ausblenden:
Schlagwörter:
Neurosciences & Neurology; Psychiatry; Childhood Trauma; Transcriptomics; miRNAs; Animal Model; Depression;
Zusammenfassung:
To date, gene-environment (GxE) interaction studies in depression have been limited to hypothesis-based candidate
genes, since genome-wide (GWAS)-based GxE interaction studies would require enormous datasets with genetics,
environmental, and clinical variables. We used a novel, cross-species and cross-tissues “omics” approach to identify genes
predicting depression in response to stress in GxE interactions. We integrated the transcriptome and miRNome profiles
from the hippocampus of adult rats exposed to prenatal stress (PNS) with transcriptome data obtained from blood mRNA
of adult humans exposed to early life trauma, using a stringent statistical analyses pathway. Network analysis of the
integrated gene lists identified the Forkhead box protein O1 (FoxO1), Alpha-2-Macroglobulin (A2M), and Transforming
Growth Factor Beta 1 (TGF-β1) as candidates to be tested for GxE interactions, in two GWAS samples of adults either with
a range of childhood traumatic experiences (Grady Study Project, Atlanta, USA) or with separation from parents in
childhood only (Helsinki Birth Cohort Study, Finland). After correction for multiple testing, a meta-analysis across both
samples confirmed six FoxO1 SNPs showing significant GxE interactions with early life emotional stress in predicting
depressive symptoms. Moreover, in vitro experiments in a human hippocampal progenitor cell line confirmed a functional
role of FoxO1 in stress responsivity. In secondary analyses, A2M and TGF-β1 showed significant GxE interactions with
emotional, physical, and sexual abuse in the Grady Study. We therefore provide a successful ‘hypothesis-free’ approach for the identification and prioritization of candidate genes for
GxE interaction studies that can be investigated in GWAS datasets.
