Genome-Wide Analysis Uncovers Genetic Drivers of IPF and Its Overlap With COVID-19

A large-scale genomic investigation has identified new genetic risk factors for idiopathic pulmonary fibrosis (IPF) and revealed substantial overlap with pathways that also predispose individuals to severe COVID-19, offering fresh insight into disease biology and potential avenues for shared therapeutic development.

Integrating whole-genome sequencing with existing global datasets, the researchers say their study, published in eBioMedicine, has generated the most comprehensive picture to date of common and rare genetic variations underlying IPF.

Although several genetic associations have been identified over the last decade, much of the heritable risk of IPF remains unexplained. The research team sought to narrow this gap by combining whole-genome sequencing from the UK’s 100,000 Genomes Project with a meta-analysis of more than 11,700 patients with the condition and 1.4 million controls, enabling both fine-scale variant mapping and rare-variant burden testing.

The analysis uncovered a previously unreported risk locus at 1q21.2, with the lead variant (rs16837903) exhibiting a protective effect and mapping near the gene MCL1, a known regulator of apoptosis. This association was replicated in an independent cohort, strengthening confidence that it reflects a true biological signal.

The authors explored MCL1 because of its role in cell survival pathways and its increased expression in epithelial cells from patients with fibrotic lung disease, as seen in the single-cell data they examined. However, in vitro experiments showed that pharmacologic inhibition of MCL1 did not selectively eliminate senescent epithelial cells, suggesting that targeting this pathway alone may not yield therapeutic benefit.

“If MCL1 is the effector gene for the 1q21.2 association, our results suggest that epithelial cells might not be the prime target for an anti-MCL1 strategy to induce senolytic effects and improve the outcome for patients with IPF,” detailed the researchers. “Targeting other cell types using an anti-MCL1 strategy might have beneficial effects and further studies will be required to address these questions.”

A second putatively novel locus at 8q22.1 was also identified but did not replicate after statistical correction, leaving its contribution uncertain. Beyond common variants, the whole-genome sequencing dataset allowed rare-variant burden testing, revealing an intriguing association with ANGPTL7 driven by a single loss-of-function variant (rs143435072). This variant demonstrated an odds ratio of nearly 29 (odds ratio, 28.8; 95% CI, 8.51-97.4), indicating a substantial increase in IPF risk despite its low population frequency.

The study also revisited the genetic overlap between IPF and severe COVID-19, revealing a genetic correlation of 0.39 (95% CI, 0.25-0.53). Six loci were identified where the same genetic variant likely contributes to both diseases. These include shared signals at MUC5B, ATP11A, and DDP9, which have been previously implicated, but also newly reported overlapping loci near MCL1, DSP, and RHBDF1. Notably, some variants exhibited effects in the same direction for both conditions, suggesting shared pathological mechanisms, while others diverged, highlighting disease-specific pathways.

Through multi-trait meta-analysis, the researchers identified an additional association at 2p16.1, implicating the gene BCL11A, a regulator of hematopoiesis and immune cell development.

“Association signal at 2p16.1 displayed a protective effect and had lead variant rs1123573, which is in an intron of gene BCL11A, a zinc finger protein transcription factor involved in the regulation of the developmental switch from foetal to adult haemoglobin, is essential for lymphocyte development and have previously been linked with a wide range of diseases,” wrote the researchers.

Previous research has explored the overlap between COVID-19 and IPD, with one study pointing to a shared pathophysiology characterized by myeloid cell overactivation, impaired lymphocyte responses, and fibroblast proliferation.²

References

1. Kousathanas A, Odhams CA, Cook J, et al. Common and rare variant analyses reveal genetic factors underlying idiopathic pulmonary fibrosis and its shared aetiology with severe COVID-19. eBioMedicine. Published online November 27, 2025. doi:0.1016/j.ebiom.2025.106048

2. Mara G, Ninii G, Frent SM, Cotoraci C. Hematologic and immunologic overlap between COVID-19 and idiopathic pulmonary fibrosis. J Clin Med. 2025;14(15):5229. doi:10.3390/jcm14155229