The co-morbidities of smoking: uncovering underlying mechanisms

Cigarette smoking remains a common cause of premature disease and death, with 25.4% of Dutch men and 18.1% of Dutch women smoking in 2019 (1). There is a strong association between smoking and poor mental health, with smokers more often being diagnosed with a mental illness (such as schizophrenia (2)) and showing poorer cognitive functioning (3) when compared to non-smokers. The nature of these co-morbidities is still poorly understood. It may be that there are shared risk factors, but there is also evidence for causal effects, such that smoking negatively impacts mental health or the other way around, that poor mental health increases smoking. 
This project focusses on two smoking related co-morbidities that are particularly poorly understood and for which high-quality evidence is lacking: the relationship between smoking and poor cognitive functioning and the relationship between smoking, schizophrenia and cardiovascular disease. Both topics will be described in more detail below. 
Smoking and poor cognitive functioning: Individual differences in executive functioning – e.g. inhibitory control and working memory – are related to a dominance of short-term over long-term goals. Accordingly, poorer executive functioning is associated with smoking initiation, heavier smoking and lower odds of quitting. However, the causal nature of these relationships is unclear Weaker executive functions may precede smoking initiation, but there is also evidence that smoking can cause cognitive changes, and nicotine withdrawal has been linked to decreased executing functioning. Well-powered, longitudinal population studies that look at the association between smoking and cognitive functioning are currently lacking in the literature. We propose to use the large data-set of Lifelines to shed light on this important question by looking at cross-sectional and longitudinal associations between smoking behaviour and cognitive functioning and how changes in one of the variables relate to changes in the other. 
Smoking, schizophrenia and cardiovascular disease: Individuals diagnosed with schizophrenia live, on average, 15 years shorter than individuals from the general population (4). The most important reason for this stark figure is that schizophrenia patients are at increased risk of cardiovascular mortality. This is reflected by the high prevalence of cardiovascular disease markers among individuals with schizophrenia, including hypertension, high levels of cholesterol, low heart rate variability (an index of cardiac autonomic function) and abnormal ECG patterns (5,6). While there is little research into the mechanism underlying this association, it is likely that smoking is of importance. Schizophrenia patients show disproportionally high smoking rates compared to the general population (2) and smoking is well-known to cause cardiovascular disease (CVD). However, to what degree smoking explains the link between schizophrenia and CVD is unclear and there are also other important factors to consider including related lifestyle factor such as alcohol use, lack of physical activity and BMI (6). In addition, antipsychotic medication use is known to cause weight gain and dyslipidemia (increased amounts of fat in blood plasma) meaning that this also needs to be corrected for (7). There are only a handful of longitudinal studies that have investigated this relationship, but because not all (important) confounders were taken into account, the evidence for causal effects that these studies provide may be biased. In addition, schizophrenia is a very rare disorder, which means that many studies lack power when comparing diagnosed patients to controls. An alternative but as of yet not yet applied method is to test associations between genetic risk for schizophrenia (so-called polygenic risk scores) and relate these to smoking and cardiovascular disease. We propose to use the large data-set of Lifelines to shed light on this important question by looking at associations between schizophrenia diagnosis, smoking behaviour and cardiovascular disease, and at associations between polygenic risk scores for schizophrenia, smoking behaviour and cardiovascular disease.