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

for the IMAGEN Consortium

doi:10.3389/fnsys.2021.725413

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

for the IMAGEN Consortium

Ecole Normale Supérieure Paris-Saclay
Institut de Neurosciences de la Timone
EPS Barthélémy Durand
University Paris Descartes
Department of Psychology and Neuroscience
King's College London
Hôpital Sainte-Marguerite
Universitatsklinikum Mannheim
Department of Urology
Heidelberg University
Université Paris-Saclay
University of Vermont
University of Nottingham
Comprehensive Allergy Center
Physikalisch-Technische Bundesanstalt
University Medical Center Schleswig-Holstein
University of Montreal
University Health Network, Toronto
University Medical Center Göttingen
TU Dresden
PONS Research Group
Humboldt-Universitat zu Berlin
Fudan University
Assistance Publique-Hôpitaux de Paris
Pôle Neurosciences

Research output: Contribution to journal › Article › peer-review

5 Citations (Scopus)

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.

Original language	English
Article number	725413
Number of pages	1
Journal	Frontiers in systems neuroscience
Volume	15
DOIs	https://doi.org/10.3389/fnsys.2021.725413
Publication status	Published - 1 Jan 2021

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This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 16 Peace, Justice and Strong Institutions

Keywords

adolescence
childhood maltreatment
immunity genes
MRI
psychiatric symptoms

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10.3389/fnsys.2021.725413

Cite this

@article{d1ab14909e3246d59cc6623e8399efb1,

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

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.",

keywords = "adolescence, childhood maltreatment, immunity genes, MRI, psychiatric symptoms",

author = "Lukas Penninck and Ibrahim, \{El Ch{\'e}rif\} and Eric Artiges and Victor Gorgievski and Sylvane Desrivi{\`e}res and Severine Farley and Irina Filippi and \{de Macedo\}, \{Carlos E.A.\} and Raoul Belzeaux and Tobias Banaschewski and Bokde, \{Arun L.W.\} and Quinlan, \{Erin Burke\} and Herta Flor and Antoine Grigis and Hugh Garavan and Penny Gowland and Andreas Heinz and R{\"u}diger Br{\"u}hl and Frauke Nees and \{Papadopoulos Orfanos\}, Dimitri and Tom{\'a}{\v s} Paus and Luise Poustka and Fr{\"o}hner, \{Juliane H.\} and Smolka, \{Michael N.\} and Henrik Walter and Robert Whelan and Julien Grenier and Gunter Schumann and \{Paill{\`e}re Martinot\}, \{Marie Laure\} and Tzavara, \{Eleni T.\} and Martinot, \{Jean Luc\} and \{for the IMAGEN Consortium\}",

note = "Funding Information: This work received support from the following sources: the European Union-funded FP6 Integrated Project IMAGEN (Reinforcement-related behaviour in normal brain function and psychopathology) (LSHM-CT-2007-037286), the Horizon 2020 funded ERC Advanced Grant “STRATIFY” (Brain network based stratification of reinforcement-related disorders) (695313), Human Brain Project (HBP SGA 2, 785907, and HBP SGA 3, 945539), the Medical Research Council Grant “c-VEDA” (Consortium on Vulnerability to Externalizing Disorders and Addictions) (MR/N000390/1), the National Institute of Health (NIH) (R01DA049238, A decentralized macro and micro gene-by-environment interaction analysis of substance use behavior and its brain biomarkers), the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King{\textquoteright}s College London, the Bundesministeriumf{\"u}r Bildung und Forschung (BMBF grants 01GS08152; 01EV0711; Forschungsnetz AERIAL 01EE1406A, 01EE1406B; Forschungsnetz IMAC-Mind 01GL1745B), the Deutsche Forschungsgemeinschaft (DFG grants SM 80/7-2, SFB 940, TRR 265, NE 1383/14-1), the Medical Research Foundation and Medical Research Council (grants MR/R00465X/1 and MR/S020306/1), the National Institutes of Health (NIH) funded ENIGMA (grants 5U54EB020403-05 and 1R56AG058854-01). Further support was provided by grants from: – the ANR (ANR-12-SAMA-0004, AAPG2019 – GeBra, ANR-19-NEUR-ANTaRES), the Eranet Neuron (AF12-NEUR0008-01 – WM2NA; and ANR-18-NEUR00002-01 – ADORe), the Fondation de France (00081242), the Fondation pour la Recherche M{\'e}dicale (DPA20140629802), the Mission Interminist{\'e}rielle de Lutte-contre-les-Drogues-et-les-Conduites-Addictives (MILDECA), the Assistance-Publique-H{\^o}pitaux-de-Paris and INSERM (interface grant), Paris Sud University IDEX 2012, the Fondation de l{\textquoteright}Avenir (grant AP-RM-17-013), the F{\'e}d{\'e}ration pour la Recherche sur le Cerveau; the National Institutes of Health, Science Foundation Ireland (16/ERCD/3797), United States (Axon, Testosterone and Mental Health during Adolescence; RO1 MH085772-01A1), and by NIH Consortium grant U54 EB020403, supported by a cross-NIH alliance that funds Big Data to Knowledge Centres of Excellence. Publisher Copyright: {\textcopyright} Copyright {\textcopyright} 2021 Penninck, Ibrahim, Artiges, Gorgievski, Desrivi{\`e}res, Farley, Filippi, de Macedo, Belzeaux, Banaschewski, Bokde, Quinlan, Flor, Grigis, Garavan, Gowland, Heinz, Br{\"u}hl, Nees, Papadopoulos Orfanos, Paus, Poustka, Fr{\"o}hner, Smolka, Walter, Whelan, Grenier, Schumann, Paill{\`e}re Martinot, Tzavara and Martinot.",

year = "2021",

month = jan,

day = "1",

doi = "10.3389/fnsys.2021.725413",

language = "English",

volume = "15",

journal = "Frontiers in systems neuroscience",

issn = "1662-5137",

publisher = "Frontiers Media S.A.",

}

TY - JOUR

T1 - Immune-Related Genetic Overlap Between Regional Gray Matter Reductions and Psychiatric Symptoms in Adolescents, and Gene-Set Validation in a Translational Model

AU - Penninck, Lukas

AU - Ibrahim, El Chérif

AU - Artiges, Eric

AU - Gorgievski, Victor

AU - Desrivières, Sylvane

AU - Farley, Severine

AU - Filippi, Irina

AU - de Macedo, Carlos E.A.

AU - Belzeaux, Raoul

AU - Banaschewski, Tobias

AU - Bokde, Arun L.W.

AU - Quinlan, Erin Burke

AU - Flor, Herta

AU - Grigis, Antoine

AU - Garavan, Hugh

AU - Gowland, Penny

AU - Heinz, Andreas

AU - Brühl, Rüdiger

AU - Nees, Frauke

AU - Papadopoulos Orfanos, Dimitri

AU - Paus, Tomáš

AU - Poustka, Luise

AU - Fröhner, Juliane H.

AU - Smolka, Michael N.

AU - Walter, Henrik

AU - Whelan, Robert

AU - Grenier, Julien

AU - Schumann, Gunter

AU - Paillère Martinot, Marie Laure

AU - Tzavara, Eleni T.

AU - Martinot, Jean Luc

AU - for the IMAGEN Consortium

N1 - Funding Information: This work received support from the following sources: the European Union-funded FP6 Integrated Project IMAGEN (Reinforcement-related behaviour in normal brain function and psychopathology) (LSHM-CT-2007-037286), the Horizon 2020 funded ERC Advanced Grant “STRATIFY” (Brain network based stratification of reinforcement-related disorders) (695313), Human Brain Project (HBP SGA 2, 785907, and HBP SGA 3, 945539), the Medical Research Council Grant “c-VEDA” (Consortium on Vulnerability to Externalizing Disorders and Addictions) (MR/N000390/1), the National Institute of Health (NIH) (R01DA049238, A decentralized macro and micro gene-by-environment interaction analysis of substance use behavior and its brain biomarkers), the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London, the Bundesministeriumfür Bildung und Forschung (BMBF grants 01GS08152; 01EV0711; Forschungsnetz AERIAL 01EE1406A, 01EE1406B; Forschungsnetz IMAC-Mind 01GL1745B), the Deutsche Forschungsgemeinschaft (DFG grants SM 80/7-2, SFB 940, TRR 265, NE 1383/14-1), the Medical Research Foundation and Medical Research Council (grants MR/R00465X/1 and MR/S020306/1), the National Institutes of Health (NIH) funded ENIGMA (grants 5U54EB020403-05 and 1R56AG058854-01). Further support was provided by grants from: – the ANR (ANR-12-SAMA-0004, AAPG2019 – GeBra, ANR-19-NEUR-ANTaRES), the Eranet Neuron (AF12-NEUR0008-01 – WM2NA; and ANR-18-NEUR00002-01 – ADORe), the Fondation de France (00081242), the Fondation pour la Recherche Médicale (DPA20140629802), the Mission Interministérielle de Lutte-contre-les-Drogues-et-les-Conduites-Addictives (MILDECA), the Assistance-Publique-Hôpitaux-de-Paris and INSERM (interface grant), Paris Sud University IDEX 2012, the Fondation de l’Avenir (grant AP-RM-17-013), the Fédération pour la Recherche sur le Cerveau; the National Institutes of Health, Science Foundation Ireland (16/ERCD/3797), United States (Axon, Testosterone and Mental Health during Adolescence; RO1 MH085772-01A1), and by NIH Consortium grant U54 EB020403, supported by a cross-NIH alliance that funds Big Data to Knowledge Centres of Excellence. Publisher Copyright: © 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.

PY - 2021/1/1

Y1 - 2021/1/1

N2 - 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.

AB - 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.

KW - adolescence

KW - childhood maltreatment

KW - immunity genes

KW - MRI

KW - psychiatric symptoms

UR - https://www.scopus.com/pages/publications/85117118851

U2 - 10.3389/fnsys.2021.725413

DO - 10.3389/fnsys.2021.725413

M3 - Article

AN - SCOPUS:85117118851

SN - 1662-5137

VL - 15

JO - Frontiers in systems neuroscience

JF - Frontiers in systems neuroscience

M1 - 725413

ER -

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

Abstract

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Keywords

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