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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

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 Thumbnail


Authors

Lukas Penninck

El Chérif Ibrahim

Eric Artiges

Victor Gorgievski

Sylvane Desrivières

Severine Farley

Irina Filippi

Carlos E. A. de Macedo

Raoul Belzeaux

Tobias Banaschewski

Arun L. W. Bokde

Erin Burke Quinlan

Herta Flor

Antoine Grigis

Hugh Garavan

Andreas Heinz

Rüdiger Brühl

Frauke Nees

Dimitri Papadopoulos Orfanos

Tomáš Paus

Luise Poustka

Juliane H. Fröhner

Michael N. Smolka

Henrik Walter

Robert Whelan

Julien Grenier

Gunter Schumann

Marie-Laure Paillère Martinot

Eleni T. Tzavara

Jean-Luc Martinot



Abstract

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.

Citation

Penninck, L., Ibrahim, E. C., Artiges, E., Gorgievski, V., Desrivières, S., Farley, S., Filippi, I., de Macedo, C. E. A., Belzeaux, R., Banaschewski, T., Bokde, A. L. W., Quinlan, E. B., Flor, H., Grigis, A., Garavan, H., Gowland, P., Heinz, A., Brühl, R., Nees, F., Papadopoulos Orfanos, D., …Martinot, J.-L. (2021). Immune-Related Genetic Overlap Between Regional Gray Matter Reductions and Psychiatric Symptoms in Adolescents, and Gene-Set Validation in a Translational Model. Frontiers in Systems Neuroscience, 15, 1-14. https://doi.org/10.3389/fnsys.2021.725413

Journal Article Type Article
Acceptance Date Aug 31, 2021
Online Publication Date Sep 30, 2021
Publication Date Sep 30, 2021
Deposit Date Oct 6, 2021
Publicly Available Date Oct 6, 2021
Journal Frontiers in Systems Neuroscience
Electronic ISSN 1662-5137
Publisher Frontiers Media
Peer Reviewed Peer Reviewed
Volume 15
Article Number 725413
Pages 1-14
DOI https://doi.org/10.3389/fnsys.2021.725413
Keywords Cellular and Molecular Neuroscience; Cognitive Neuroscience; Developmental Neuroscience; Neuroscience (miscellaneous)
Public URL https://nottingham-repository.worktribe.com/output/6393216
Publisher URL https://www.frontiersin.org/articles/10.3389/fnsys.2021.725413/full

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