Immune-Related Genetic Overlap Between Regional Gray Matter Reductions and Psychiatric Symptoms in Adolescents, and Gene-Set Validation in a Translational Model
Résumé
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.
Domaines
Sciences du Vivant [q-bio]| Origine | Fichiers éditeurs autorisés sur une archive ouverte |
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