Nature’s largest genomic analysis highlights COVID-19 risk factors

An international collaboration of over 3500 scientists from 25 countries, uncovers several genetic markers associated with SARS-CoV-2 infection and COVID-19 severity.

In March 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?

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. The researchers also identified causal factors such as smoking and high body mass index. These results come from one of the largest genome-wide association studies ever performed, which includes nearly 50,000 COVID-19 patients and two million uninfected controls.

This global effort, called the “COVID-19 Host Genomics 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 3,500 authors and 61 studies from 25 countries. The initiative has become one of the largest collaborations in the field of human genetics. In Italy, in addition to Humanitas University, the University of Milan and the University of Milan Bicocca also joined the GENIUS (GENetics AgaInst CoronavirUS) project, supported by Intesa Sanpaolo.

Harnessing diversity to study COVID-19 in details

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. “Because of the large amount of data pouring in from around the world – says Prof. Rosanna Asselta    Associate Professor of Medical Genetics at Humanitas University – 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”.

“We’ve been much more successful than past efforts in sampling genetic diversity because we’ve made a concerted effort to reach out to populations around the world – says Prof. Stefano Duga    Humanitas researcher and Full Professor of Molecular Biology at Humanitas University – I think we still have a long way to go, but we’re making very good progress”.

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. 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.

A new way of doing research

Scientists have been able to obtain these results by means of collaboration, data sharing, transparency and the urgency that comes from knowing that the whole world faces the same threat. Indeed geneticists, who regularly work with large data sets, have long known the benefits of open collaboration.

These discoveries have been very useful to understand genetics studies, and potentially develop therapeutics for infectious disease, setting an example of international collaboration in the field of research.

The early beginning in Humanitas

The very first study on the Italian population, conducted in Humanitas back in March 2020 by Stefano Duga, Rosanna Asselta, Elvezia Maria Paraboschi and Alberto Mantovani – and supported by Dolce&Gabbana – was aimed at understanding the factors that influence the susceptibility to infection, the severity of the disease and the higher severity of symptoms observed in men compared to women affected by COVID-19.

The study revealed information on the frequency of variants in important genes for the infection that causes COVID-19 in the Italian population, which have been made available to scientists around the world. The results obtained provided the basis for offering better care to COVID-19 patients and for identifying more effective therapeutic strategies to address this extremely difficult health emergency.