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Identifying severe COVID-19 risk variants modulating enhancer reporter activity in lung cells
Giovanna Weykopf1, Wendy A Bickmore1, Simon C Biddie1,2
1MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, United Kingdom.
Plos Genetics
|July 17, 2026
Summary
Genetic variants influence COVID-19 severity by altering gene expression. This study identified specific severe COVID-19 risk variants impacting regulatory activity in lung cells, revealing potential therapeutic targets.
Area of Science:
- Genomics
- Molecular Biology
- Infectious Disease Research
Background:
- Common genetic variants are linked to complex diseases, but their functional roles, especially in non-coding regions, remain unclear.
- Genetic risk variants for severe COVID-19 are often in non-coding DNA, potentially affecting gene expression in relevant tissues.
- Understanding the functional impact of these variants is crucial for developing targeted therapies.
Purpose of the Study:
- To systematically assess the functional impact of severe COVID-19-associated genetic variants on regulatory activity.
- To identify variants that specifically alter gene expression in lung epithelial cells.
- To explore the combined effects of variant combinations on gene regulation.
Main Methods:
- Utilized Self-Transcribing Active Regulatory Region sequencing (STARR-seq), a massively parallel reporter assay, to test over 4800 severe COVID-19 risk variants.
- Focused experiments on a lung epithelial cell line (A549) to model lung-specific effects.
- Employed deep learning models to interpret variant effects on regulatory activity and genomic features.
Main Results:
- Identified 166 severe COVID-19 variants within active regulatory sequences in lung epithelial cells.
- Discovered 29 variants that modulate regulatory activity in an allele-specific manner.
- Observed both additive and non-additive effects when evaluating combinations of variants.
- Prioritized variants, transcription factors, and target genes with potential disease-modifying roles.
Conclusions:
- This study provides a prioritized list of severe COVID-19 genetic variants that affect regulatory activity in lung epithelial cells.
- The findings highlight the role of non-coding variants in COVID-19 pathogenesis and offer insights into potential therapeutic targets.
- The integration of massively parallel reporter assays and deep learning advances the functional interpretation of genetic risk variants.
