The role of our genes and the role of the environment
Numerous studies so far have shown there is a connection between depression and inflammation. Nearly 20%-30% of depressed patients have C-reactive protein (CRP) levels, an inflammatory biomarker, above 3mg/L indicating low-grade inflammation. Inflammation is a biological process activated by our immune system, usually as a response to an external threat that can cause an infection, and it is most of the time short-lived. However, in some cases, inflammation is triggered without any viruses or bacteria present, for example in people with obesity, diabetes or cardiovascular disorders, and it can even become chronic.
One of these cases is depression. However, it isn’t exactly clear yet how these two are connected. Does depression cause inflammatory levels to rise, or is inflammation the one that causes depressive symptoms? What factors are involved in this relationship? While previous blogs in InSPIre the Mind have discussed the link between depression and inflammation, here I want to discuss my research addressing an important question in this context: Do our genes play a role, or is it our everyday choices that have a higher likelihood of causing inflammation in depression — an effect that keeps getting captured in different studies around the globe? A psychologist by training, I was until recently a research assistant at King’s College London, where I conducted this research; I am now a PhD student at University College London (UCL) and Birkbeck, University of London.
In our recent study, we have decided to explore in more depth the association between depression and C-reactive protein (CRP). We used data from the UK Biobank, a large health resource. To our knowledge, our study is the largest of its kind to date to investigate the association between depression and inflammation, including data from 85,895 participants. To investigate the relationship between depression and inflammation, we used biomarker, genetic and questionnaire data.
First, we were interested to see if we can find an association between depression and inflammation, as has been described in previous studies. We were also curious whether there is a genetic predisposition to inflammation when you are experiencing depression, and whether polygenic risk scores (PRS; I will explain it below) for depression are associated with CRP levels. In addition, we were interested in the role of other external factors, such as body mass index (BMI), smoking, childhood trauma, socioeconomic and health status and whether they influence the depression-inflammation association.
Polygenic Risk Scores (PRS)
Before we examine the role of polygenic risk scores, it is important to understand what they are. The human genome is almost identical for all of us. However, some parts differ, and those parts, called genetic variants, give us our unique characteristics. These genetic variants are often harmless but some of them can increase or decrease our chances of experiencing various illnesses. Using statistical genetic methodologies, we can identify which genetic variants are associated with diseases of interest and then calculate a total score, called a polygenic risk score, that represents our chances of experiencing a particular disorder based on our genes.
Lifetime depression, raised CRP levels, and risk factors for inflammation
31.3% of the participants included in the study were classified as having major depressive disorder, matching the prevalence on a global scale that has been described in other studies. As expected, the participants with depression in our study had higher CRP levels compared to people without depression. They were also more likely to be smokers, to have experienced more childhood trauma, and to have higher Body Mass Index (BMI), more self-reported health problems and lower socioeconomic status. CRP levels were also strongly, associated with age (higher), sex (higher in males), BMI (higher), smoking (higher), socioeconomic status (higher in those with lower status) and ill health (higher), meaning that all the above factors are associated with CRP levels independently from depression.
Depression PRS is associated with CRP levels
We calculated PRSs for CRP and depression, and for a variety of autoimmune disorders, to investigate the genetic association with the measured CRP levels in our sample. A genetic correlation between depression and CRP showed that these two share some common genetic basis.
As expected, the CRP PRS was strongly positively associated with the participants’ measured CRP levels, even after taking into account the age, sex, BMI and smoking status of our participants.
Depression PRS was also positively associated with the measured CRP levels when considering the age and sex of the participants. To our surprise, this stopped being the case after taking into account the effect of BMI and smoking.
To gain a better understanding and interpretation of the findings mentioned above, we used the PRSs calculated for different autoimmune disorders to see if and how these were associated with CRP levels in our sample. The PRSs for Crohn’s disease, biliary cirrhosis and rheumatoid arthritis were also positively associated with CRP levels, even after taking into consideration the age, sex, BMI and smoking habits of our sample, unlike the depression PRS. This shows that the genetic association between depression and CRP levels is mediated by BMI and smoking. Therefore, the genetic contribution to the increased inflammation in depression is due to the regulation of eating and smoking rather than an autoimmune genetic predisposition.
Other factors and their effect on the association between depression and inflammation
We performed further analyses, using the mental health questionnaire data we had at our disposal (no genetic data were used in this analysis), and we tested whether depression was associated with CRP levels. There was a positive association between depression and inflammation after considering the effect of age and sex. This remained the case after taking into account the effect of BMI and smoking as well, even though the effect was slightly reduced.
We were interested then to see if other environmental factors could explain further the effect we were capturing in our analysis. The environmental factors refer to anything external, such as childhood trauma and socioeconomic status. We were also curious about the effect of general ill health, alcohol consumption and whether taking antidepressants or anti-inflammatory medication could explain the association between depression and inflammation fully. Our analyses showed that all these factors could explain a part of the association. However, even after considering all these, the association remains positively significant.
Our findings show that inflammation is potentially a core feature of depression, but there might still be factors playing a role in this association that we haven’t investigated yet.
However, it could also mean that the association between depression and inflammation remains no matter how many other factors, either internal or external, we take into consideration in our analyses.
One of the important points to remember is that even though genetics are important and can increase or decrease our chances to experience an illness, quite often environmental factors can have an equal or bigger impact. Depression PRS was positively associated with CRP levels. Yet, when we take into account the two environmental factors we can control, BMI and smoking, the significant association disappeared. This shows that up to a certain point, we can actively affect different health outcomes in our life by making healthier decisions, such as adopting a healthier diet, exercising and stopping smoking.
And these healthier decisions can improve not only physical health but also our mental health — possibly by reducing inflammation.