Extra-pulmonary effects of lung function and lung disease

  • Daniel H Higbee

Student thesis: Doctoral ThesisDoctor of Philosophy (PhD)


Traditional observational epidemiology has described an association between reduced lung function and lung disease with extra-pulmonary diseases. However, this method cannot establish causality and is affected by bias from residual confounding and reverse causation. If the observed association is causal, then treatments to maintain or improve lung function could reduce the huge burden of extra-pulmonary co-morbidity. My objective was to utilise novel genetic epidemiological techniques to determine if reduced lung function or lung disease has a causal effect on extra-pulmonary disease. I used both traditional and genetic epidemiology to research an understudied pathological lung function state, Preserved Ratio Impaired Spirometry (PRISm), and its extra-pulmonary associations. The COVID pandemic created a need to examine asthma and mental health during lockdown.
Two Sample Mendelian Randomisation (MR) techniques were used to determine if reduced lung function and COPD have a causal effect on Alzheimer’s Disease, cardiovascular disease, and cognitive function. I used the UK Biobank to examine the risk factors, associations, and mortality of PRISm and then performed a Genome-Wide Association Study of PRISm. Traditional epidemiology was used to examine the effect of asthma on mental health outcomes during COVID-19 lockdown in the Avon Longitudinal Parents and Child Cohort.
MR studies showed no strong evidence for an effect of reduced lung function/lung disease on cognitive function or the risk of Alzheimer’s disease. However, there was strong evidence that reduced Forced Vital Capacity (FVC), but not Forced Expiratory Volume in one second (FEV1), causes an increased risk of coronary artery disease. PRISm is common, and despite being a relatively transient state is associated with co-morbidities and an increase in mortality compared to those with normal spirometry. Genetic studies show that there may be shared genetic risk factors for PRISm and its co-morbidities. Mental health outcomes in those with asthma worsened during the lockdown to lower levels than the general population.
There is a strong association between lung function, lung disease and extra-pulmonary disease, with genetic epidemiology providing evidence that this relationship is causal, and there may be shared genetic risk factors. This thesis demonstrates the value of triangulating different epidemiological methods and highlights future areas of research that may lead to lung function becoming a screening tool and/or modifiable risk factor for extra-pulmonary diseases.
Date of Award12 May 2022
Original languageEnglish
Awarding Institution
  • University of Bristol
SupervisorGeorge Davey Smith (Supervisor), James Dodd (Supervisor) & Raquel Granell (Supervisor)

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