Unraveling the genetics of human lung disease

In contrast to Mendelian diseases, most modern and 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 polygenic nature of these diseases has been investigated in genome-wide association studies (GWAS), that have associated thousands of genetic variants (mainly single-nucleotide variants; or SNVs) to disease.

The central theme of this thesis is to investigate how GWAS data can be used to gain a deeper understanding of the molecular pathways underlying human respiratory diseases. Drawing causal, biological inferences from these data remains challenging, as causals variants have cell type-specific effects and predominantly reside in the non-coding genome, where it is unclear what gene(s) are affected. Moreover, causals variants are often obscured by linkage disequilibrium (LD), the phenomenon of nonrandom association of alleles at multiple DNA markers because of their close proximity. In this thesis, the main focus was on translating genetic variants found in GWAS into pathophysiological mechanisms for asthma and COVID-19.