Identification of novel protein drug targets for respiratory diseases by integrating human plasma proteome with GWAS

<bold>Background:</bold> Common respiratory diseases collectively stand as a leading cause of health complications and deaths worldwide, and identifying new drug targets for common respiratory diseases is urgently needed. Here we employed proteome-wide Mendelian randomization (MR) and colocalization analyses to identify potential targets for these diseases. <bold>Methods:</bold> Summary-level data of circulating protein levels were extracted from two large-scale protein quantitative trait loci studies. Genetic associations with common respiratory diseases were mainly obtained from the Global Biobank Meta-analysis Initiative and the FinnGen study. MR analysis was conducted to estimate the associations between protein and risk of common respiratory diseases. The colocalization analysis and summary-data-based MR analyses were performed sequentially to verify the causal role of candidate protein-trait associations. <bold>Results:</bold> Genetically predicted levels of 2,942 circulating proteins were associated with common respiratory diseases. Of 582 associations supported by evidence from MR, 29 were supported by results of colocalization analyses, including five proteins (NRXN3, NRXN3B, MAPK3, COMMD1, and PRSS27) in relation to chronic obstructive pulmonary disease, three proteins (TEF, CASP8, and IL7R) associated with asthma, and the FUT3_FUT5 linked to idiopathic pulmonary fibrosis. <bold>Conclusion:</bold> The current study reveals causal proteins implicated in prevalent respiratory disorders, enriching our understanding of disease molecular etiology and aiding the development of therapeutic interventions.