Genome-wide association study of Idiopathic Pulmonary Fibrosis susceptibility using clinically-curated European-ancestry datasets
Authors: Chin Daniel , Hernandez-Beeftink Tamara , Donoghue Lauren , Guillen-Guio Beatriz , Leavy Olivia C , Adegunsoye Ayodeji , Booth Helen L ,   CleanUP-IPF Investigators of the Pulmonary Trials Cooperative, Fahy William A , Fingerlin Tasha E , Gooptu Bibek , Hall Ian P , Hart Simon P , Hill Mike R , Hirani Nik , Hubbard Richard B , Johnson Simon , Kaminski Naftali , Lorenzo-Salazar Jose Miguel , Ma Shwu-Fan , McAnulty Robin J , McCarthy Mark , Stockwell Amy D , Maher Toby M , Millar Ann B , Molyneaux Philip L , Molina-Molina Maria , Navaratnam Vidya , Neighbors Margaret , Oldham Justin M , Parfrey Helen , Saini Gauri , Sayers Ian , Sheng X Rebecca , Stewart Iain D , Strek Mary E , Tobin Martin D , Whyte Moira KB , Zarcone Maria C , Zhang Yingze , Martinez Fernando , Yaspan Brian L , Reynolds Carl J , Schwartz David A , Flores Carlos , Noth Imre , Jenkins R Gisli , Allen Richard J , Wain Louise V 
Published: February 2025

Background

Idiopathic pulmonary fibrosis (IPF) is a rare, incurable lung disease with a median survival of 3-5 years after diagnosis. Treatment options are limited. Genetic association studies can identify new genes involved in disease that might represent potential new drug targets, and it has been shown that drug targets with support from genetic studies are more likely to be successful in clinical development. Previous genome-wide association studies (GWAS) of IPF susceptibility have identified more than 20 signals implicating genes involved in multiple mechanisms, including telomere dysfunction, cell-cell adhesion, host defence immunity, various signalling pathways and, more recently, mitotic spindle assembly complex.

Aim

To leverage new datasets and genotype imputation to discover further genes involved in development of IPF that could yield new pathobiological avenues for exploration and to guide future drug target discovery.

Methods

We conducted a GWAS of IPF susceptibility including seven IPF case-control studies comprising 5,159 IPF cases and 27,459 controls of European ancestry, where IPF diagnosis was made by a respiratory clinician according to international guidelines. Genotypes were obtained from Whole Genome Sequencing (WGS) or from array-based imputation to the TOPMed WGS reference panel. New signals were replicated in independent biobanks with IPF defined using Electronic Healthcare Records. Bayesian fine-mapping was performed to identify the most likely causal variant(s) and bioinformatic investigation undertaken to map associated variants to putative causal genes.

Results

We identified three novel genetic signals of association with IPF susceptibility. Genes prioritised by functional evidence at these signals includedMUC1, which encodes a large transmembrane glycoprotein and known biomarker of lung fibrosis, andNTN4encoding Netrin-4 whose known roles include angiogenesis. The third signal may map toSLC6A6,a taurine and beta-alanine transporter gene, previously implicated in retinal, cardiac and kidney dysfunction.

Conclusion

Our study has identified new associations not previously identified by previous large biobank-based studies thereby highlighting the value of utilising clinically-curated IPF case-control studies, and new genotype imputation. We present new evidence for disease-driving roles ofMUC1and of endothelial cell and vascular changes in IPF.