Glucocorticoid Receptor Gene (NR3C1) Methylation Childhood Maltreatment Multilevel Reward Responsiveness and Depressive and Anxiety Symptoms: A Neuroimaging Epigenetic Study

Yajing Xu; Shan Yang; Cong Cao

doi:10.1016/j.neuroimage.2025.121003

Glucocorticoid Receptor Gene (NR3C1) Methylation Childhood Maltreatment Multilevel Reward Responsiveness and Depressive and Anxiety Symptoms: A Neuroimaging Epigenetic Study

Neuroimage. 2025 Jan 6:121003. doi: 10.1016/j.neuroimage.2025.121003. Online ahead of print.

Authors

Yajing Xu¹, Shan Yang¹, Cong Cao²

Affiliations

¹ School of Nursing and Rehabilitation, Cheeloo College of Medicine, Shandong University, Jinan, China.
² School of Nursing and Rehabilitation, Cheeloo College of Medicine, Shandong University, Jinan, China. Electronic address: caocong@sdu.edu.cn.

PMID: 39778819
DOI: 10.1016/j.neuroimage.2025.121003

Abstract

Background: Although epigenomic and environment interactions (Epigenome × Environment; Epi × E) might constitute a novel mechanism underlying reward processing direct evidence is still scarce. We conducted the first longitudinal study to investigate the extent to which DNA methylation of a stress-related gene-NR3C1-interacts with childhood maltreatment in association with young adult reward responsiveness (RR) and the downstream risk of depressive (anhedonia dimension in particular) and anxiety symptoms.

Method: A total of 192 Chinese university students aged 18∼25 (M_age = 21.08 ± 1.91 years; 59.4% females) were followed in two waves. Reward positivity (RewP) and its time‒frequency components were elicited via a classic monetary reward task. Cytosine methylation in the promoter exon 1F of NR3C1 (NR3C1-1F) was sequenced via buccal cells. Childhood maltreatment self-reported RR and depressive and anxiety symptoms were assessed via questionnaires.

Results: NR3C1-1F methylation significantly interacted with childhood maltreatment on RewP but not the delta and theta components or self-reported RR. The severity and exposure number of childhood maltreatment were negatively associated with RewP among individuals with heightened NR3C1-1F methylation but positively associated with RewP among individuals with blunted NR3C1-1F methylation demonstrating a "goodness-of-fit" interaction. This interaction was specifically linked with anhedonia dimension but not with total scores of depressive or anxiety symptoms.

Conclusions: The current findings provide preliminary evidence for an Epi × E interaction underlying reward processing highlight cross-level analyses of electrophysiological signals and advance knowledge of the biological foundation of stress-induced reward function and relevant symptoms. However caution should be paid to the generalizability of these findings in high-risk clinical samples given the high-functioning characteristic of the present sample.

Keywords: NR3C1 methylation; childhood maltreatment; event-related potential; goodness-of-fit; neuroimaging epigenetics; reward responsiveness.