DNA methylations of brain-derived neurotrophic factor exon VI are associated with major depressive disorder and antidepressant-induced remission in females

Background: Brain-derived neurotrophic factor (BDNF) has been suggested to play important roles in major depressive disorder (MDD) and antidepressant treatment. The main purpose of this study was to evaluate the association of DNA methylation changes in the BDNF gene with MDD and antidepressant treatment. Methods: A total of 291 MDD patients and 100 healthy controls were included and followed up for 6 weeks. The Hamilton Depression Rating Scale-17 (HDRS-17) was used to measure treatment improvement. The life events scales (LES) and childhood trauma questionnaire (CTQ) were used to rate recent and early life stress. DNA methylation levels of CpG sites in the BDNF gene were measured. Results: Two CpG sites in BDNF exon VI (BDNF133 and BDNF134) were demonstrated to have significantly higher methylation in MDD patients than in controls (both FDR-adjusted P = 0.001). A logistics regression model indicated that the interaction between the hypermethylation of BDNF133 and negative subscore of LES was associated to MDD (OR=0.0075, P<0.001). Methylation of BDNF140 at baseline was significantly elevated in remitters (FDR-adjusted P = 0.046) at week 6. In subgroup analyses, these findings could be replicated in females, but not in males. Limitations: The methylation status of BDNF after 6 weeks of antidepressant treatment was not measured and the DNA methylation were detected in peripheral blood cells. Conclusions: These findings highlight gender-specific alteration of methylation at several CpG sites in BDNF exon VI as a promising candidate indicator of MDD and antidepressant-induced remission.