Peripheral GRID2 DNA methylation as a diagnostic biomarker for adolescent depression: Linking self-compassion to...

Adolescent depression is a prevalent psychiatric disorder that impairs psychosocial development and increases the risk of recurrence and comorbidities. Current diagnosis depends on subjective symptom assessments, highlighting the need for objective biomarkers. The glutamate receptor delta-2 (GRID2), involved in synaptic plasticity and mood regulation, may be epigenetically altered in depression. Self-compassion, a modifiable protective factor, is linked to lower depression risk, yet its neurobiological basis remains unclear. In this case-control study, 152 adolescents aged 10-19 years (102 with major depressive disorder and 50 healthy controls) completed depression assessments and the Self-Compassion Scale, and provided peripheral blood samples for targeted bisulfite sequencing of GRID2 DNA methylation. Depressed adolescents showed significantly lower methylation at GRID2-N and GRID2_09_107, and higher methylation at GRID2_09_195, compared with controls. Receiver operating characteristic analysis indicated that GRID2_09_107 methylation yielded the highest diagnostic performance (AUC = 0.689, sensitivity = 64.6 %, specificity = 70.0 %). Among depressed participants, GRID2 methylation was positively correlated with total self-compassion scores, particularly reduced feelings of isolation and over-identification, while higher GRID2-N methylation was associated with lower depression severity. Mediation analysis did not support GRID2 methylation as a mediator between self-compassion and depression severity. These findings identify GRID2 methylation, especially at CpG site 09_107, as a potential peripheral biomarker for adolescent depression, and reveal an epigenetic link between self-compassion and glutamatergic signaling. The results bridge psychological resilience factors with molecular mechanisms, supporting the integration of GRID2 methylation profiling into precision psychiatry and interventions that enhance self-compassion in adolescents.