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

• Published in: Nature 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
• Language: English
• Published: New York Nature Publishing Group US 01.11.2021; Nature Publishing Group
• Subjects: 45/15; 45/70; 631/208/200; 631/208/205/2138; 631/208/212; 631/326/596/4130; 692/699/1785; Agriculture; Animal Genetics and Genomics; Biomedical and Life Sciences; Biomedicine; Biopsy; Cancer Research; Case-Control Studies; Chromosomes; Chromosomes, Human, Pair 3 - genetics; Chronic fatigue syndrome; Conformation; Coronaviruses; COVID-19; COVID-19 - complications; COVID-19 - transmission; COVID-19 - virology; Epithelial cells; Epithelial Cells - metabolism; Epithelial Cells - pathology; Epithelial Cells - virology; Epithelial-Mesenchymal Transition; Epithelium; Female; Gene expression; Gene Function; Genome-wide association studies; Genome-Wide Association Study; Genomes; Haplotypes; Health aspects; Hominids; Human Genetics; Humans; Identification and classification; Immune system; Learning algorithms; Leucine; Leucine zipper proteins; Lung - metabolism; Lung - pathology; Lung - virology; Machine learning; Male; Mesenchyme; MicroRNAs; Mortality; Pandemics; Polymorphism, Single Nucleotide; Proteins; Respiratory diseases; Respiratory failure; Risk; SARS-CoV-2 - isolation & purification; Severe acute respiratory syndrome coronavirus 2; Single nucleotide polymorphisms; Single-nucleotide polymorphism; Spatial analysis; Therapeutic targets; Transcription factors; Transcription Factors - genetics; Transcription Factors - metabolism; Transcriptomics; Viral diseases; United Kingdom
• ISSN: 1061-4036; 1546-1718
• DOI: 10.1038/s41588-021-00955-3

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.