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Arcego, D.M.* ; Buschdorf, J.P.* ; O'Toole, N.* ; Wang, Z.* ; Barth, B.* ; Pokhvisneva, I.* ; Rayan, N.A.* ; Patel, S.* ; de Mendonça Filho, E.J.* ; Lee, P.* ; Tan, J.* ; Koh, M.X.* ; Sim, C.M.* ; Parent, C.* ; de Lima, R.M.S.* ; Clappison, A.* ; O'Donnell, K.J.* ; Dalmaz, C.* ; Arloth, J. ; Provençal, N.* ; Binder, E.B.* ; Diorio, J.* ; Silveira, P.P.* ; Meaney, M.J.*

A glucocorticoid-sensitive hippocampal gene network moderates the impact of early life adversity on mental health outcomes.

Biol. Psychiatry 95, 48-61 (2023)

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Background: Early stress increases the risk for psychiatric disorders. Glucocorticoids are stress mediators that regulate transcriptional activity and morphology in the hippocampus, which is implicated in the pathophysiology of multiple psychiatric conditions. We aimed to establish the relevance of hippocampal, glucocorticoid-induced transcriptional activity as a mediator of the effects of early life on later psychopathology in humans. Methods: RNA sequencing was performed with anterior and posterior hippocampal dentate gyrus from adult female macaques (n = 12/group) that were chronically treated with betamethasone (glucocorticoid receptor agonist) or vehicle. Coexpression network analysis identified a preserved gene network in the posterior hippocampal dentate gyrus that was strongly associated with glucocorticoid exposure. The single nucleotide polymorphisms in the genes in this network were used to create an expression-based polygenic score in humans. Results: The expression-based polygenic score significantly moderated the association between early adversity and psychotic disorders in adulthood (UK Biobank, women, n = 44,519) and on child peer relations (ALSPAC [Avon Longitudinal Study of Parents and Children], girls, n = 1666 for 9-year-olds and n = 1594 for 11-year-olds), an endophenotype for later psychosis. Analyses revealed that this network was enriched for glucocorticoid-induced epigenetic remodeling in human hippocampal cells. We also found a significant association between single nucleotide polymorphisms from the expression-based polygenic score and adult brain gray matter density. Conclusions: We provide an approach for the use of transcriptomic data from animal models together with human data to study the impact of environmental influences on mental health. The results are consistent with the hypothesis that hippocampal glucocorticoid-related transcriptional activity mediates the effects of early adversity on neural mechanisms implicated in psychiatric disorders.

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