Applying a multidisciplinary approach to defining molecular pathways in lung function impairment (360G-Wellcome-225221_Z_22_Z)

We have led advances in the genetic epidemiology of lung function, but the causal genetic variants and causal genes, and the mechanisms by which they influence lung function, chronic obstructive pulmonary disease (COPD) and other respiratory diseases remain incompletely understood. Through a new collaborative interdisciplinary endeavour, we will accelerate discovery of genetic risk factors for lung function impairment, and define the mechanisms and biological pathways underpinning the observed associations. To achieve this, we will use new genomic data from population studies, building on the cross-ancestry studies of the SpiroMeta consortium, and integrate with new multi-omic datasets using improved statistical genetic methodologies. To prioritise pathways we will undertake high-throughput functional genomic screens using CRISPR, perform lung digital spatial transcriptomic profiling and utilise informative mouse models. This will inform in-depth mechanistic assays at the cell, tissue and organ scales to identify the key mechanisms underpinning regulation of lung function in health and disease. The complementary strengths in each contributing centre will enable a co-ordinated approach for efficient prioritisation of key pathways. This programme of research will improve the diagnosis, treatment and prevention of respiratory disease through mechanistic discoveries that identify new drug targets and biomarkers, and that highlight drug re-purposing opportunities.