The GenOMICC study, the world’s largest study of the genetics of critical COVID-19, has revealed details about some of the biological mechanisms behind the severe form of the disease.

The NIHR-supported trial involved more than 57,000 people, with Guy’s and St Thomas’ the top recruiting site nationally. The trial has discovered 16 new genetic variants associated with severe COVID-19, including some related to blood clotting, immune response and intensity of inflammation.

These findings will act as a roadmap for future efforts, opening new fields of research focused on potential new therapies and diagnostics with pinpoint accuracy, experts say.

Researchers from the GenOMICC consortium – a global collaboration to study genetics in critical illness – led by University of Edinburgh in partnership with Genomics England, made these discoveries by sequencing the genomes of 7,491 patients from 224 intensive care units in the UK.

Their DNA was compared with 48,400 other people who had not had COVID-19, participants in Genomics England’s 100,000 Genomes Project and that of a further 1,630 people who had experienced mild cases of the disease.

Determining the whole genome sequence (an organism’s complete set of genetic instructions) for all participants in the study allowed the team to create a precise map and identify genetic variation linked to severity of COVID-19.

The team found key differences in 16 genes from intensive care unit patients when compared with the DNA of the other groups.

They also confirmed the involvement of seven other genetic variations already associated with severe COVID-19.

The findings included how a single gene variant that disrupts a key messenger molecule in immune system signalling – called interferon alpha-10 – was enough to increase a patient’s risk of severe disease.

This highlights the gene’s key role in the immune system and suggests that treating patients with interferon – proteins released by immune cells to defend against viruses – may help manage disease in the early stages.

The study also found that variations in genes that control the levels of a central component of blood clotting – known as Factor 8 – were associated with critical illness in COVID-19. This may explain some of the clotting abnormalities that are seen in severe cases of COVID-19. Factor 8 is the gene underlying the most common type of haemophilia.

Professor Nick Hart, Clinical Director of Respiratory, Sleep and Critical Care Medicine and Director of Research Delivery at Guy’s and St Thomas’ said: “It’s so important to understand why some people might get very sick with COVID-19, so that we can ensure we are treating the condition in the best way for each patient. I’m so proud that Guy’s and St Thomas’ were able to support by recruiting the most patients to the study. Thank you to the patients who took part and their families, and well done to the team who recruited so many patients.”

Professor Kenneth Baillie, the project’s chief investigator and a Consultant in Critical Care Medicine at University of Edinburgh, said: “Our latest findings point to specific molecular targets in critical COVID-19. These results explain why some people develop life-threatening COVID-19, while others get no symptoms at all. But more importantly, this gives us a deep understanding of the process of disease and is a big step forward in finding more effective treatments.

“It is now true to say that we understand the mechanisms of COVID-19 better than the other syndromes we treat in intensive care in normal times – sepsis, flu, and other forms of critical illness. COVID-19 is showing us the way to tackle those problems in the future.”