Abstract
Previous evidence suggests that the serotonin transporter gene (SLC6A4) is associated with the structure of brain regions that are critically involved in dysfunctional limbic-cortical network activity associated with major depressive disorder (MDD). Diffusion tensor imaging (DTI) and tract-based spatial statistics were used to investigate changes in white matter integrity in patients with MDD compared with healthy controls. A possible association between structural alterations in white matter tracts and DNA methylation of the SLC6A4 promoter region was also assessed. Thirty-five medication-naive patients with MDD (mean age: 40.34, male/female: 10/25) and age, gender and education level matched 49 healthy controls (mean age: 41.12, male/female: 15/34) underwent DTI. SLC6A4 DNA methylation was also measured at five CpG sites of the promoter region, and the cell type used was whole-blood DNA. Patients with MDD had significantly lower fractional anisotropy (FA) values for the genu of the corpus callosum and body of the corpus callosum than that in healthy controls (family-wise error corrected, P<0.01). Significant inverse correlations were observed between SLC6A4 DNA methylation and FA (CpG3, Pearson's correlation: r=−0.493, P=0.003) and axial diffusivity (CpG3, Pearson's correlation: r=−0.478, P=0.004) values of the body of the corpus callosum in patients with MDD. These results contribute to evidence indicating an association between epigenetic gene regulation and structural brain alterations in depression. Moreover, we believe this is the first report of a correlation between DNA methylation of the SLC6A4 promoter region and white matter integrity in patients with MDD.
Highlights
The pathophysiology of major depressive disorder (MDD) involves interactions between susceptible genotypes, chronic stress and an adverse developmental environment, which lead to alterations in the biochemistry, neuroplasticity and structure of the brain.[1]
There were no significant differences in the demographic variables tested between patients with MDD and the healthy controls, with the predicted exception of Hamilton Depression Rating Scale (HDRS) scores (Table 1)
Medication-naive patients with MDD showed significantly lower fractional anisotropy (FA) values for the genu of the corpus callosum and body of the corpus callosum compared with healthy controls (FWE corrected, P = 0.004; Table 2 and Figure 1)
Summary
The pathophysiology of major depressive disorder (MDD) involves interactions between susceptible genotypes, chronic stress and an adverse developmental environment, which lead to alterations in the biochemistry, neuroplasticity and structure of the brain.[1] Neuroimaging studies on depression have consistently identified neuroanatomical alterations in gray matter regions that participate in affect regulation.[2] Given that white matter tracts connect various gray matter areas of the brain, many studies have investigated possible alterations in white matter architecture and integrity in patients with MDD. The heritability of MDD is estimated to range from 31 to 42%5 and the pathogenesis is thought to be significantly influenced by multiple genes, genetic linkage and association studies have not identified specific strong and consistent MDD susceptibility genes.[6] Altered serotonergic neurotransmission has repeatedly been implicated as a key contributor to the etiology of depression;[7] genes that contribute to regulation of serotonin activity have been widely studied in relation to MDD
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