Understanding the genetic basis of stress-sensitivity and depression.
In recent papers published in PLOS One and Translational Psychiatry, Dr Pippa Thomson describes work from her lab on the genetics of stress response and depressive symptoms. February 2019
It has been well recognised that Stressful Life Events (SLE) are a determinant of depressive symptoms. However, the observation has also been made that some individuals facing severe stress never present symptoms of depression. Experience of stress has also been associated with poorer physical and mental health in those affected, as a person’s response to stress is a predictor of the onset of Major Depressive Disorder (MDD). The way in which a person responds to such negative events is termed stress-sensitivity.
This variability of stress-sensitivity between different people has led to the theory that interaction between the stress experienced and a person’s vulnerability risk factors (termed diathesis) are key to explain this. Under this model genetic risk factors would be seen as a genetic diathesis, and their interaction with stress would be seen as a Gene-by-Environment interaction (GxE).
Understanding the genetics underpinning stress-sensitivity may lead to an identification of the molecular pathways involved. However, MDD is understood to be a highly polygenic disorder, composed of common variants with small effect and/or rare variants.
Across the three papers recently publish Dr Thomson’s lab have used data from the UK Biobank, Generation Scotland and the Major Depressive Disorder working group of the Psychiatric Genomics Consortium to allow them to study genetic response to stress and identify some potential candidate genes.
Understanding the effects of stress on mental health is of increasing importance in the modern world. Our results suggest that an individual’s sensitivity to stress is in part related to their genetic predisposition to depression.
Results published in Translation Psychiatry (link) validated the diathesis-stress theory supporting a previous study by Colodro-Conde et al. They also showed possible sex-specific differences in the effect of genetic response to SLE, though larger samples would be needed to confirm these observed differences. In the paper published in PLOS One (link), a gene ZNF366, was identified as significant. This gene is a negative regulator of glucocorticoid receptor function – moderating the cortisol stress response pathway, and has previously been implicated in alcohol dependence and has the potential to lead to a better understanding of the links between alcohol dependency and depression.
The link between stress and poor physical and mental health was examined in a second Translational Psychiatry paper (link). Here variants were identified that can predispose to depressive symptoms and may also show stress-related effects on personality traits, heart disease and progressive lung disease. This work indicates that further studies in this area could potentially result in improved treatments for depression and other stress-related conditions.
These studies highlight the need to combine the study of environmental and genetic risk factors to better understand their effects on health.
Genome-wide interaction study of a proxy for stress-sensitivity and its prediction of major depressive disorder. PLOS One 2018 Dec 20;13(12):e0209160: https://doi.org/10.1371/journal.pone.0209160
A validation of the diathesis-stress model for depression in Generation Scotland. Translational Psychiatry 2019 Jan 18;9(1):25: https://doi.org/10.1038/s41398-018-0356-7
Genome-wide by environment interaction studies of depressive symptoms and psychosocial stress in UK Biobank and Generation Scotland. Translational Psychiatry. (2019) 9:14: https://doi.org/10.1038/s41398-018-0360-y