Five Genes found associated with most severe form of Covid-19

The new results have helped to identify new potential treatments for Covid-19. Genetic information from over 20,000 Generation Scotland volunteers played a vital role in the findings.

Green dna on black background surrounded by green Covid-19 viruses

Genetic evidence is second only to clinical trials as a way to tell which treatments might be effective against a disease. Existing drugs that target the actions of the five genes identified should be repurposed to treat Covid-19 in clinical trials, experts say.

Genes involved in two molecular processes - antiviral immunity and lung inflammation - were pinpointed. The breakthrough will help doctors understand how Covid-19 damages lungs at a molecular level.

Researchers from the GenOMICC consortium, from the University of Edinburgh, made the discovery. They studied the DNA of 2,700 patients in 208 intensive care units (ICUs), in the UK.

Comparing samples

The GenOMICC consortium is a global partnership used to study genetics in critical illness. It compared the genetic information of Covid-19 patients in an ICU with samples provided by healthy volunteers from other studies, such as UK Biobank and 100,000 Genomes. They also compared the genetic information against 20,000 healthy Generation Scotland volunteer samples.

The team found key differences in five genes of the ICU patients compared with samples provided by healthy volunteers. The genes - IFNAR2, TYK2, OAS1, DPP9 and CCR2 – partly explain why some people become desperately sick with Covid-19, while others are not affected.

Target genes

Having highlighted the genes, the team were able to predict the effect of drug treatments on patients. That's because some genetic variants respond in a similar way to particular drugs.

For example, they showed that a reduced activity of the TYK2 gene protects against Covid-19. A class of anti-inflammatory drugs called JAK inhibitors, which includes the drug baricitinib, can reproduce this effect.

They also discovered that a boost in the activity of the gene IFNAR2 is likely to create protection because it is likely to mimic the effect of treatment with interferon. These are proteins released by cells in the immune system that defend against viruses. However, experts caution that to be effective, patients might need the treatment early in disease.

Based on the findings, published in Nature, the researchers say that clinical trials should focus on drugs targeting these specific antiviral and anti-inflammatory pathways.

This is a stunning realisation of the promise of human genetics to help understand critical illness. Just like in sepsis and influenza, in Covid-19, damage to the lungs is caused by our own immune system, rather than the virus itself. Our genetic results provide a roadmap through the complexity of immune signals, showing the route to key drug targets.

Dr Kenneth Baillie
Chief investigator and Academic Consultant in Critical Care Medicine and Senior Research Fellow at University of Edinburgh’s Roslin Institute

When looking for genetic clues about something completely new like COVID-19, it is vital that you have a ‘control’ group for comparison. That’s where Generation Scotland came in.  We are delighted to have played a small, but important part in this landmark study.

Professor David Porteous
Principal Investigator, Generation Scotland

If you'd like to read more on the study, the publication can be found on the Nature website, in the link below:

Genetic mechanisms of critical illness in Covid-19