field neuroimaging to perform a comparative whole-brain characterization of functional and structural mechanisms linked to high-risk states. Resting-state functional and structural magnetic resonance imaging data were acquired on mice carrying heterozygous microdeletions in 22q11.2 (N = 12), 15q13.3 (N = 11), and 1q21.1 (N = 11) loci. We performed network-based statistic, graph, and morphometric analyses. The three microdeletions did not share significant systems-level features. Instead, morphometric analyses revealed microcephaly in 1q21.1 and macrocephaly in 15q13.3 deletions, whereas cerebellar volume was specifically reduced in 22q11.2 deletion. In function, 22q11.2 deletion mice showed widespread cortical hypoconnectivity, accompanied by opposing hyperconnectivity in dopaminergic pathways, which was confirmed by graph analysis. 1q21.1 exhibited distinct changes in posterior midbrain morphology and function, especially in periaqueductal gray, whereas 15q13.3 demonstrated alterations in auditory/striatal system. The combination of cortical hypoconnectivity and dopaminergic hyperconnectivity and reduced cerebellum in 22q11.2 deletion mirrors key neurodevelopmental features of schizophrenia, whereas changes in midbrain and auditory/striatal morphology and topology in 1q21.1 and 15q13.3 rather indicate focal processes possibly linked to the emergence of abnormal salience perception and hallucinations. In addition to insights into pathophysiological processes in these microdeletions, our results establish the general point that microdeletions might increase risk for overlapping neuropsychiatric phenotypes through separable neural mechanisms. Nature Publishing Group UK 2020-03-13 /pmc/articles/PMC7069945/ /pubmed/32170065 http://dx.doi.org/10.1038/s41398-020-0771-4 Text en © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Reinwald, Jonathan R.
Sartorius, Alexander
Weber-Fahr, Wolfgang
Sack, Markus
Becker, Robert
Didriksen, Michael
Stensbøl, Tine B.
Schwarz, Adam J.
Meyer-Lindenberg, Andreas
Gass, Natalia
Separable neural mechanisms for the pleiotropic association of copy number variants with neuropsychiatric traits
title Separable neural mechanisms for the pleiotropic association of copy number variants with neuropsychiatric traits
title_full Separable neural mechanisms for the pleiotropic association of copy number variants with neuropsychiatric traits
title_fullStr Separable neural mechanisms for the pleiotropic association of copy number variants with neuropsychiatric traits
title_full_unstemmed Separable neural mechanisms for the pleiotropic association of copy number variants with neuropsychiatric traits
title_short Separable neural mechanisms for the pleiotropic association of copy number variants with neuropsychiatric traits
title_sort separable neural mechanisms for the pleiotropic association of copy number variants with neuropsychiatric traits
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7069945/
https://www.ncbi.nlm.nih.gov/pubmed/32170065
http://dx.doi.org/10.1038/s41398-020-0771-4
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