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

IF: 41.307

Cited by: 72

Abstract

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.

Keywords

Spatial Transcriptomics

MeSH terms

COVID-19

Case-Control Studies

Chromosomes, Human, Pair 3

Epithelial Cells

Epithelial-Mesenchymal Transition

Female

Genome-Wide Association Study

Humans

Lung

Male

Polymorphism, Single Nucleotide

SARS-CoV-2

Transcription Factors

Authors

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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