Common and rare variant analyses reveal genetic factors underlying idiopathic pulmonary fibrosis and its shared aetiology with severe COVID-19.

Abstract

Idiopathic pulmonary fibrosis (IPF) is a progressive and debilitating respiratory disease with limited therapeutic options. Genetic association studies for IPF have identified several associations and probable effector genes that could not only help understanding IPF pathogenesis but also develop effective treatments. Assessing genetic overlap between IPF and severe COVID-19, an acute respiratory disease that can trigger pulmonary fibrosis, may reveal shared aetiology and mechanisms, thereby supporting the development of common treatments. We carried out genome-wide association studies (GWAS), post-GWAS, and rare variant analyses using whole genome sequencing data from the 100,000 Genomes Project IPF cohort (n = 586). We performed a meta-analysis combining 100 kGP with published IPF GWASs (total 11,746 cases and 1,416,493 controls). We tested inhibition in vitro for a probable effector gene of an identified association. We also investigated genetic colocalisation between IPF and severe COVID-19 and leveraged their genetic correlation through multi-trait meta-analysis for discovery. IPF meta-analysis identified an additional association at 1q21.2 (rs16837903, OR [95% CI] = 0.88 [0.85, 0.92], P = 9.5 × 10^-9), which was replicated in independent data. MCL1, one of the probable effector genes of the 1q21.2 signal has a known antiapoptotic role, but MCL1 inhibition in vitro did not selectively deplete senescent alveolar epithelial cells. Rare variant burden analysis identified ANGPTL7, a secreted glycoprotein involved in the regulation of angiogenesis, as an IPF candidate gene (OR [95% CI] = 28.8 [8.51, 97.4], P = 6.7 × 10^-8). We discovered additional shared genetic loci between IPF and severe COVID-19 at 1q21.2, 6p24.3, and 16p13.3, with probable effector genes MCL1, DSP, and RHBDF1, implicating regulation of apoptosis, cell adhesion, and epidermal growth factor signalling, respectively. The genetic correlation between IPF and severe COVID-19 was rg [95% CI] = 0.39 [0.25, 0.53]. Using multi-trait meta-analysis, we identified and replicated an additional candidate IPF signal at 2p16.1 with probable effector gene BCL11A, a regulator of haematopoiesis and lymphocyte development. These findings prioritise probable effector genes mediating IPF risk and identify potential therapeutic targets that require validation, with genes colocalising with severe COVID-19 suggesting potential for developing common treatments. None.