Using Mendelian Randomisation to Establish the Causal Role of Cigarette Smoking in Anxiety and Depression

Cigarette smokers typically have higher levels of anxiety and depression, while people with anxiety and depression are more likely to smoke. There are broadly two explanations for this: One is that cigarette smoking increases the risk of anxiety and depression, while the other is that people with anxiety and depression are more likely to smoke because it helps them to regulate their mood. This is an important question, not least because it may help to identify novel ways with which to treat depression (for example, by isolating some of the relevant chemicals within cigarette smoke). However, it is difficult to disentangle these possibilities because it is unethical to randomly assign some people to smoke and others not to. Other factors which influence both how likely you are to smoke, and how likely you are to be anxious or depressed, may also give the impression of a causal relationship when in fact there is none - a problem known as confounding.

We know that genes may influence the likelihood of starting smoking, how much one smokes, and how easy it is to stop smoking. Recently, some specific genes which predict the likelihood of how much one smokes have been identified. The version of a gene which you have is an essentially random process which means that it is unrelated to other factors which might introduce confounding. This means that these genes can be used as "instrumental variants" which influence, for example, how much one smokes - people with one version may, on average, smoke slightly more than those with a different version in a way which is unrelated to other factors (such as income level, which is a common confounding factor). If these genes are also associated with the likelihood of anxiety and depression, in particular among smokers but not among non-smokers, this would provide evidence of a causal relationship between cigarette smoking and anxiety and depression.

We propose to use existing data which has been collected on a large number of people about their smoking habits, anxiety and depression, as well as genetic data on genes which influence heaviness of smoking and the ability to stop smoking. This will provide very important insights into whether and how cigarette smoking is causally related to anxiety and depression, and potentially lead to the development of novel treatments for these very common and disabling mental health problems.

Anxiety and depression are highly prevalent in the general population, and constitute a substantial burden of disease - for example, in Europe 7.2% of morbidity in adults can be attributed to depression. Cigarette smoking is highly co-morbid with anxiety and depression. However, despite the popular belief that cigarette smoking can reduce anxiety and low mood, there is evidence that the association is in the opposite direction, namely that smoking leads to anxiety and depression. Given the profound public health burden of both tobacco-related disease, and anxiety and depression, understanding this relationship is of great importance. In particular, it will inform the development of novel treatments for anxiety and depression which target this pathway.

One possible answer to both of these difficulties lies in the application of the principle of Mendelian randomisation, whereby genetic information can be used to test causal hypotheses regarding the effects of environmental exposures such as cigarette smoking. This requires specific polymorphisms that have been shown to be robustly associated with measures of exposure (e.g. smoking quantity or smoking cessation). Given the random assortment of genes from parents to offspring that occurs during gamete formation and conception, genotype should not be related to potential confounders. A robust genetic influence on cigarette smoking would be akin to a randomised trial where individuals are effectively assigned to a high or low smoking exposure group, and could be used to test the causal relationship between smoking and depression.

We propose to use single nucleotide polymorphisms associated with tobacco use phenotypes (heaviness of use and cessation) as genetic instruments to address the causal effects of cigarette smoking on anxiety and depression. We propose to do this, using data from an international consortium of epidemiological studies.

In the short-term, researchers investigating the nature of the co-morbidity between cigarette smoking, anxiety and depression will benefit from this research. In particular, our research will help to clarify whether there is a causal relationship which underpins this co-morbidity and, if so, in which direction it will operate.

In the medium-term, researchers in psychiatric genetics and psychiatric epidemiology will also benefit from exposure to the Mendelian randomisation techniques which we will employ. As genetic variants associated with modifiable exposures such as cigarette smoking are discovered, the scope for implementing this technique to explore the aetiology of mental health outcomes will increase.

In the longer-term, the establishment of a causal relationship between cigarette smoking and anxiety and depression will aid in the search for novel treatment targets, through the implication of specific pathways involved related to the genetic variants used as instruments in our analyses. While a downstream consequence of our research, this has the potential to generate substantial impact.