Epigenetic and expression-based modifications of depression-relevant genes as peripheral biomarkers for treatment-resistant depression and major depressive disorder
Mechanisms contributing to treatment resistant depression (TRD) and major depressive disorder (MDD) are poorly understood. Identifying peripheral biomarkers in an easily accessible tissue, such as whole blood, will enhance the mechanistic understanding of these disorders and could potentially establish targets for personalized treatment development. It has been shown that CpG methylation-based epigenetic modifications in the brain are associated with stress-related phenotypes. Therefore, the first portion of the current study sought to identify CpG methylation-based peripheral biomarkers of TRD concordant with brain CpG methylation in the rat, in a hormone-induced model of TRD. Many factors, both environmental and biological, can alter CpG methylation in blood and/or brain tissues in eukaryotes. This differential CpG methylation is a well-documented functional mechanism by which genes are differentially expressed. Depending on the specific gene, this functional alteration of expression can have downstream physiological and phenotypic effects. Taking into account the need to identify peripheral biomarkers of MDD in humans, the second portion of the current study sought to identify the association between lifetime MDD diagnosis status and peripheral, blood-derived methylation and expression. Finally, supplementary analyses of publically available datasets highlight the association between neuronal CpG methylation and lifetime MDD diagnosis status and using a cohort of deceased subjects with balanced prevalence of lifetime MDD cases and “healthy” controls, as well as intra-subject brain and blood CpG methylation correlations in “healthy” controls. The current study identified one salient peripheral biomarker for TRD that is concordant in CNS tissue, as well as one potential peripheral biomarker for MDD. In the TRD rat model, the first CpG site upstream of the transcription start site (TSS) in the promoter region of Slc6a3 was differentially methylated between case and control group animals in both mPFC and whole blood. Second, using blood drawn from human participants from the Detroit Neighborhood Health Study, SLC6A4 mRNA expression approached a significant association with lifetime MDD diagnosis status. Efforts to elucidate additional peripheral biomarkers should continue to expand to include polygenic CpG methylation measurements in multiple tissues.
Methylation, Expression, Blood, Brain, Human, Rat, Major depressive disorder, Treatment-resistant depression, Peripheral biomarker
University of Illinois - Urbana-Champaign
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University of Illinois at Urbana-Champaign