FKBP5 and NR3C1 epigenetic signatures are related to HPA-axis function in children and adolescents exposed to childhood maltreatment
N. San Martín-González, D. Czamara, M. Acosta-Díez, L. Marqués-Feixa, H. Palma-Gudiel, S. Romero, M. Rapado-Castro, I. Zorrilla, H. Blasco-Fontecilla, B. Arias, S. Papiol, L. FañanásIntroduction
Childhood maltreatment (CM) is a widely recognized risk factor for mental disorders across the lifespan, although the underlying neurobiological mechanisms remain partially understood. The hypothalamic-pituitary-adrenal (HPA) axis is the primary physiological stress response system, and genetic and epigenetic variability in associated genes, such as FKBP5 and NR3C1, have been proposed as mechanisms of risk or resilience in interaction with environmental exposures.
Objectives
i) to investigate whether CM leaves detectable epigenetic marks in exposed children and adolescents, genome-wide and in candidate genes, and (ii) to examine how epigenetic variability in FKBP5 and NR3C1 modulate HPA-axis diurnal and psychosocial stress responses.
Methods
203 children and adolescents were enrolled in the Epi_Young_Stress_Project (130 with psychiatric diagnoses and 81 controls). Cortisol diurnal profiles were assessed using four saliva samples collected throughout the day. Psychosocial stress responses were measured with five samples during the Trier-Social-Stress test. DNA methylation was quantified in PBMCs using Illumina EPIC_array_v1. Epigenome-wide association analyses (EWAS) were conducted using “Limma”. Principal component analyses were applied to characterize gene-level variability in candidate genes. Linear regression models were used for the study aims.
Results
EWAS analyses revealed 29 differentially methylated positions between maltreated and non-maltreated youths, although none of them survived FDR correction. CM was associated with methylation in FKBP5 , but not NR3C1. Diurnal cortisol profile was related to methylation in both genes, and interaction effects between genes were detected. TSST cortisol profile was associated with FKBP5 methylation .
Conclusions
CM leaves epigenetic signatures HPA-axis related genes, which may influence diurnal and psychosocial cortisol secretion in youths.
Disclosure of Interest
None Declared