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Immune-Related Genetic Overlap Between Regional Gray Matter Reductions and Psychiatric Symptoms in Adolescents, and Gene-Set Validation in a Translational Model

Adolescence is a period of vulnerability for the maturation of gray matter (GM) and also for the onset of psychiatric disorders such as major depressive disorder (MDD), bipolar disorder and schizophrenia. Chronic neuroinflammation is considered to play a role in the etiology of these illnesses. Howe...

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Autores principales: Penninck, Lukas, Ibrahim, El Chérif, Artiges, Eric, Gorgievski, Victor, Desrivières, Sylvane, Farley, Severine, Filippi, Irina, de Macedo, Carlos E. A., Belzeaux, Raoul, Banaschewski, Tobias, Bokde, Arun L. W., Quinlan, Erin Burke, Flor, Herta, Grigis, Antoine, Garavan, Hugh, Gowland, Penny, Heinz, Andreas, Brühl, Rüdiger, Nees, Frauke, Papadopoulos Orfanos, Dimitri, Paus, Tomáš, Poustka, Luise, Fröhner, Juliane H., Smolka, Michael N., Walter, Henrik, Whelan, Robert, Grenier, Julien, Schumann, Gunter, Paillère Martinot, Marie-Laure, Tzavara, Eleni T., Martinot, Jean-Luc
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8514661/
https://www.ncbi.nlm.nih.gov/pubmed/34658802
http://dx.doi.org/10.3389/fnsys.2021.725413
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author Penninck, Lukas
Ibrahim, El Chérif
Artiges, Eric
Gorgievski, Victor
Desrivières, Sylvane
Farley, Severine
Filippi, Irina
de Macedo, Carlos E. A.
Belzeaux, Raoul
Banaschewski, Tobias
Bokde, Arun L. W.
Quinlan, Erin Burke
Flor, Herta
Grigis, Antoine
Garavan, Hugh
Gowland, Penny
Heinz, Andreas
Brühl, Rüdiger
Nees, Frauke
Papadopoulos Orfanos, Dimitri
Paus, Tomáš
Poustka, Luise
Fröhner, Juliane H.
Smolka, Michael N.
Walter, Henrik
Whelan, Robert
Grenier, Julien
Schumann, Gunter
Paillère Martinot, Marie-Laure
Tzavara, Eleni T.
Martinot, Jean-Luc
author_facet Penninck, Lukas
Ibrahim, El Chérif
Artiges, Eric
Gorgievski, Victor
Desrivières, Sylvane
Farley, Severine
Filippi, Irina
de Macedo, Carlos E. A.
Belzeaux, Raoul
Banaschewski, Tobias
Bokde, Arun L. W.
Quinlan, Erin Burke
Flor, Herta
Grigis, Antoine
Garavan, Hugh
Gowland, Penny
Heinz, Andreas
Brühl, Rüdiger
Nees, Frauke
Papadopoulos Orfanos, Dimitri
Paus, Tomáš
Poustka, Luise
Fröhner, Juliane H.
Smolka, Michael N.
Walter, Henrik
Whelan, Robert
Grenier, Julien
Schumann, Gunter
Paillère Martinot, Marie-Laure
Tzavara, Eleni T.
Martinot, Jean-Luc
author_sort Penninck, Lukas
collection PubMed
description Adolescence is a period of vulnerability for the maturation of gray matter (GM) and also for the onset of psychiatric disorders such as major depressive disorder (MDD), bipolar disorder and schizophrenia. Chronic neuroinflammation is considered to play a role in the etiology of these illnesses. However, the involvement of neuroinflammation in the observed link between regional GM volume reductions and psychiatric symptoms is not established yet. Here, we investigated a possible common immune-related genetic link between these two phenomena in european adolescents recruited from the community. Hippocampal and medial prefrontal cortex (mPFC) were defined a priori as regions of interest (ROIs). Their GM volumes were extracted in 1,563 14-year-olds from the IMAGEN database. We found a set of 26 SNPs that correlated with the hippocampal volumes and 29 with the mPFC volumes at age 14. We formed two ROI-Related Immune-gene scores (RRI) with the inflammation SNPs that correlated to hippocampal GM volume and to mPFC GM volume. The predictive ability of both RRIs with regards to the presence of psychiatric symptoms at age 18 was investigated by correlating the RRIs with psychometric questionnaires obtained at age 18. The RRIs (but not control scores constructed with random SNPs) correlated with the presence of depressive symptoms, positive psychotic symptoms, and externalizing symptoms in later adolescence. In addition, the effect of childhood maltreatment, one of the major environmental risk factors for depression and other mental disorders, interacted with the RRI effect. We next sought to validate this finding by investigating our set of inflammatory genes in a translational animal model of early life adversity. Mice were subjected to a protocol of maternal separation at an early post-natal age. We evaluated depressive behaviors in separated and non-separated mice at adolescence and their correlations with the concomitant expression of our genes in whole blood samples. We show that in mice, early life adversity affected the expression of our set of genes in peripheral blood, and that levels of expression correlated with symptoms of negative affect in adolescence. Overall, our translational findings in adolescent mice and humans provide a novel validated gene-set of immune-related genes for further research in the early stages of mood disorders.
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spelling pubmed-85146612021-10-15 Immune-Related Genetic Overlap Between Regional Gray Matter Reductions and Psychiatric Symptoms in Adolescents, and Gene-Set Validation in a Translational Model Penninck, Lukas Ibrahim, El Chérif Artiges, Eric Gorgievski, Victor Desrivières, Sylvane Farley, Severine Filippi, Irina de Macedo, Carlos E. A. Belzeaux, Raoul Banaschewski, Tobias Bokde, Arun L. W. Quinlan, Erin Burke Flor, Herta Grigis, Antoine Garavan, Hugh Gowland, Penny Heinz, Andreas Brühl, Rüdiger Nees, Frauke Papadopoulos Orfanos, Dimitri Paus, Tomáš Poustka, Luise Fröhner, Juliane H. Smolka, Michael N. Walter, Henrik Whelan, Robert Grenier, Julien Schumann, Gunter Paillère Martinot, Marie-Laure Tzavara, Eleni T. Martinot, Jean-Luc Front Syst Neurosci Neuroscience Adolescence is a period of vulnerability for the maturation of gray matter (GM) and also for the onset of psychiatric disorders such as major depressive disorder (MDD), bipolar disorder and schizophrenia. Chronic neuroinflammation is considered to play a role in the etiology of these illnesses. However, the involvement of neuroinflammation in the observed link between regional GM volume reductions and psychiatric symptoms is not established yet. Here, we investigated a possible common immune-related genetic link between these two phenomena in european adolescents recruited from the community. Hippocampal and medial prefrontal cortex (mPFC) were defined a priori as regions of interest (ROIs). Their GM volumes were extracted in 1,563 14-year-olds from the IMAGEN database. We found a set of 26 SNPs that correlated with the hippocampal volumes and 29 with the mPFC volumes at age 14. We formed two ROI-Related Immune-gene scores (RRI) with the inflammation SNPs that correlated to hippocampal GM volume and to mPFC GM volume. The predictive ability of both RRIs with regards to the presence of psychiatric symptoms at age 18 was investigated by correlating the RRIs with psychometric questionnaires obtained at age 18. The RRIs (but not control scores constructed with random SNPs) correlated with the presence of depressive symptoms, positive psychotic symptoms, and externalizing symptoms in later adolescence. In addition, the effect of childhood maltreatment, one of the major environmental risk factors for depression and other mental disorders, interacted with the RRI effect. We next sought to validate this finding by investigating our set of inflammatory genes in a translational animal model of early life adversity. Mice were subjected to a protocol of maternal separation at an early post-natal age. We evaluated depressive behaviors in separated and non-separated mice at adolescence and their correlations with the concomitant expression of our genes in whole blood samples. We show that in mice, early life adversity affected the expression of our set of genes in peripheral blood, and that levels of expression correlated with symptoms of negative affect in adolescence. Overall, our translational findings in adolescent mice and humans provide a novel validated gene-set of immune-related genes for further research in the early stages of mood disorders. Frontiers Media S.A. 2021-09-30 /pmc/articles/PMC8514661/ /pubmed/34658802 http://dx.doi.org/10.3389/fnsys.2021.725413 Text en Copyright © 2021 Penninck, Ibrahim, Artiges, Gorgievski, Desrivières, Farley, Filippi, de Macedo, Belzeaux, Banaschewski, Bokde, Quinlan, Flor, Grigis, Garavan, Gowland, Heinz, Brühl, Nees, Papadopoulos Orfanos, Paus, Poustka, Fröhner, Smolka, Walter, Whelan, Grenier, Schumann, Paillère Martinot, Tzavara and Martinot. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Neuroscience
Penninck, Lukas
Ibrahim, El Chérif
Artiges, Eric
Gorgievski, Victor
Desrivières, Sylvane
Farley, Severine
Filippi, Irina
de Macedo, Carlos E. A.
Belzeaux, Raoul
Banaschewski, Tobias
Bokde, Arun L. W.
Quinlan, Erin Burke
Flor, Herta
Grigis, Antoine
Garavan, Hugh
Gowland, Penny
Heinz, Andreas
Brühl, Rüdiger
Nees, Frauke
Papadopoulos Orfanos, Dimitri
Paus, Tomáš
Poustka, Luise
Fröhner, Juliane H.
Smolka, Michael N.
Walter, Henrik
Whelan, Robert
Grenier, Julien
Schumann, Gunter
Paillère Martinot, Marie-Laure
Tzavara, Eleni T.
Martinot, Jean-Luc
Immune-Related Genetic Overlap Between Regional Gray Matter Reductions and Psychiatric Symptoms in Adolescents, and Gene-Set Validation in a Translational Model
title Immune-Related Genetic Overlap Between Regional Gray Matter Reductions and Psychiatric Symptoms in Adolescents, and Gene-Set Validation in a Translational Model
title_full Immune-Related Genetic Overlap Between Regional Gray Matter Reductions and Psychiatric Symptoms in Adolescents, and Gene-Set Validation in a Translational Model
title_fullStr Immune-Related Genetic Overlap Between Regional Gray Matter Reductions and Psychiatric Symptoms in Adolescents, and Gene-Set Validation in a Translational Model
title_full_unstemmed Immune-Related Genetic Overlap Between Regional Gray Matter Reductions and Psychiatric Symptoms in Adolescents, and Gene-Set Validation in a Translational Model
title_short Immune-Related Genetic Overlap Between Regional Gray Matter Reductions and Psychiatric Symptoms in Adolescents, and Gene-Set Validation in a Translational Model
title_sort immune-related genetic overlap between regional gray matter reductions and psychiatric symptoms in adolescents, and gene-set validation in a translational model
topic Neuroscience
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8514661/
https://www.ncbi.nlm.nih.gov/pubmed/34658802
http://dx.doi.org/10.3389/fnsys.2021.725413
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