Identification of LZTFL1 as a candidate effector gene at a COVID-19 risk locus.
IF: 41.307
Cited by: 72


The severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) disease (COVID-19) pandemic has caused millions of deaths worldwide. Genome-wide association studies identified the 3p21.31 region as conferring a twofold increased risk of respiratory failure. Here, using a combined multiomics and machine learning approach, we identify the gain-of-function risk A allele of an 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 lung biopsies from patients with COVID-19 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 responsible for the 3p21.31-associated risk. Since the 3p21.31 effect is conferred by a gain-of-function, LZTFL1 may represent a therapeutic target.


Spatial Transcriptomics

MeSH terms

Case-Control Studies
Chromosomes, Human, Pair 3
Epithelial Cells
Epithelial-Mesenchymal Transition
Genome-Wide Association Study
Polymorphism, Single Nucleotide
Transcription Factors


Downes, Damien J
Cross, Amy R
Hua, Peng
Roberts, Nigel
Schwessinger, Ron
Cutler, Antony J
Munis, Altar M
Brown, Jill
Mielczarek, Olga
de Andrea, Carlos E
Melero, Ignacio
Gill, Deborah R
Hyde, Stephen C
Knight, Julian C
Todd, John A
Sansom, Stephen N
Issa, Fadi
Davies, James O J
Hughes, Jim R

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