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 identified the 3p21.31 region as conferring a twofold increased risk of respiratory failure. Here, using a combined multiomics and mac...

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Published inNature genetics Vol. 53; no. 11; pp. 1606 - 1615
Main 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.
Format Journal Article
LanguageEnglish
Published New York Nature Publishing Group US 01.11.2021
Nature Publishing Group
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Summary: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. SNP rs17713054 in the 3p21.31 COVID-19 risk locus is identified as a probable causative variant for disease association. Chromatin conformation and gene expression data indicate that LZTFL1 is impacted by rs17713054 in pulmonary epithelial cells.
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Present address: Immunology Research Unit, GSK, Stevenage, UK
ISSN:1061-4036
1546-1718
DOI:10.1038/s41588-021-00955-3