Abstract
The pathophysiology of major depressive disorder (MDD) encompasses an array of changes at molecular and neurobiological levels. As chronic stress promotes neurotoxicity there are alterations in the expression of genes and gene-regulatory molecules. The hippocampus is particularly sensitive to the effects of stress and its posterior volumes can deliver clinically valuable information about the outcomes of antidepressant treatment. In the present work, we analyzed individuals with MDD (N = 201) and healthy controls (HC = 104), as part of the CAN-BIND-1 study. We used magnetic resonance imaging (MRI) to measure hippocampal volumes, evaluated gene expression with RNA sequencing, and assessed DNA methylation with the (Infinium MethylationEpic Beadchip), in order to investigate the association between hippocampal volume and both RNA expression and DNA methylation. We identified 60 RNAs which were differentially expressed between groups. Of these, 21 displayed differential methylation, and seven displayed a correlation between methylation and expression. We found a negative association between expression of Brain Abundant Membrane Attached Signal Protein 1 antisense 1 RNA (BASP1-AS1) and right hippocampal tail volume in the MDD group (β = −0.218, p = 0.021). There was a moderating effect of the duration of the current episode on the association between the expression of BASP1-AS1 and right hippocampal tail volume in the MDD group (β = −0.48, 95% C.I. [−0.80, −0.16]. t = −2.95 p = 0.004). In conclusion, we found that overexpression of BASP1-AS1 was correlated with DNA methylation, and was negatively associated with right tail hippocampal volume in MDD.
Highlights
Major depressive disorder (MDD) is one of the leading causes of morbidity and disability worldwide
RNA expression and DNA methylation We identified 60 RNAs which were differentially expressed between groups
We found no effects of blood cell composition on DNA methylation (Table S2)
Summary
Major depressive disorder (MDD) is one of the leading causes of morbidity and disability worldwide. Neuroimaging and biological studies may provide insight into the pathophysiology of depression and potentially aid in the diagnostic process. One candidate mechanism is structural abnormalities within the hippocampus. This region is known to regulate behavioral and neuroendocrine responses to stress and can be sensitive to excessive exposure to stress-induced release of steroidal and inflammatory signaling molecules [5, 6]. The hippocampus seems to be a highly stress-sensitive brain region [7, 8] and MDD is a highly stress-sensitive illness [9]. Preclinical studies suggest that stress can result in structural changes to the hippocampus [10, 11]. Several metanalyses of magnetic resonance imaging (MRI) data suggest
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