Abstract: Background: A shared genetic component between coronavirus disease 2019 (COVID-19) and idiopathic pulmonary fibrosis (IPF) has been described based on analyses of individual risk variants. Here we used a whole-genome polygenic risk score (PRS) approach to further evaluate age- and sex-stratified genetic overlap between IPF and severe COVID-19 to give insight into shared biological mechanisms that might both inform therapeutic strategies for both diseases. Methods: We used results from the largest genome-wide association study of clinically defined IPF risk (4125 cases/20?464 controls) and individual-level data from the SCOURGE European study of COVID-19 (5968 cases/9056 controls). We calculated IPF PRSs and assessed their association with COVID-19 severity, stratified by age and sex. We performed replication in an independent dataset of Latin-American patients (1625 cases/1887 controls). Enrichment and pathway-specific PRS analyses were performed to study biological pathways associated with COVID-19 severity. Results: IPF PRSs were significantly associated with COVID-19 hospitalisation and severe illness in Europeans and replicated in a Latin-American cohort. The strongest association was found in <60 years patients, especially among younger males (p=6.39×10?5). Pathway-specific PRSs analyses supported a link to cadherin and integrin signalling pathways. Conclusions: The study indicates age and sex-dependent genome-wide genetic overlap between IPF and severe COVID-19 and highlights specific shared biological mechanisms underlying both conditions. This could also imply that individuals with a high IPF genetic risk are at an overall increased risk of developing lung sequelae resulting from severe COVID-19.

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