Identification of LZTFL1 as a candidate effector gene at a COVID-19 risk locus

The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) disease (COVID-19) pandemic has caused millions of deaths worldwide. Genome-wide association studies (GWAS) identified the 3p21.31 region as conferring a two-fold increased risk of respiratory failure. Here, using a combined multiomics and machine-learning approach, we identify the gain-of-function risk A allele of a single-nucleotide polymorphism (SNP), rs17713054G>A, as a probable causative variant. We show with chromosome conformation capture and gene expression analysis that the rs17713054-affected enhancer upregulates the interacting gene, Leucine Zipper Transcription Factor Like 1 (LZTFL1). Selective spatial transcriptomic analysis of COVID-19 patient lung biopsies shows the presence of signals associated with epithelial-mesenchymal transition (EMT), a viral response pathway that is regulated by LZTFL1. We conclude that pulmonary epithelial cells undergoing EMT, rather than immune cells, are likely to be responsible for the 3p21.31 associated risk. As the 3p21.31 effect is conferred by a gain-of-function, LZTFL1 may provide a therapeutic target.