Large Genomic Study Identifies New Variants Linked to Severe COVID-19 Predisposition

Large Genomic Study Identifies New Variants Linked to Severe COVID-19 Predisposition
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A research consortium led by Genomics England and the University of Edinburgh has discovered 16 new genetic variants predisposing carriers to severe COVID-19 during a large-scale whole genome sequencing (WGS) study including more than 55,000 individuals.

Many of the variants identified were in genes with functions relating to inflammation, immune system function and blood clotting, in line with the symptoms seen in more severe patients. The research team also confirmed associations with seven previously discovered variants linked with severe disease.

The GenOMICC (Genetics of Mortality in Critical Care) study is by no means the first group to investigate the links between host genetics and the response to infection with SARS-CoV-2. Others, such as The COVID Human Genetic Effort and The COVID-19 Host Genetics Initiative have been working on the problem since shortly after the pandemic began and have published a range of papers on the topic.

However, the U.K. led effort is one of the first to use genomic rather than purely genome wide association study (GWAS) data. As reported in Nature, the researchers used WGS data from 7491 critically ill patients with COVID-19 admitted to 224 intensive care units in the U.K. and compared the findings with sequence from 48,400 controls who did not experience severe disease, many of whom were participants in the 100,000 genomes project.

“Strategically, we’re at a point where genomic science is becoming an integral part of the national infrastructure in routine healthcare. This study illustrates the value of whole genome sequencing to detect rare and common variants that influence critical illness requiring intensive care. It represents a major leap forward in our understanding of how our genetic makeup influences severe illness with COVID-19,” commented Richard Scott, Chief Medical Officer at Genomics England, and a co-author on the study, in a press release.

As part of the study, 16 new and seven previously identified variants linked with severe disease were uncovered including those in genes involved in interferon signaling, such as IL10RB and PLSCR1, as well as the formation of a type of white blood cell called leukocyte –BCL11A, and linked to blood type antigen status –FUT2.

Variation in genes involved in producing Factor 8, a crucial blood clotting protein, were also uncovered, possibly explaining some of the blood clotting issues observed in patients with severe COVID-19.

“Our results are broadly consistent with a multi-component model of Covid-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication, or an enhanced tendency towards pulmonary inflammation and intravascular coagulation,” write the authors.

“We show that comparison between critically-ill cases and population controls is highly efficient for detection of therapeutically-relevant mechanisms of disease.”

The GenOMICC consortium began in 2015 and initially had a more general focus to discover genetic factors that could influence outcomes in a range of severe diseases by studying patients admitted to intensive care units with infections such as SARS or flu, as well as sepsis. Since 2020, it has focused more specifically on outcomes from SARS-CoV-2 infection and subsequent COVID-19.