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Whole-Genome Sequencing IDs New Host Genetic Variants Associated With Severe COVID-19


NEW YORK — Researchers have identified additional host genetic variants that make individuals susceptible to developing severe COVID-19.

Researchers from the global Genetics of Mortality in Critical Care (GenOMICC) consortium uncovered and replicated nearly two dozen loci linked to susceptibility to severe COVID-19 in their analysis of about 7,500 individuals with critical COVID-19 and more than 48,000 controls, published in Nature on Monday. These variants included 16 new associations and underscored the role of interferon signaling and other processes in disease severity. They also pointed to possible therapeutic targets for the treatment of severe COVID-19, which is in part due to people's own immune responses.

"The idea behind GenOMICC is that, if only we understood that process well enough, we could find drugs to stop the immune system from causing damage to organs without switching it off completely and causing infection to go rife," senior author Kenneth Baillie, a consultant in critical care medicine at the University of Edinburgh, said during a recorded press briefing.

The GenOMICC consortium, which started in 2015 with the aim of studying genetic factors affecting infectious disease outcomes, previously conducted a microarray-based genome-wide association analysis of severe COVID-19. That analysis, reported in Nature in 2020, implicated genes involved in antiviral and inflammatory immune responses in risk of severe COVID-19.

In their new analysis, the researchers conducted whole-genome sequencing of 7,491 critically ill COVID-19 patients from 224 intensive care units across the UK, who they compared to 48,400 controls, including participants from the 100,000 Genomes Project and people who had mild COVID-19.

Through this, the researchers homed in on 22 signals associated with severe disease through a GWAS of individuals from the cohort with European ancestry and three additional independent signals from the multi-ancestry meta-analysis. They further replicated 23 of these 25 signals in a second analysis of 9,937 hospitalized COVID-19 patients and 1 million controls from the UK Biobank, AncestryDNA, the Penn Medicine Biobank, and Geisinger Health System.

Of these signals, 16 were new genetic associations. These included variants in IFNA10 and PLSCR1, which are involved in the signaling of interferon, a protein usually released by immune cells to combat viral intruders. According to Baillie, the missense variant in IFNA10 likely causes the protein it encodes to misfold and affects its signaling ability.

Other new associations could be traced to the leucocyte differentiation gene BCL11A and the blood type antigen secretor status gene FUT2. Previous studies have also suggested ties between ABO blood type and COVID-19 susceptibility and severity, including one published last week that implicated the chromosome 9 ABO gene.

The researchers further conducted a transcriptome-wide association study in two disease-related tissues, lung and whole blood. This analysis uncovered genes whose expression is linked to COVID-19 severity, such as a link between increased expression of the mucin-producing gene MUC1 and critical disease.

A Mendelian randomization analysis additionally implicated the myeloid cell adhesion molecules SELE, ICAM5, and CD209, and the coagulation factor F8 as causal and suggested a role for coagulation factors and platelet activation in risk of severe COVID-19.

Many of these variants, the researchers noted, could be therapeutic targets.

Baillie added in the briefing that their previous study implicated TYK2 in severe COVID-19, which is a target of the JAK inhibitor baricitinib. In part based on that finding, baricitinib was included in the Randomized Evaluation of COVID-19 Therapy (RECOVERY) trial, which reported last week that baricitinib is an effective treatment for severe COVID-19.

"I think this demonstrates, as close as I ever could hope for, proof of the principle that you can find new treatments using genetics," Baillie said.