An international collaboration uncovers several genetic markers associated with SARS-CoV-2 infection and COVID-19 severity.

In March of 2020, thousands of scientists around the world united to answer a pressing and complex question: what genetic factors influence why some COVID-19 patients develop severe, life-threatening disease requiring hospitalization, while others escape with mild symptoms or none at all?

This global effort, called the COVID-19 Host Genetics Initiative, was founded in March 2020 by Andrea Ganna, group leader at the Institute for Molecular Medicine Finland (FIMM), University of Helsinki and Mark Daly, director of FIMM and institute member at the Broad Institute of MIT and Harvard. The initiative has grown to be one of the most extensive collaborations in human genetics and currently includes more than 3,300 authors and 61 studies from 25 countries and The IBB researcher Mario Cáceres, group leader of the Comparative and Functional Genomics Group, was one of the scientists that were involved within the initiative.

A comprehensive summary of their findings to date, published in Nature, reveals 13 loci, or locations in the human genome, that are strongly associated with infection or severe COVID-19. To do their analysis, the consortium pooled clinical and genetic data from the nearly 50,000 patients in their study who tested positive for the virus, and 2 million controls across numerous biobanks, clinical studies, and direct-to-consumer genetic companies such as 23andMe. Because of the large amount of data pouring, thanks to collaborative efforts and a cohesive spirit of data-sharing and transparency from around the world, the scientists were able to produce statistically robust analyses far more quickly, and from a greater diversity of populations, than any one group could have on its own.

Of the 13 loci identified so far by the team, two had higher frequencies among patients of East Asian or South Asian ancestry than in those of European ancestry, underscoring the importance of diversity in genetic datasets.

The team highlighted one of these two loci in particular, near the FOXP4 gene, which is linked to lung cancer. The FOXP4 variant associated with severe COVID-19 increases the gene’s expression, suggesting that inhibiting the gene could be a potential therapeutic strategy. Other loci associated with severe COVID-19 included DPP9, a gene also involved in lung cancer and pulmonary fibrosis, and TYK2, which is implicated in some autoimmune diseases.

The researchers also identified causal factors such as smoking and high body mass index.

The findings could help provide targets for future therapies, including the use of repurposed drugs, and illustrate the power of genetic studies in learning more about infectious disease. An improvement in COVID-19 treatment, which can be informed by genetic analysis, can shift the pandemic to an endemic disease that is more localized and present at low but consistent levels in the population, much like the flu. This will considerably decrease the burden to the health system and the impact on country’s economy.

The COVID-19 Host Genetics Initiative. Mapping the human genetic architecture of COVID-19. Nature. Online July 8, 2021. https://www.nature.com/articles/s41586-021-03767-x