Common and rare variant analyses reveal novel genetic factors underlying Idiopathic Pulmonary Fibrosis and shared aetiology with COVID-19

Idiopathic pulmonary fibrosis (IPF) is a progressive and debilitating respiratory disease with limited therapeutic options. We carried out genome-wide association (GWAS), post-GWAS and rare variant analyses utilising the whole genome sequencing data (WGS) from the 100,000 Genomes Project (100kGP) of a cohort of IPF participants ( n =586) to identify novel associations and potential drug targets. Meta-analysis combining 100kGP and published GWASs of IPF (total 11,746 cases and 1,416,493 controls) identified a novel association signal at the 1q21.2 locus (rs16837903, OR[95%CI]=0.88[0.85, 0.92], P =9.54×10 ⁻⁹ ) which was also successfully replicated with independent data and linked to the probable effector gene MCL1. MCL1 showed increased expression levels in IPF patients versus controls in alveolar epithelial type I cells. Despite its known antiapoptotic role, inhibition of MCL1 in vitro did not selectively deplete senescent cells, hinting at the complexity involved in targeting MCL1 . Rare variant burden analysis identified ANGPTL7 , a secreted glycoprotein involved in the regulation of angiogenesis, as a novel IPF candidate gene (OR[95%CI]=28.79 [8.51-97.43], P =6.73×10 ⁻⁸ ). Transcriptome-wide association analysis (TWAS) revealed that overexpression of cell cycle regulator SERTAD2 and nuclear importer TPNO3 were associated with increased IPF risk. We also investigated shared genetic mechanisms between IPF with severe COVID-19 and expanded the list of shared genetic loci with three novel colocalised signals 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. By leveraging the genetic correlation between IPF and severe COVID-19 ( r _g [95% CI]) = 0.39 [0.25-0.53]) through multi-trait meta-analysis, we further identified and replicated an additional novel candidate IPF signal at 2p16.1 with probable effector gene BCL11A , a regulator of haematopoiesis and lymphocyte development. Based on prioritized genes across analyses, we propose mechanisms mediating IPF disease risk and shared mechanisms between IPF and severe COVID-19, thereby expanding the potential for developing common treatments.