PhD defence B.S. (Bernard) Stikker

Below is a brief summary of the dissertation: 

Most common diseases such as asthma, Alzheimer’s disease or cardiovascular disease are not caused by a single DNA mutation, but are influenced by both genetic and environmental factors. The genetic susceptibility to these diseases have been investigated in genome-wide association studies (GWAS), that have associated thousands of small genetic to disease. 
The central theme of this thesis is to investigate how GWAS data can be used to gain a deeper understanding of the biology underlying human respiratory diseases. Drawing causal inferences from these data remains challenging, as these genetic variants have cell type-specific effects and it is often unclear what gene(s) are affected. Moreover, causals variants are often obscured by their tendency to be inherited together with non-causal variants during cell division. In this thesis, the main focus was on translating genetic variants found in GWAS into pathophysiological mechanisms for asthma and COVID-19. 
We investigated why some individuals are more prone to worse COVID-19 outcomes and identified common genetic variants that might disrupt genes important for inflammatory cell migration towards the lung, leading to increased risk of hospitalization. In the case of asthma, we present an extensive review on the current knowledge of asthma (epi)genetics and present a data platform that can be used to link common genetic variants to potentially disrupted mechanisms in asthma. Lastly, we show so-called ‘polygenic risk scores’, that are able to predict asthma risk for individuals in the Dutch population, and shed light on the underlying mechanism across different asthma subtypes.