Association Between DNA Methylation In Brain-derived Neurotrophic Factor Gene And Antidepressant Outcomes And Brain Structures In Patients With Major Depressive Disorder

BackgroundMajor depressive disorder(MDD)is one of the most common mental disorders,characterized by persistent and marked depressed mood and loss of pleasure.Recurrence,partial remission,and functional impairment caused by MDD lead to a heavy disease burden.According to the report of the Global Burden of Disease(GBD)Study 2019,MDD has become the second leading cause of years lived with disability(YLD).MDD is now a public health problem that cannot be ignored.MDD is suggested to be a consequence of the interaction of genetic and environmental factors.Environmental factors,e.g.,early life adversity,could influence gene expression via epigenetic mechanisms.DNA methylation in the brain-derived neurotrophic factor(BDNF)gene was suggested to be a biomarker of early life adversity.Accumulating evidence has indicated that DNA methylations in BDNF were associated with MDD and antidepressant outcomes.Nevertheless,the gene structure of BDNF was complex with at least nine exons,in which only exons Ⅰ and Ⅳ were widely analyzed by previous studies.Further studies should clarify the relationship between DNA methylation in other exons and MDD.BDNF is abundant in the brain,which could moderate the proliferation,differentiation,and maturation progress of neurons and oligodendrocytes.Therefore,the DNA methylation in BDNF could be speculated to moderate the brain structure in patients with MDD.Prior studies have demonstrated that DNA methylation in the BDNF gene was associated with cortical thickness in frontal and occipital lobes and white matter integrity in the anterior corona radiata in MDD.Future studies should focus on the influence of DNA methylation on cortical gyrification and the age-related alterations in white matter,which might reveal early brain development related to MDD.Therefore,we will conduct the research through the following steps:Firstly,we will detect the peripheral DNA methylation in multiple exons of the BDNF gene as MDD epigenetic markers.Secondly,we will analyze group differences in cortical thickness and gyrification between patients with MDD and healthy controls.Then,we will explore the relationship between epigenetic markers and grey matter features.Lastly,we will analyze the group different diffusion features of white matter between patients with MDD and healthy controls,especially the age-related white matter changes in MDD.This research will help further understand the epigenetic mechanism underlying unique brain structural changes in MDD.Part 1 DNA methylations in BDNF exon Ⅵ are associated with major depressive disorder and antidepressant-induced remissionObjective:The primary purpose of this study was to evaluate the association of the BDNF methylation with MDD and antidepressant treatment.Methods:A total of 291 MDD patients and 100 healthy controls were included and followed up for six 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 the negative subscore of LES was associated with MDD(OR=0.008,P<0.001).Methylation of BDNF140 at baseline was significantly elevated in remitters(FDR-adjusted P=0.046)at week 6.These findings could be replicated in females but not males.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.Part 2 The Association between DNA methylations in BDNF exon Ⅵ and grey matter changes in MDDObjectives:The present study aimed to investigate the relationship between cortical structural changes and DNA methylation in BDNF exon Ⅵ in MDD.Methods:Data from 93 patients and 59 controls were involved in statistics.FreeSurfer was recruited to analyze group differences in cortical thickness and gyrification between patients with MDD and healthy controls.General linear models(GLM)were recruited to analyze the moderate effects of DNA methylations in BDNF exon Ⅵ on cortical structural features between 2 groups.Results:The present study demonstrated significantly decreased cortical thickness(CT)in the left lateral orbitofrontal cortex(LOFC),left superior temporal lobe(ST),and right frontal pole(FP)and decreased local gyrification index(1GI)in the left superior parietal lobe(SP)in MDD patients(cluster wise P,CWP<0.05).Interaction effects between DNA methylation in 3 CpG sites in BDNF exon Ⅵ and MDD were associated with 1GI in left SP.These 3 CpG sites were BDNF 132(β=-0.417,FDR-adjusted P=0.019),BDNF137(β=-0.444,FDR-adjusted P=0.026),and BDNF151(β=-0.442,FDR-adjusted P=0.019).Post hoc analyses demonstrated negative associations between DNA methylations in 3 CpG sites and 1GI in left SP in MDD but not in controls.Conclusion:The present study has demonstrated decreased cortical thickness or gyrification in frontal,temporal,and parietal regions in patients with MDD.The inverse association between DNA methylation in BDNF exon Ⅵ and the gyrification changes in left SP highlight a potential epigenetic mechanism influencing cortical development in the brains of patients with MDD.Part 3 The Association between DNA methylation and white matter changes in BDNF exon Ⅵ in MDDObjective:The present study will investigate the group differences,especially the agerelated differences,between patients with MDD and health controls.We will further determine whether DNA methylation in BDNF exon Ⅵ could moderate age-related changes of white matter in MDD.Methods:A total of 88 MDD patients and 59 healthy controls were included.We used FSL software to preprocess diffusion images.White matters in the whole brain were segmented into 48 bundles according to the JHU ICBM-DTI-81 atlas.The means of fractional anisotropy(FA),mean diffusivity(MD),axial diffusivity(AD),and radial diffusivity(RD)in each bundle were calculated.GLMs were recruited to analyze the group differences and the age-related group differences.Detected differences were used to determine whether DNA methylation in the BDNF gene could moderate age-related white matter changes in MDD.Results:Significantly higher AD,MD,and RD could be found in several white matter bundles compared with healthy controls.Accelerated age-related AD,MD,RD increase,and FA decrease could be widely found in patients with MDD.Importantly,DNA methylations in BDNF134 and BDNF135 in BDNF exon VI could moderated agerelated increase of AD(βBDNF134=1.568,FDR-adjusted P=0.008;βBDNF135=1.300,FDR-adjusted P=0.013)and MD(βBDNF134=1.609,FDR-adjusted P=0.005;βBDNF135=1.172,FDR-adjusted P=0.049)in left SFO in patients with MDD.Conclusion:MDD showed accelerated aging with spreading white matter abnormality.DNA methylation in 2 CpG sites in BDNF exon Ⅵ could moderate the age-related abnormality in left SFO in patients with MDD.The SFO is a white matter bundle projecting to the left superior parietal lobe.