Gene-Environment Interplay in Depression and Body Inflammation: How do our genes interact with our childhood experiences?
I am a researcher in Psychobiology and Epidemiology at University College London trying to understand the pathways through which psychosocial factors (e.g., stressful life events) influence our mental and physical health. I have been fascinated by the nature vs nurture debate surrounding the origins of depression since the beginning of my scientific career.
I’m pleased that this debate has finally been solved, and it is now recognised that both the environment in which we grow up and our genes may contribute to depression and its underlying biology. But how does this happen? How do nature and nurture work together to shape our mental health?
I’m very excited to share with you some new insights into the mechanisms by which our genes and early-life experiences may interact with each other and affect our risk of experiencing depression and body inflammation later in life.
The role of early-life experiences in depression and body inflammation
As discussed in an earlier blog, depression is a common mental health problem characterised by varying and sometimes opposing psychological and physical symptoms (e.g. depressed mood, feelings of guilt and worthlessness, loss of energy and fatigue, restlessness, decreased or increased sleep and appetite), which can have a devastating impact on our daily lives. Depression negatively affects the way we feel, think, and behave, influencing our relationships with people, productivity, and ability to work, and it can also lead to chronic physical diseases such as cardiovascular disease and diabetes.
Unfortunately, many people affected by depression do not respond well to current antidepressant treatments, and the reasons for this variability are not clearly understood. Several environmental and biological factors are thought to contribute to depression, as no single mechanism can fully explain all aspects of this complex, multifactorial disorder. Childhood experiences, for example, are particularly important in shaping our mental health throughout the course of our life.
Many studies have found a strong connection between exposure to adverse childhood experiences (ACEs), such as abuse, neglect, and family conflict, and the risk of depression in both children and adults. Our brain undergoes many changes during childhood, and for this reason, it is particularly vulnerable to the neurobiological effects of early-life stress.
The immune system is an important pathway through which ACEs may become “biologically embedded” and affect our susceptibility to depression. When we experience high levels of stress our immune system acts as if there was an infection (even if it’s not actually there!) and produces more immune signals (i.e. cytokines), leading to high levels of inflammation in the body.
In turn, elevated body inflammation can affect the way in which our brain works and predispose us to the psychological and behavioural symptoms of depression. Indeed, many studies suggest that individuals with ACEs, as well as people affected by depression, often have increased levels of inflammation in their bodies. A recent study has also found that adults who experienced traumatic events during childhood have elevated body inflammation, which in turn is related to a higher risk of future depressive symptoms. This suggests that early-life stress may affect depression through its long-term negative effects on the immune system.
What about the role of genes?
At this point, you are probably wondering how our genes are involved in all this. It is worth noting that not everyone experiencing high levels of stress will necessarily manifest body inflammation and develop depression later in life. Our genes could help us understand why some of us respond more negatively to stressful environments than others.
Thanks to recent advances in the field of genetics, researchers have been able to identify specific genetic variants found across all genes carried by an individual that are associated with their susceptibility to specific diseases. These variants can then be combined into a polygenic score that represents our genetic risk of developing a particular disorder, as explained in a previous blog.
An important finding of this research is that both depression and body inflammation are associated with several genetic variants, which means that many genes could affect the development of these disorders. However, these polygenic influences only explain a small proportion of our overall likelihood of experiencing depression and body inflammation (around 10%). This result is perhaps not surprising if we consider the multitude of environmental factors associated with these disorders (e.g. stress and unhealthy lifestyles).
How are our genes and early-life experiences linked together?
It is thus apparent that both ACEs and genetic factors can increase our susceptibility to depression and body inflammation. But it’s not exactly clear whether and how these two factors might interact with each other to shape our mental health.
Some researchers have suggested that our genetic make-up can make us more or less sensitive to the impact of early-life stress on mental health. In other words, the chances of developing depression following the experience of traumatic events might be much greater for a person who is at high genetic risk for depression than for someone at low genetic risk for depression — in science, this is known as a ‘gene-environment (GxE) interaction’. So, our genes could explain why not all people affected by ACEs will become depressed later in life.
Earlier research testing the interplay between genetic and environmental factors in depression has provided us with inconsistent results. Some studies found evidence for the proposed GxE interactions, but many others failed to replicate these effects. The main issue here is that most studies to date have focused on individual genetic variants linked to depression, rather than considering individual differences in polygenic scores. Polygenic scores capture the cumulative effects of several genetic variants, and therefore they are better indicators of our genetic risk for a particular disease, compared with the effects of individual genetic variants.
We also don’t know yet whether GxE interactions might contribute to our inflammatory responses to early-life stress, as very limited research has looked at this. For instance, the impact of stressful events on the immune system could be greater in people with a high genetic risk for body inflammation than in those at low genetic risk.
What did my research show?
During my PhD in Psychobiology & Epidemiology at University College London, I carried out a study focusing on the interplay between ACEs and polygenic scores in depression and body inflammation, which is now published in Psychological Medicine. I analysed data from a large cohort study of older adults living in England, known as ELSA (English Longitudinal Study of Ageing). This dataset is well suited to study the role of genetic, environmental, and biological factors in depression because it includes many assessments of depressive symptoms and blood concentrations of C-reactive protein (CRP; an inflammatory marker) over time, polygenic scores (PGSs) of depression and inflammation, and data regarding the participants’ childhood experiences.
First, I wanted to understand whether the PGSs and different types of ACEs, including threat-related adversities (sexual or physical abuse), experiences of household dysfunction (parent arguments, parent mental illness/substance abuse, parent separation/divorce), loss-related adversities (separation from mother, parent death, foster care/adoption), and poor child-parent relationships, were independently associated with depression and low-grade inflammation (i.e. CRP levels above 3mg/L). Second, I was interested in knowing whether the relationship of ACEs with depression and inflammation varied according to the participants’ genetic susceptibility to these conditions (i.e. low vs high PGSs), as suggested by the GxE theory discussed above.
My first finding was that all types of ACEs and the PGSs were independently associated with depression and increased body inflammation in this sample of older adults. The second finding was that the associations of ACEs with depression and inflammation were larger in participants with higher PGSs than for those with lower PGSs — yes, I did find some evidence for GxE interactions! Let’s now try to make sense of these interactions by considering some examples…
For instance, the odds of severe depressive symptoms for participants reporting at least three ACEs and with a high PGS of depression were almost 4 times larger than the odds for those with the same number of ACEs but a low PGS of depression.
I also found similar but smaller differences for body inflammation.
Among participants with multiple ACEs, the odds of low-grade inflammation were about 1.5 times larger for participants with a high PGS of inflammation compared with those who had a low PGS (see figure below). The graph on the left-hand side shows the estimated odds of depression according to the total number of ACEs and the value of the PGS of major depressive disorder (MDD); the graph on the right-hand side shows the estimated odds of low-grade inflammation according to the total number of ACEs and the value of the PGS of C-reactive protein (CRP).
How can we use this knowledge to improve mental health interventions?
To wrap it up, my research shows that both our genes and early-life experiences can have a long-lasting impact on our mental and physical health. Another striking result is that people with a high genetic risk for depression and body inflammation are more likely to manifest these disorders if they experienced traumatic events during childhood, compared with people who were also affected by childhood trauma but are at low genetic risk. So, our genes might, at least in part, determine whether or not we will develop body inflammation and depression when we experience high levels of stress.
Besides offering us new insights into the mechanisms influencing depression and body inflammation, these findings have relevant implications for mental health interventions. In particular, they highlight the importance of improving the detection of childhood trauma and the potential value of using genetic risk scores of stress-related disorders as clinical tools to design personalised treatment approaches for depression.
For example, some research suggests that GxE interactions could affect not only the development of depression but also the way in which depressed people respond to psychotherapy and pharmacological treatment. Therefore, the adoption of personalised approaches that take into account the patient’s history of traumatic events, genetic risk, and biological alterations can be useful for tailoring depression treatments and enhancing their effectiveness.
Although we still have a long road ahead of us, I hope that these results will stimulate more research into the role of GxE interactions in depression and body inflammation, which will ultimately help researchers and clinicians to develop new personalised interventions for depression.
