Depression affects over 350 million people worldwide.
A prospective cohort study identified that exposure to adverse or traumatic early life experiences significantly increases the likelihood of depression in childhood. However, until recently the biological processes by which this happens are poorly understood.
Image Credit: Stock-Asso/Shutterstock.com
Nonetheless, the identification of the molecular mechanisms through which adverse events become biologically embedded is likely to offer new insights into its pathogenesis and therapeutic target.
DNA modification and linked genes
DNA methylation is a molecular modification that alters gene expression without a change in the DNA sequence. This alteration of DNA can be influenced by stressful and socioenvironmental factors.
Aberrant methylation of DNA has been previously been associated with numerous neuropsychiatric disorders such as depression and schizophrenia.
Therefore, emphasizing the possibility that early life events can become embedded in mental illness in later life.
There is mounting evidence from experimental and human studies suggesting that a stressful childhood experience or a psychological trauma in adulthood can have significant and lasting impacts on DNA methylation or other epigenetic modifications.
Several genes have previously been identified as part of the stress response pathway. These genes include the glucocorticoid receptor (NR3C1), brain-derived neurotrophic factor (BDNF), serotonin transporter (SLC6A4) and monoamine oxidase (MAOA, MAOB).
The altered methylation status of these genes could lead to an impaired negative feedback response of the HPA-axis thereby contributing to depression. Possibly through the blunting the HPA-axis response to stress.
In two monozygotic twin studies, Peng et al. (2018) demonstrated that the methylation of the above stress genes was jointly associated with depressive symptoms and partially mediated the effect between childhood trauma and depressive symptoms in adulthood.
These findings highlighted the importance of examining the combined epigenetic effects of multiple CpG loci on complex human traits.
It is well recognized that adversity in early life is a strong predictor of health outcomes in later life. Therefore, different forms of childhood trauma may result in different clinical outcomes, although the molecular mechanisms underpinning it are yet to be determined.
A previous study including 533 children of those exposed to physical or sexual abuse in early childhood years displayed different patterns of cortisol fluctuations during a day, possibly indicating differential neuroendocrine responses to early traumatic experiences.
A similar phenomenon has been observed whereby women who were sexually abused before puberty exhibited a different architecture of their brains.
This similarly reflects the neuroendocrine response to traumatic exposures in their early childhood. It is interesting to note that in Peng’s study there was specific hypermethylation of one CpG probe in the MAOB gene that appeared to respond to sexual abuse (P=0.04) but not to any other forms of traumatic experiences.
It was also observed the hypermethylation of several CpG sites of the NR3C1 gene was associated with physical abuse, but no other forms of a traumatic event.
An interesting element of this study to note was the hypermethylation of the CpG probe in the BDNF gene was positively associated with depressive symptoms.
This is consistent with previous research that identified a decreased serum BDNF level associated with depression and a decreased synthesis of the BDNF level in the neurons was correlated with the hypermethylation of the BDNF gene.
Limitations and future directions
Whilst numerous studies have been carried out, there is still limited evidence of epigenetic alterations and differential health outcomes induced by childhood trauma are limited. Whilst there is evidence to suggest the NR3C1 gene methylation and childhood trauma are linked this has not been consistently replicated.
The full complements of the molecular mechanisms involved in childhood trauma-related health outcomes are yet to be fully elucidated.
This is further complicated by the possibility of coordinate regulation of epigenetic processes in multiple genes or pathways. Pleiotropic effects (where more than one gene is associated) is commonly seen in multiple psychiatric disorders.
However, new technologies and strategies are emerging in the field. An example of which is the nanopore sequencing framework, which can distinguish five types of methylation with high- throughput. This reduces the preparation processes and increases the detection speed.
Whilst earlier methods have identified parts of the brain which are ‘highlighted’ in response to stressful situations.
There is a greater need to determine the cell- type specificity of epigenetic changes therefore achieving a single cell or single-cell type resolution is a key goal. Single-cell sequencing can allow us to distinguish methylated changes in different cell types reducing possible errors.
Using a technique such as this alongside sex-dependent stratification the responses in males and females could be distinguished. However, as psychiatric disorders could be reliant on a network of cell types and neuronal pathways a technique such as this may not be sufficient.
- Organization., W.H. Depression: A Global Crisis. World Mental Health Day, October 10, 2012. Occoquan: World Federation for Mental Health. 2012available at: http://www.who.int/mental_health/management/depression/wfmh_paper_depression_wmhd_2012.pdf.
- Peng H, Zhu Y, Strachan E, et al. Childhood Trauma, DNA Methylation of Stress-Related Genes, and Depression: Findings From Two Monozygotic Twin Studies. Psychosomatic Medicine. 2018 Sep;80(7):599-608. DOI: 10.1097/PSY.0000000000000604.
- Heim C, Binder EB. Current research trends in early life stress and depression: a review of human studies on sensitive periods, gene-environment interactions, and epigenetics. Exp Neurol. 2012;233(1):102–11.