Molecular Signatures of Major Depression

Abstract

SummaryAdversity, particularly in early life, can cause illness. Clues to the responsible mechanisms may lie with the discovery of molecular signatures of stress, some of which include alterations to an individual’s somatic genome. Here, using genome sequences from 11,670 women, we observed a highly significant association between a stress-related disease, major depression, and the amount of mtDNA (p = 9.00 × 10−42, odds ratio 1.33 [95% confidence interval [CI] = 1.29–1.37]) and telomere length (p = 2.84 × 10−14, odds ratio 0.85 [95% CI = 0.81–0.89]). While both telomere length and mtDNA amount were associated with adverse life events, conditional regression analyses showed the molecular changes were contingent on the depressed state. We tested this hypothesis with experiments in mice, demonstrating that stress causes both molecular changes, which are partly reversible and can be elicited by the administration of corticosterone. Together, these results demonstrate that changes in the amount of mtDNA and telomere length are consequences of stress and entering a depressed state. These findings identify increased amounts of mtDNA as a molecular marker of MD and have important implications for understanding how stress causes the disease.

The Cellular Sequelae of Early Stress: Focus on Aging and Mitochondria

“…In the same subjects, telomere length was reduced and mtDNA and telomere length were correlated (Tyrka et al, 2015a). Similar findings were reported in saliva of subjects with early stress and depression (Cai et al, 2015) and, in animals exposed to chronic stress or depression models, mitochondrial activity is impaired in the hippocampus, thalamus, and cortex (Picard et al, 2014). mtDNA copy number is a gross measure of mitochondrial activity; increases may occur as a compensatory response to impaired mitochondrial function (Picard et al, 2014).…”

“…Glucocorticoid exposure, and associated inflammatory and oxidative stress pathway activation, is linked with telomere shortening and may be a mechanism through which early stress contributes to telomere decline (Ridout et al, 2015). Glucocorticoid signaling is also involved in mitochondrial replication (Cai et al, 2015) and can damage mitochondria via elevating glucose levels, promoting systemic inflammation, altering gene expression in proapoptotic pathways, and hastening cellular aging (Picard et al, 2014). Increased demands on mitochondria in brain regions impacted by early stress such as the hippocampus may increase ROS production and mtDNA damage, contributing to reduced energy production and proapoptotic signaling in these brain regions, which may result in changes in neurotransmitter signaling, neuronal cell function, and viability (Picard et al, 2014).…”

Exploring the link between depression and accelerated cellular aging: telomeres hold the key

“…[43][44][45] Recently, in a large sample of 11,647 women, recurrent major depression was associated with shorter telomere length. 46 In addition, the chronicity of depression has been observed to be inversely associated with telomere length. In a previous study where only marginal association between current major depression disorder and telomere length was found, a significant inverse relationship was observed between total cumulative lifetime duration of depression and telomere length, with the mean difference of 281 bp, reflecting approximately 7 years of accelerated aging in those with cumulative lifetime depression.…”

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“…Many other genes may be involved in the pathogenesis of depression [35,36] (Table 1). New players, such as epigenetic changes, alterations in mtDNA related to oxidative stress, and modifications in telomere length may also contribute to alter neuronal mechanisms involved in depressive conditions [37]. SNPs of genes involved in DNA repair, such as genes encoding three glycosylases (hOGG1, MUTYH and NEIL1) (c.977C>G -hOGG1 (rs1052133), c.972G>C -MUTYH (rs3219489) and c.*589G>C -NEIL1 (rs4462560)), particularly in the base excision repair (BER) pathway, may also modulate the risk of recurrent Depression (rDD).…”